当前期刊: Clinical Cancer Research Go to current issue    加入关注   
显示样式:        排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Inhibition of MDR1 Overcomes Resistance to Brentuximab Vedotin in Hodgkin Lymphoma
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Robert Chen; Alex F. Herrera; Jessie Hou; Lu Chen; Jun Wu; Yuming Guo; Timothy W. Synold; Vu N. Ngo; Sandrine Puverel; Matthew Mei; Leslie Popplewell; Shuhua Yi; Joo Y. Song; Shu Tao; Xiwei Wu; Wing C. Chan; Stephen J. Forman; Larry W. Kwak; Steven T. Rosen; Edward M. Newman

    Purpose: In classical Hodgkin lymphoma, the malignant Reed–Sternberg cells express the cell surface marker CD30. Brentuximab vedotin is an antibody–drug conjugate (ADC) that selectively delivers a potent cytotoxic agent, monomethyl auristatin E (MMAE), to CD30-positive cells. Although brentuximab vedotin elicits a high response rate (75%) in relapsed/refractory Hodgkin lymphoma, most patients who respond to brentuximab vedotin eventually develop resistance. Patients and Methods: We developed two brentuximab vedotin–resistant Hodgkin lymphoma cell line models using a pulsatile approach and observed that resistance to brentuximab vedotin is associated with an upregulation of multidrug resistance-1 (MDR1). We then conducted a phase I trial combining brentuximab vedotin and cyclosporine A (CsA) in patients with relapsed/refractory Hodgkin lymphoma. Results: Here, we show that competitive inhibition of MDR1 restored sensitivity to brentuximab vedotin in our brentuximab vedotin–resistant cell lines by increasing intracellular MMAE levels, and potentiated brentuximab vedotin activity in brentuximab vedotin–resistant Hodgkin lymphoma tumors in a human xenograft mouse model. In our phase I trial, the combination of brentuximab vedotin and CsA was tolerable and produced an overall and complete response rate of 75% and 42% in a population of patients who were nearly all refractory to brentuximab vedotin. Conclusions: This study may provide a new therapeutic strategy to combat brentuximab vedotin resistance in Hodgkin lymphoma. This is the first study reporting an effect of multidrug resistance modulation on the therapeutic activity of an ADC in humans. The expansion phase of the trial is ongoing and enrolling patients who are refractory to brentuximab vedotin to confirm clinical activity in this population with unmet need.

    更新日期:2020-01-17
  • Surfactant expression defines an inflamed subtype of lung adenocarcinoma brain metastases that correlates with prolonged survival
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Kolja Pocha; Andreas Mock; Carmen Rapp; Steffen Dettling; Rolf Warta; Christoph Geisenberger; Christine Jungk; Leila R Martins; Niels Grabe; David Reuss; Jürgen Debus; Andreas von Deimling; Amir Abdollahi; Andreas Unterberg; Christel C Herold-Mende

    Purpose: To provide a better understanding of the interplay between the immune system and brain metastases (BMs) to advance therapeutic options for this life-threatening disease. Experimental Design: Tumor-infiltrating lymphocytes (TILs) were quantified by semi-automated whole slide analysis in BMs from 81 lung adenocarcinomas (LUAD). Multi-color staining enabled phenotyping of TILs (CD3, CD8, and FOXP3) on a single cell resolution. Molecular determinants of the extent of TILs in BMs were analyzed by transcriptomics in a subset of 63 patients. Findings in LUAD BMs were related to published multi-omic primary LUAD TCGA data (n=230) and single-cell RNA-seq (scRNA-seq) data (n=52,698). Results: TIL numbers within tumor islands was an independent prognostic marker in patients with LUAD BMs. Comparative transcriptomics revealed that expression of three surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) was closely associated with TIL numbers. Their expression was not only prognostic in BM but also in primary LUADs. Correlation with scRNA-seq data revealed that brain metastases with high expression of surfactant genes might originate from tumor cells resembling alveolar type 2 cells. Methylome-based estimation of immune cell fractions in primary LUAD confirmed a positive association between lymphocyte infiltration and surfactant expression. Tumors with a high surfactant expression displayed a transcriptomic profile of an inflammatory microenvironment. Conclusion: The expression of surfactant metabolism-related genes (SFTPA1, SFTPB, NAPSA) defines an inflamed subtype of lung adenocarcinoma brain metastases characterized by high abundance of TILs in close vicinity to tumor cells, a prolonged survival and a tumor microenvironment which might be more accessible to immunotherapeutic approaches.

    更新日期:2020-01-17
  • ONO-7475, a novel AXL inhibitor, suppresses the adaptive resistance to initial EGFR-TKI treatment in EGFR-mutated non-small lung cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Naoko Okura; Naoya Nishioka; Tadaaki Yamada; Hirokazu Taniguchi; Keiko Tanimura; Yuki Katayama; Akihiro Yoshimura; Satoshi Watanabe; Toshiaki Kikuchi; Shinsuke Shiotsu; Takeshi Kitazaki; Akihiro Nishiyama; Masahiro Iwasaku; Yoshiko Kaneko; Junji Uchino; Hisaori Uehara; Mano Horinaka; Toshiyuki Sakai; Kohei Tanaka; Ryohei Kozaki; Seiji Yano; Koichi Takayama

    Purpose: Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR-TKIs. In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475. Experimental design: We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR mutated NSCLC patients with acquired resistance to initial EGFR-TKIs. Results: ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing EGFR mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor re-growth compared to osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib. Conclusion: These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.

    更新日期:2020-01-17
  • Determining the optimal adjuvant therapy for improving survival in elderly patients with glioblastoma: a systematic review and meta-analysis
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Farshad Nassiri; Shervin Taslimi; Justin Z Wang; Jetan H Badhiwala; Tatyana Dalcourt; Nazanin Ijad; Neda Pirouzmand; Saleh Almenawer; Roger Stupp; Gelareh Zadeh

    Purpose: Older patients with glioblastoma(GBM) are underrepresented in clinical trials. Several abbreviated and standard chemoradiotherapy regimens are advocated with no consensus on the optimal approach. Our objective was to quantitatively evaluate which of these regimens would provide the most favourable survival outcomes in older patients with GBM using a network meta-analysis. Experimental Design: MEDLINE, Embase, Google Scholar, and the Cochrane Library were searched. Patients >60 years of age with histologically confirmed GBM were included. Primary outcome of interest was the pooled hazard ratio(HR) from randomized controlled trials. Secondary outcomes of interest included pooled HR from studies controlling for MGMT promoter methylation status, and safety. Results: Fourteen studies, including 5 randomized control trials (RCTs), reporting 4561 patients were included. Using highest quality data from RCTs, our network-based approach demonstrated that standard radiotherap(SRT) and temozolomide(TMZ) provided similar survival benefit when compared to hypofractionated radiotherapy(HRT) and TMZ(HR=.90, 95%CI 0.43-1.87), TMZ alone(HR 1.25, 95%CI 0.69-2.26), HRT alone(HR 1.34, 95%CI 0.73-2.45) or SRT alone(HR 1.43, 95%CI 0.87-2.36). HRT-TMZ had the highest probability(85%) of improving survival in older GBM patients followed by SRT-TMZ(72%). Pooled analysis of trials controlling for MGMT promoter methylation status demonstrated that TMZ monotherapy confers similar survival benefit to combined chemoradiotherapy. Conclusions: Statistical comparisons using a network approach demonstrates that the common treatment regimens for older patients with GBM in previous RCTs confer similar survival benefits. Adjustments for MGMT promoter methylation status demonstrated that radiotherapy alone were inferior to TMZ-based approaches. Head-to-head comparison of TMZ monotherapy to combined TMZ and radiation are warranted.

    更新日期:2020-01-17
  • Adenosine signalling is prognostic for cancer outcome and has predictive utility for immunotherapeutic response
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Ben Sidders; Pei Zhang; Kelly Goodwin; Greg O'Connor; Deanna L. Russell; Alexandra Borodovsky; Joshua Armenia; Robert McEwen; Bolan Linghu; Johanna C. Bendell; Todd M. Bauer; Manish R. Patel; Gerald S. Falchook; Melinda Merchant; Gayle Pouliot; J. Carl Barrett; Jonathan R Dry; Richard Woessner; Kris Sachsenmeier

    Purpose: There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification of cancers with a significant adenosine drive is critical to understand the potential for these molecules. However, it is challenging to measure tumour adenosine levels at scale, thus novel, clinically tractable biomarkers are needed. Experimental Design: We generate a gene expression signature for the adenosine signaling using regulatory networks derived from the literature and validate this in patients. We apply the signature to large cohorts of disease from TCGA and cohorts of immune checkpoint inhibitor treated patients. Results: The signature captures baseline adenosine levels in vivo (r2=0.92, p=0.018), is reduced after small molecule inhibition of A2AR in mice (r2 = -0.62, p=0.001) & humans (reduction in 5 of 7 patients (70%)) and is abrogated after A2AR knock-out. Analysis of TCGA confirms a negative association between adenosine and overall survival (OS, HR=0.6, p<2.2e-16) as well as progression free survival (PFS, HR=0.77, p=0.0000006). Further, adenosine signaling is associated with reduced OS (HR=0.47, p<2.2e-16) and PFS (HR=0.65, p=0.0000002) in CD8+ T-cell infiltrated tumours. Mutation of TGFβ superfamily members are associated with enhanced adenosine signaling and worse OS (HR=0.43, p<2.2e-16). Finally, adenosine signaling is associated with reduced efficacy of anti-PD1 therapy in published cohorts (HR=0.29, p=0.00012). Conclusions: These data support the adenosine pathway as a mediator of a successful anti-tumour immune response, demonstrate the prognostic potential of the signature for immuno-therapy and inform patient selection strategies for adenosine pathway modulators currently in development.

    更新日期:2020-01-17
  • Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissue
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-17
    Danique Giesen; Linda N Broer; Marjolijn N. Lub-de Hooge; Irina Popova; Bruce Howng; Margaret Nguyen; Olga Vasiljeva; Elisabeth G E de Vries; Martin Pool

    Purpose: Probody™ therapeutic CX-072 is a protease-activatable antibody that is cross-reactive with murine and human programmed death-ligand 1 (PD-L1). CX-072 can be activated in vivo by proteases present in the tumor microenvironment, thereby potentially reducing peripheral, anti-PD-L1-mediated toxicities. To study its targeting of PD-L1-expressing tissues, we radiolabeled CX-072 with the positron emission tomography (PET) isotope zirconium-89 (89Zr). Experimental Design: 89Zr-labeled CX-072, non-specific Probody control molecule (PbCtrl) and CX-072 parental antibody (CX-075) were injected in BALB/c nude mice bearing human MDA-MB-231 tumors or C57BL/6J mice bearing syngeneic MC38 tumors. Mice underwent serial PET imaging 1, 3 and 6 days post intravenous injection (pi), followed by ex vivo biodistribution. Intratumoral 89Zr-CX-072 distribution was studied by autoradiography on tumor tissue sections, which were subsequently stained for PD-L1 by immunohistochemistry. Activated CX-072 species in tissue lysates were detected by Western capillary electrophoresis. Results: PET imaging revealed 89Zr-CX-072 accumulation in MDA-MB-231 tumors with 2.1-fold higher tumor-to-blood ratios at 6 days pi compared to 89Zr-PbCtrl. Tumor tissue autoradiography showed high 89Zr-CX-072 uptake in high PD-L1-expressing regions. Activated CX-072 species were detected in these tumors, with 5.3-fold lower levels found in the spleen. Furthermore, 89Zr-CX-072 uptake by lymphoid tissues of immune-competent mice bearing MC38 tumors was low compared to 89Zr-CX-075, which lacks the Probody design. Conclusions: 89Zr-CX-072 accumulates specifically in PD-L1-expressing tumors with limited uptake in murine peripheral lymphoid tissues. Our data may enable clinical evaluation of 89Zr-CX-072 whole-body distribution as a tool to support CX-072 drug development ([NCT03013491][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03013491&atom=%2Fclincanres%2Fearly%2F2020%2F01%2F17%2F1078-0432.CCR-19-3137.atom

    更新日期:2020-01-17
  • Cell-Free Circulating Tumor DNA Variant Allele Frequency Associates with Survival in Metastatic Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-16
    Seyed Pairawan; Kenneth R. Hess; Filip Janku; Nora S Sánchez; Kenna R Mills Shaw; Cathy Eng; Senthilkumar Damodaran; Milind Javle; Ahmed O Kaseb; David S. Hong; Vivek Subbiah; Siqing Fu; David R Fogelman; Victoria M Raymond; Richard B. Lanman; Funda Meric-Bernstam

    Purpose: Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision-making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis. Experimental Design: We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival. Results: cfDNA mutations were detected in 240 (80.5%) patients. Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types; being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3, p < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, p = 0.0069: VAF Q4 HR = 3.8, p < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level < 3.5 g/dL, number of non-visceral metastatic sites > 0 and number of prior therapies > 4 were independent predictors of worse OS. Conclusions: Higher levels of cfDNA VAF and higher number of NSM were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision-making and the utility of cfDNA VAF as a prognostic marker in different tumor types.

    更新日期:2020-01-16
  • Targeting PD-1 or PD-L1 in Metastatic Kidney Cancer - Combination Therapy in the First Line Setting
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-16
    David H Aggen; Charles G. Drake; Brian I. Rini

    Recent FDA approvals of regimens targeting programmed death 1 (PD-1) in combination with anti-CTLA-4 or with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) are reshaping front-line therapy for metastatic kidney cancer. In parallel, therapeutics specific for programmed death ligand 1 (PD-L1), one of the two major ligands for PD-1, are under continued investigation. Surprisingly, not all PD-1 and PD-L1 agents lead to similar clinical outcomes, potentially due to biological differences in the cellular expression and regulation of these targets. Here, we review current clinical data on combination immune checkpoint inhibitor therapy in metastatic kidney cancer and discuss the relevant biology of PD-1 and PD-L1. The design of future rational combination therapy trials in metastatic renal cell carcinoma will rely upon an understanding of this biology, along with an evolving understanding of immune cell populations and their functional states in the tumor microenvironment.

    更新日期:2020-01-16
  • FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-16
    Charles Fouillade; Sandra Curras-Alonso; Lorena Giuranno; Eddy Quelennec; Sophie Heinrich; Sarah Bonnet-Boissinot; Arnaud Beddok; Sophie Leboucher; Hamza Umut Karakurt; Mylène Bohec; Sylvain Baulande; Marc Vooijs; Pierre Verrelle; Marie Dutreix; Arturo Londoño-Vallejo; Vincent Favaudon

    Purpose: One of the main limitations to anticancer radiotherapy lies in irreversible damage to healthy tissues located within the radiation field. “FLASH” irradiation at very high dose-rate is a new treatment modality that has been reported to specifically spare normal tissue from late radiation-induced toxicity in animal models and therefore could be a promising strategy to reduce treatment toxicity. Experimental Design: Lung responses to FLASH irradiation were investigated by qPCR, single-cell RNA sequencing (sc-RNA-Seq), and histologic methods during the acute wound healing phase as well as at late stages using C57BL/6J wild-type and Terc−/− mice exposed to bilateral thorax irradiation as well as human lung cells grown in vitro . Results: In vitro studies gave evidence of a reduced level of DNA damage and induced lethality at the advantage of FLASH. In mouse lung, sc-RNA-seq and the monitoring of proliferating cells revealed that FLASH minimized the induction of proinflammatory genes and reduced the proliferation of progenitor cells after injury. At late stages, FLASH-irradiated lungs presented less persistent DNA damage and senescent cells than after CONV exposure, suggesting a higher potential for lung regeneration with FLASH. Consistent with this hypothesis, the beneficial effect of FLASH was lost in Terc−/− mice harboring critically short telomeres and lack of telomerase activity. Conclusions: The results suggest that, compared with conventional radiotherapy, FLASH minimizes DNA damage in normal cells, spares lung progenitor cells from excessive damage, and reduces the risk of replicative senescence.

    更新日期:2020-01-16
  • Phase Ia Study of Anti-NaPi2b Antibody–Drug Conjugate Lifastuzumab Vedotin DNIB0600A in Patients with Non–Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-15
    David E. Gerber; Jeffrey R. Infante; Michael S. Gordon; Sarah B. Goldberg; Miguel Martín; Enriqueta Felip; Maria Martinez Garcia; Joan H. Schiller; David R. Spigel; Julie Cordova; Valerie Westcott; Yulei Wang; David S. Shames; YounJeong Choi; Robert Kahn; Randall C. Dere; Divya Samineni; Jian Xu; Kedan Lin; Katie Wood; Stephanie Royer-Joo; Vanessa Lemahieu; Eva Schuth; Anjali Vaze; Daniel Maslyar; Eric W. Humke; Howard A. Burris

    Purpose: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody–drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). Patients and Methods: LIFA was administered to patients with non–small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). Results: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D ( n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). Conclusions: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

    更新日期:2020-01-16
  • A Phase II Study of Cabozantinib and Androgen Ablation in Patients with Hormone-Naïve Metastatic Prostate Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-15
    Paul G. Corn; Miao Zhang; Graciela M. Nogueras-Gonzalez; Lianchun Xiao; Amado J. Zurita; Sumit K. Subudhi; Shi-Ming Tu; Ana M. Aparicio; Cristian Coarfa; Kimal Rajapakshe; Shixia Huang; Nora M. Navone; Sue-Hwa Lin; Guocan Wang; Sumankalai Ramachandran; Mark A. Titus; Theocharis Panaretakis; Gary E. Gallick; Eleni Efstathiou; Patricia Troncoso; Christopher Logothetis

    Purpose: Cabozantinib, an oral inhibitor of c-MET/VEGFR2 signaling, improved progression-free survival (mPFS) but not overall survival (OS) in metastatic castrate-resistant prostate cancer. We evaluated cabozantinib plus androgen deprivation therapy (ADT) in hormone-naïve metastatic prostate cancer (HNMPCa). Patients and Methods: Patients received ADT plus cabozantinib starting at 60 mg daily. The primary endpoint was castrate-resistant PFS by radiographic criteria, clinical progression, or receipt of additional therapy. Secondary endpoints included OS, safety, radiographic responses, and biomarker modulation. Results: Sixty-two patients received treatment. With a median follow-up of 31.2 months, the mPFS was 16.1 months (95% CI, 14.6–22.7 months), and mOS was not reached. Reductions in PSA ≥ 90%, bone-specific alkaline phosphatase ≥ 50%, and urine N-telopeptides ≥ 50% occurred in 83%, 87%, and 86% of evaluable patients, respectively. Responses in bone scan and measurable disease were observed in 81% of and 90% of evaluable patients, respectively. Most common grade 3 adverse events were hypertension (19%), diarrhea (6%), and thromboembolic events (6%), and dose reductions occurred in 85% of patients. Analysis of baseline cytokine and angiogenic factors (CAFs) revealed that higher plasma concentrations of Lumican, CXCL5, CD25, and CD30 were associated with shorter PFS as was high tumor expression of pFGFR1. Conclusions: Cabozantinib plus ADT has promising clinical activity in HNMPCa. CAF profiles and tissue markers suggest candidate prognostic and predictive markers of cabozantinib benefit and provide insights for rational therapy combinations.

    更新日期:2020-01-15
  • Serial ctDNA monitoring to predict response to systemic therapy in metastatic gastrointestinal cancers
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-15
    Aparna R. Parikh; Amirkasra Mojtahed; Jaime L Schneider; Katie Kanter; Emily E. Van Seventer; Isobel J Fetter; Ashraf Thabet; Madeleine G Fish; Bezaye Teshome; Kathryn Fosbenner; Brandon Nadres; Heather A. Shahzade; Jill N. Allen; Lawrence S. Blaszkowsky; David P. Ryan; Bruce Giantonio; Lipika Goyal; Ryan D Nipp; Eric Roeland; Colin D. Weekes; Jennifer Y. Wo; Andrew X. Zhu; Dora Dias-Santagata; A. John Iafrate; Jochen K. Lennerz; Theodore S. Hong; Giulia Siravegna; Nora Horick; Jeffrey W. Clark; Ryan B. Corcoran

    Introduction: ctDNA offers a promising, non-invasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and PFS in metastatic GI cancer patients. Methods: 138 patients with metastatic GI cancers and tumor profiling by NGS had serial blood draws pre-treatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor makers and radiographic response. Results: 138 patients enrolled. 101 were evaluable for ctDNA and 68 for tumor markersat four weeks. Percent change of ctDNA by four weeks predicted partial response (PR, p<0.0001) and clinical benefit (CB: PR and stable disease (SD), p<0.0001). ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at eight-weeks, but not two-weeks, also predicted CB (p<0.0001). Four-week change in tumor markers also predicted response (p=0.0026) and CB (p=0.022). However, at a clinically relevant specificity threshold of 90%, four-week ctDNA change more effectively predicted CB versus tumor makers, with a sensitivity of 60% vs. 24%, respectively (p=0.0109). Patients whose four-week ctDNA decreased beyond this threshold (30% decrease) had a median PFS of 175 days versus 59.5 days (Hazard Ratio 3.29; 95% CI 1.55-7.00; p<0.0001). Conclusions: serial ctDNA monitoring may provide early indication of response to systemic therapy in metastatic GI cancer patients prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.

    更新日期:2020-01-15
  • PD-1 blockade reinvigorates bone marrow CD8+ T cells from patients with multiple myeloma in the presence of TGF-b inhibitors
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-15
    Minsuk Kwon; Chang Gon Kim; Hoyoung Lee; Hyunsoo Cho; Youngun Kim; Eung Chang Lee; Seong Jin Choi; Junsik Park; In-Ho Seo; Bjarne Bogen; Ik Chan Song; Deog Yeon Jo; Jin Seok Kim; Su-Hyung Park; Inhak Choi; Yoon Seok Choi; Eui-Cheol Shin

    Purpose: Immune checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma (MM). Experimental Design: Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed MM patients. We examined the expression of immune checkpoint receptors in BM CD8+ T cells and their functional restoration by ex vivo treatment with anti-PD-1 and TGF-b inhibitors. Results: We confirmed the upregulation of PD-1 and PD-L1 expression in CD8+ T cells and myeloma cells, respectively, from the BM of MM patients. PD-1-expressing CD8+ T cells from the BM of MM patients co-expressed other checkpoint inhibitory receptors and exhibited a terminally differentiated phenotype. These results were also observed in BM CD8+ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM CD8+ T cells from MM patients exhibited reduced proliferation and cytokine production upon T-cell receptor stimulation. However, anti-PD-1 did not increase the proliferation of BM CD8+ T cells from MM patients, indicating that T-cell exhaustion in MM is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation of BM CD8+ T cells from MM patients in the presence of inhibitors of TGF-b, which was overexpressed by myeloma cells. Conclusions: Our findings indicate that combined blockade of PD-1 and TGF-b may be useful for the treatment of MM.

    更新日期:2020-01-15
  • Selected Articles from This Issue
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-15
    American Association for Cancer Research

    ### [Ghobrial et al. Page 344][1] Preclinical studies have revealed CXCR4 as a promising target in multiple myeloma (MM). In a Phase Ib/II clinical trial, Ghobrial and colleagues assessed ulocuplumab, a first-in-class anti-CXCR4 antibody, combined with lenalidomide or bortezomib plus dexamethasone

    更新日期:2020-01-15
  • The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma—Letter
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-15
    Alessandro Di Federico; Daria M. Filippini; Filippo G. Dall'Olio; Nicole Conci; Roberta Minari; Marcello Tiseo; Andrea Ardizzoni

    We read with interest the recently published paper by Truini and colleagues ([1][1]) describing the peculiar in vitro activity of afatinib on non–small cell lung cancer cell lines harboring the EGFR L747-A750>P mutation. We reviewed our patient database and found 6 cases out of 265 with this

    更新日期:2020-01-15
  • Genomic and Phenotypic Characterization of a Broad Panel of Patient-Derived Xenografts Reflects the Diversity of Glioblastoma
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Rachael A. Vaubel; Shulan Tian; Dioval Remonde; Mark A. Schroeder; Ann C. Mladek; Gaspar J. Kitange; Alissa Caron; Thomas M. Kollmeyer; Rebecca Grove; Sen Peng; Brett L. Carlson; Daniel J. Ma; Gobinda Sarkar; Lisa Evers; Paul A. Decker; Huihuang Yan; Harshil D. Dhruv; Michael E. Berens; Qianghu Wang; Bianca M. Marin; Eric W. Klee; Andrea Califano; Daniel H. LaChance; Jeanette E. Eckel-Passow; Roel G. Verhaak; Erik P. Sulman; Terry C. Burns; Fredrick B. Meyer; Brian P. O'Neill; Nhan L. Tran; Caterina Giannini; Robert B. Jenkins; Ian F. Parney; Jann N. Sarkaria

    Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. Experimental Design: PDXs were established from glioblastoma, IDH-wildtype ( n = 93), glioblastoma, IDH-mutant ( n = 2), diffuse midline glioma, H3 K27M-mutant ( n = 1), and both primary ( n = 60) and recurrent ( n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing ( n = 68), and genome-wide methylation profiling ( n = 76). WES data from 24 patient tumors was compared with derivative models. Results: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF , and IDH1 , most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient–PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. Conclusions: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.

    更新日期:2020-01-14
  • Identification of Hypermutation and Defective Mismatch Repair in ctDNA from Metastatic Prostate Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Elie Ritch; Simon Y.F. Fu; Cameron Herberts; Gang Wang; Evan W. Warner; Elena Schönlau; Sinja Taavitsainen; Andrew J. Murtha; Gillian Vandekerkhove; Kevin Beja; Yulia Loktionova; Daniel Khalaf; Ladan Fazli; Igal Kushnir; Cristiano Ferrario; Sebastien Hotte; Matti Annala; Kim N. Chi; Alexander W. Wyatt

    Purpose: DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer (mPC). Furthermore, because hypermutated MMRd prostate cancers can respond to immune checkpoint inhibitors, there is an urgent need for practical detection tools. Experimental Design: We analyzed plasma cell-free DNA-targeted sequencing data from 433 patients with mPC with circulating tumor DNA (ctDNA) purity ≥2%. Samples with somatic hypermutation were subjected to 185 × whole-exome sequencing and capture of mismatch repair gene introns. Archival tissue was analyzed with targeted sequencing and IHC. Results: Sixteen patients (3.7%) had somatic hypermutation with MMRd etiology, evidenced by deleterious alterations in MSH2, MSH6 , or MLH1 , microsatellite instability, and characteristic trinucleotide signatures. ctDNA was concordant with mismatch repair protein IHC and DNA sequencing of tumor tissue. Tumor suppressors such as PTEN, RB1 , and TP53 were inactivated by mutation rather than copy-number loss. Hotspot mutations in oncogenes such as AKT1, PIK3CA , and CTNNB1 were common, and the androgen receptor ( AR )-ligand binding domain was mutated in 9 of 16 patients. We observed high intrapatient clonal diversity, evidenced by subclonal driver mutations and shifts in mutation allele frequency over time. Patients with hypermutation and MMRd etiology in ctDNA had a poor response to AR inhibition and inferior survival compared with a control cohort. Conclusions: Hypermutated MMRd mPC is associated with oncogene activation and subclonal diversity, which may contribute to a clinically aggressive disposition in selected patients. In patients with detectable ctDNA, cell-free DNA sequencing is a practical tool to prioritize this subtype for immunotherapy.

    更新日期:2020-01-14
  • Gene Expression Signatures Identify Novel Therapeutics for Metastatic Pancreatic Neuroendocrine Tumors
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Aaron T Scott; Michelle Weitz; Patrick J Breheny; Po Hien Ear; Benjamin Darbro; Bartley J. Brown; Terry A. Braun; Guiying Li; Shaikamjad Umesalma; Courtney Anne Kaemmer; Chandra Kumar Maharjan; Dawn E Quelle; Andrew M Bellizzi; Chandrikha Chandrasekharan; Joseph S Dillon; Thomas M O'Dorisio; James R. Howe

    Purpose: Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the last decades, most patients will die of metastatic disease. New systemic therapies are needed. Experimental Design: Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity Pathway Analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1). Results: 902 genes were differentially expressed in pNET metastases compared to primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, PKC, NF-kB, CDK and HDAC. Inhibitors of MEK and TOP2A were consistently the most active compounds. Conclusions:We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for pNET patients.

    更新日期:2020-01-14
  • A combinatorial strategy for targeting BRAF V600E mutant cancers with BRAF V600E inhibitor (PLX4720) and tyrosine kinase inhibitor (ponatinib)
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Electron Kebebew; Chandrayee Ghosh; Suresh Kumar; Yevgeniya Kushchayeva; Kelli Gaskins; Myriem Boufraqech; Darmood Wei; Sudheer Kumar Gara; Lisa Zhang; Yaqin Zhang; Min Shen; Sanjit Mukherjee

    Purpose: Most aggressive thyroid cancers are commonly associated with a BRAF V600E mutation. Preclinical and clinical data in BRAF V600E cancers suggest that combined BRAF and MEK inhibitor treatment result in a response, but resistance is common. One mechanism of acquired resistance is through persistent activation of tyrosine kinase (TK) signaling by alternate pathways. We hypothesized that combination therapy with BRAF and multitargeting TK inhibitors (MTKI) might be more effective in BRAF V600E thyroid cancer than single agent or BRAF and MEK inhibitors. Experimental Design: The combined drug activity was analyzed to predict any synergistic effect using high throughput screening (HTS) of active drugs. We performed follow up in vitro and in vivo studies to validate and determine the mechanism of action of synergistic drugs. Results: The MTKI ponatinib and the BRAF inhibitor PLX4720 showed synergistic activity by HTS. This combination significantly inhibited proliferation, colony formation, invasion and migration in BRAF V600E thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720 resistant BRAF V600E cells became sensitized to the combination treatment, with decreased proliferation at lower PLX4720 concentrations. In orthotopic thyroid cancer mouse model, combination therapy significantly reduced tumor growth ( p < 0.05), lower number of metastases ( p < 0.05) and longer survival ( p < 0.05) compared to monotherapy and vehicle control. Conclusions: Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAF V600E thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.

    更新日期:2020-01-14
  • First-in-human Phase I study to evaluate the brain-penetrant PI3K/mTOR inhibitor GDC-0084 in patients with progressive or recurrent high-grade glioma
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Patrick Y. Wen; Timothy F. Cloughesy; Alan G Olivero; Kari M Morrissey; Timothy R Wilson; Xuyang Lu; Lars U. Mueller; Alexandre F Coimbra; Benjamin M Ellingson; Elizabeth Gerstner; Eudocia Q Lee; Jordi Rodon

    Purpose: GDC-0084 is an oral, brain-penetrant small molecule inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). A first-in-human, Phase I study was conducted in patients with recurrent high-grade glioma. Experimental design: GDC-0084 was administered orally, once-daily to evaluate safety, pharmacokinetics (PK) and activity. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed to measure metabolic responses. Results: Forty-seven heavily pretreated patients enrolled in eight cohorts (2-65 mg). Dose-limiting toxicities (DLTs) included one case of Grade 2 bradycardia and Grade 3 myocardial ischemia (15 mg), Grade 3 stomatitis (45 mg) and 2 cases of Grade 3 mucosal inflammation (65 mg); the maximum tolerated dose (MTD) was 45 mg/day. GDC-0084 demonstrated linear and dose-proportional PK, with a half-life (~19 hr) supportive of once-daily dosing. At 45 mg/day, steady-state concentrations exceeded pre-clinical target concentrations producing antitumor activity in xenograft models. FDG-PET in 7 of 27 patients (26%) showed metabolic partial response. At doses ≥ 45 mg/day, a trend towards decreased median SUV in normal brain was observed, suggesting central nervous system penetration of drug. In 2 resection specimens, GDC-0084 was detected at similar levels in tumor and brain tissue, with a brain tissue/tumor to plasma ratio of > 1 and > 0.5 for total and free drug, respectively. Best overall response was stable disease in 19 patients (40%), and progressive disease in 26 patients (55%); 2 patients (4%) were non-evaluable. Conclusions: GDC-0084 demonstrated classic PI3K/mTOR-inhibitor related toxicities. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crossed the blood-brain barrier.

    更新日期:2020-01-14
  • A quantitative centrosomal amplification score predicts local recurrence in ductal carcinoma in situ
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Karuna Mittal; Michael S Toss; Guanhao Wei; Jaspreet Kaur; Da Hoon Choi; Brian D. Melton; Remus M. Osan; Islam M. Milligy; Andrew R Green; Emilius A.M. Janssen; Håvard Søiland; Keerthi Gogineni; Upender Manne; Padmashree Rida; Emad A Rakha; Ritu Aneja

    Purpose: To predict the risk of local recurrence (LR) in ductal carcinoma in situ (DCIS) with a new visualization and quantification approach using centrosome amplification (CA), a cancer-cell specific trait, widely associated with aggressiveness. Experimental Design: This first-of-its-kind methodology evaluates the severity and frequency of numerical and structural CA present within DCIS, and assigns a quantitative centrosomal amplification score (CAS) to each sample. Analyses were performed in a discovery cohort (DC, n=133) and a validation cohort (VC, n=119). Results: DCIS cases with LR exhibited significantly higher CAS than recurrence-free cases. Higher CAS was associated with a greater risk of developing LR (HR=6.3 and 4.8 for DC and VC, respectively; p<0.001). CAS remained an independent predictor of relapse-free survival (HR=7.4 and 4.5 for DC and VC, respectively; p<0.001) even after accounting for potentially confounding factors (grade, age, comedo necrosis, and radiotherapy). Patient stratification using CAS (p<0.0001) was superior to that by Van Nuys Prognostic Index (VNPI) (HR for CAS=6.2, vs. HR for VNPI=1.1). Among patients treated with breast-conserving surgery alone, CAS identified patients likely to benefit from adjuvant radiotherapy (RT). Conclusions: CAS predicted 10-year LR risk for patients who underwent surgical management alone and identified patients who may be at low risk of recurrence, and for whom adjuvant RT may not be required. CAS demonstrated the highest concordance among the known prognostic models such as VNPI and clinicopathological variables such as grade, age, and comedo necrosis.

    更新日期:2020-01-14
  • Deep learning to distinguish benign from malignant renal lesions based on routine MR imaging
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Ianto Lin Xi; Yijun Zhao; Robin Wang; Marcello Chang; Subhanik Purkayastha; Ken Chang; Raymond Y Huang; Alvin C. Silva; Martin Vallières; Peiman Habibollahi; Yong Fan; Beiji Zou; Terence P Gade; Paul J. Zhang; Michael C. Soulen; Zishu Zhang; Harrison X Bai; S. William Stavropoulos

    Purpose: With increasing incidence of renal mass, it is important to make a pre-treatment differentiation between benign renal mass and malignant tumor. We aimed to develop a deep learning model that distinguishes benign renal tumors from renal cell carcinoma (RCC) by applying a residual convolutional neural network (ResNet) on routine MR imaging. Experimental Design: Preoperative MR images (T2-weighted and T1-post contrast sequences) of 1162 renal lesions definitely diagnosed on pathology or imaging in a multicenter cohort were divided into training, validation, and test sets (70:20:10 split). An ensemble model based on ResNet was built combining clinical variables, T1C and T2WI MR images using a bagging classifier to predict renal tumor pathology. Final model performance was compared with expert interpretation and the most optimized radiomics model. Results: Among the 1162 renal lesions, 655 were malignant and 507 were benign. Compared to a baseline zero rule algorithm, the ensemble deep learning model had a statistically significant higher test accuracy (0.70 vs. 0.56, p=0.004). Compared to all experts averaged, the ensemble deep learning model had higher test accuracy (0.70 vs. 0.60, p=0.053), sensitivity (0.92 vs. 0.80, p=0.017) and specificity (0.41 vs. 0.35, p=0.450). Compared to the radiomics model, the ensemble deep learning model had higher test accuracy (0.70 vs. 0.62, p=0.081), sensitivity (0.92 vs. 0.79, p=0.012) and specificity (0.41 vs. 0.39, p=0.770). Conclusions:Deep learning can non-invasive distinguish benign renal tumors from RCC using conventional MR imaging in a multi-institutional dataset with good accuracy, sensitivity and specificity comparable to experts and radiomics.

    更新日期:2020-01-14
  • Plasma thymidine kinase activity as a biomarker in patients with luminal metastatic breast cancer treated with palbociclib within the TREnd trial
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Amelia McCartney; Martina Bonechi; Francesca De Luca; Chiara Biagioni; Giuseppe Curigliano; Erica Moretti; Alessandro Marco Minisini; Mattias Bergqvist; Matteo Benelli; Ilenia Migliaccio; Francesca Galardi; Emanuela Risi; Irene De Santo; Dario Romagnoli; Laura Biganzoli; Angelo Di Leo; Luca Malorni

    Purpose: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC. Experimental design: Modulation of TK1 levels and activity by palbociclib were studied in seven oestrogen receptor-positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1) and at disease progression on palbociclib (T2) in patients enrolled in the TREnd trial (n=46). Results: Among E2F-dependent genes, TK1 was significantly down-regulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 Du/L, with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n=8) showing an increase - correlating with a worse outcome than those with decreased/stable TKa (n= 33) (mPFS 3.0 vs 9.0 months, p= 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared to those with lower TKa (2.9 vs 8.7 months, p= 0.05). Conclusions: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. Additionally, TKa may stratify prognosis in patients with acquired resistance to palbociclib.

    更新日期:2020-01-14
  • A Phase 1 Study of Ruxolitinib, Lenalidomide and Steroids for Patients with Relapsed/Refractory Multiple Myeloma
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    James R Berenson; Jennifer To; Tanya M Spektor; Daisy Martinez; Carley Turner; Armando Sanchez; Matthew Ghermezi; Benjamin M Eades; Regina A Swift; Gary Schwartz; Shahrooz Eshaghian; Laura Stampleman; Robert A Moss; Stephen Lim; Robert Vescio

    Purpose: This Phase I trial evaluated the safety and efficacy of a novel, all-oral combination consisting of the JAK 1/2 inhibitor ruxolitinib (RUX), lenalidomide (LEN) and steroids for treating relapsed/refractory multiple myeloma patients. Many newer drugs have been evaluated together and in combination with older agents for these patients but the responses to these regimens including those containing immunomodulatory agents are transient; and, thus, new therapeutic approaches to help overcome resistance to immunomodulatory agents are needed. Experimental Design: A traditional 3+3 dose-escalation design was used to enroll subjects in four cohorts with a planned total enrollment of 28 patients. Subjects received ruxolitinib (RUX) twice daily, lenalidomide (LEN) daily on days 1‑21 of a 28-day cycle and methylprednisolone (MP) orally every other day. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results: Twenty-eight patients were enrolled. The median age was 67 years and received a median of 6 prior treatments including LEN and steroids to which 93% were refractory. No DLTs occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding pts were refractory to LEN. G3 or G4 AEs included anemia (18%), thrombocytopenia (14%) and lymphopenia (14%). Most common SAEs included sepsis (11%) and pneumonia (11%). Conclusions: This study provides the basis for studying the addition of JAK inhibitors to improve the efficacy of immunomodulatory agents with steroids for treating myeloma patients but perhaps can also be expanded for treating other cancer patients that are refractory to this class of drugs.

    更新日期:2020-01-14
  • Prospective Evaluation of Bone Metabolic Markers as Surrogate Markers of Response to Radium-223 Therapy in Metastatic Castration Resistant Prostate Cancer.
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Neeraj Agarwal; Roberto H Nussenzveig; Andrew W Hahn; John M Hoffman; Kathryn Morton; Sumati Gupta; Julia Batten; Jared Thorley; Josiah L Hawks; Victor S Santos; Gayatri Nachaegari; Xuechen Wang; Kenneth M Boucher; Benjamin Haaland; Benjamin L Maughan

    Purpose: Radium-223 is approved for metastatic castration-refractory prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMM) as surrogate markers of response to radium-223 in mCRPC. Experimental Design: A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide (Enza) alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enza was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination. Results: Thirty-nine men were randomized to RE (n=27) or Enza (n=12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% CI 0.51-0.81; P=0.00048) favored RE versus Enza. Overall, BMMs decreased with the RE therapy compared to Enza. Improved PSA response rate in RE versus Enza (P=0.024), correlated with decline in BMM. Conclusions: BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radum-223 in real-time.

    更新日期:2020-01-14
  • Impact of EGFR-TKI treatment on the tumor immune microenvironment in EGFR mutation-positive non-small cell lung cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Kohsuke Isomoto; Koji Haratani; Hidetoshi Hayashi; Shigeki Shimizu; Tomida Shuta; Takashi Niwa; Toshihide Yokoyama; Yasushi Fukuda; Yasutaka Chiba; Ryoji Kato; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Takashi Ogura; Tadashi Ishida; Akihiko Ito; Kazuhiko Nakagawa

    Introduction: The impact of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear. Methods: We retrospectively identified 138 patients with EGFR -mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by immunohistochemistry. Tumor mutation burden (TMB) was determined by next-generation sequencing. Results: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI ( P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 versus 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months. Conclusions: EGFR-TKI treatment was associated with changes in the TME of EGFR -mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.

    更新日期:2020-01-14
  • Targeting super-enhancer-associated oncogenes in osteosarcoma with THZ2, a covalent CDK7 inhibitor
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Jiajun Zhang; Weihai Liu; Changye Zou; Zhiqiang Zhao; Yuanying Lai; Zhi Shi; Xianbiao Xie; Gang Huang; Yongqian Wang; Xuelin Zhang; Zepei Fan; Qiao Su; Junqiang Yin; Jingnan Shen

    Purpose: Malignancy of cancer cells depends on the active transcription of tumor-associated genes. Recently, unique clusters of transcriptional enhancers, termed super-enhancers, have been reported to drive the expression of genes that define cell identity. In this study we characterized specific super-enhancer-associated genes of osteosarcoma, and explored their potential therapeutic value. Experimental Design: Super-enhancer regions were characterized through chromatin immunoprecipitation sequencing (ChIP-Seq). RT-qPCR was used to detect the mRNA level of CDK7 in patient specimens and confirm the regulation of sensitive oncogenes by THZ2. The phosphorylation of the initiation-associated sites of RNA polymerase II (RNAP II) C-terminal repeat domain (CTD) was measured using Western blotting. Microarray expression analysis was conducted to explore transcriptional changes after THZ2 treatment. A variety of in vitro and in vivo assays were performed to assess the effects of CDK7 knockdown and THZ2 treatment in osteosarcoma. Results: Super-enhancers were associated with oncogenic transcripts and key genes encoding cell-type-specific transcription factors in osteosarcoma. Knockdown of transcription factor CDK7 reduced phosphorylation of the RNAPII CTD, and suppressed the growth and metastasis of osteosarcoma. A new specific CDK7 inhibitor, THZ2, suppressed cancer biology by inhibition of transcriptional activity. Compared with typical enhancers, osteosarcoma super-enhancer-associated oncogenes were particular vulnerable to this transcriptional disruption. THZ2 exhibited a powerful anti-osteosarcoma effect in vitro and in vivo. Conclusions: Super-enhancer-associated genes contribute to the malignant potential of osteosarcoma, and selectively targeting super-enhancer-associated oncogenes with the specific CDK7 inhibitor THZ2 might be a promising therapeutic strategy for patients with osteosarcoma.

    更新日期:2020-01-14
  • AMG-176, an Mcl-1 antagonist, shows preclinical efficacy in chronic lymphocytic leukemia
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Xue Yi; Aloke Sarkar; Gorkem Kismali; Burcu Aslan; Mary Ayres; LaKesla R. Iles; Michael J. Keating; William Wierda; James P Long; Maria Teresa Sabrina Bertilaccio; Varsha Gandhi

    Purpose: Survival of CLL cells due to the presence of Bcl-2 and Mcl-1 has been established. Direct inhibition of Bcl-2 by venetoclax and indirect targeting of Mcl-1 with transcription inhibitors have been successful approaches for CLL. AMG-176 is a selective and direct antagonist of Mcl-1, which has shown efficacy in several hematological malignancies, however, its effect on CLL is elusive. We evaluated biological and molecular effects of AMG-176 in primary CLL cells. Experimental Design: Using samples from patients (n = 74) with CLL, we tested effects of AMG-176 on CLL and normal hematopoietic cell death and compared importance of CLL prognostic factors on this biological activity. We evaluated CLL cell apoptosis in the presence of stromal cells and identified cell death pathway including stabilization of Mcl-1 protein. Finally, we tested couplet of AMG-176 and venetoclax in CLL lymphocytes. Results: AMG-176 incubations resulted in time- and dose-dependent CLL cell death. At 100 and 300 nM, there was 30 and 45 % cell death at 24 hours. These concentrations did not result in significant cell death in normal hematopoietic cells. Presence of stroma did not affect AMG-176-induced CLL cell death. IGHV unmutated status, high β2M and Mcl-1 protein levels resulted in slightly lower cell death. Mcl-1 but not Bcl-2 protein levels in CLL cells increased with AMG-176. Low concentrations of venetoclax (1-30 nM) were additive or synergistic with AMG-176. Conclusions: AMG-176 is active in inducing CLL cell death while sparing normal blood cells. Combination with low dose venetoclax had at least additive effect.

    更新日期:2020-01-14
  • Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Meagan B. Ryan; Ferran Fece de la Cruz; Sarah Phat; David T. Myers; Edmond Wong; Heather A. Shahzade; Catriona B. Hong; Ryan B. Corcoran

    Purpose: Although KRAS represents the most commonly mutated oncogene, it has long been considered an “undruggable” target. Novel covalent inhibitors selective for the KRASG12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS–MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance. Experimental Design: A panel of KRASG12C cell lines were treated with the KRASG12C inhibitors ARS-1620 and AMG 510 to assess effects on signaling and viability. Isoform-specific pulldown of activated GTP-bound RAS was performed to evaluate effects on the activity of specific RAS isoforms over time following treatment. RTK inhibitors, SHP2 inhibitors, and MEK/ERK inhibitors were assessed in combination with KRASG12C inhibitors in vitro and in vivo as potential strategies to overcome resistance and enhance efficacy. Results: We observed rapid adaptive RAS pathway feedback reactivation following KRASG12C inhibition in the majority of KRASG12C models, driven by RTK-mediated activation of wild-type RAS, which cannot be inhibited by G12C-specific inhibitors. Importantly, multiple RTKs can mediate feedback, with no single RTK appearing critical across all KRASG12C models. However, coinhibition of SHP2, which mediates signaling from multiple RTKs to RAS, abrogated feedback reactivation more universally, and combined KRASG12C/SHP2 inhibition drove sustained RAS pathway suppression and improved efficacy in vitro and in vivo. Conclusions: These data identify feedback reactivation of wild-type RAS as a key mechanism of adaptive resistance to KRASG12C inhibitors and highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRASG12C inhibitors.

    更新日期:2020-01-14
  • Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Jiajia Zhang; Zhicheng Ji; Justina X. Caushi; Margueritta El Asmar; Valsamo Anagnostou; Tricia R. Cottrell; Hok Yee Chan; Prerna Suri; Haidan Guo; Taha Merghoub; Jamie E. Chaft; Joshua E. Reuss; Ada J. Tam; Richard L. Blosser; Mohsen Abu-Akeel; John-William Sidhom; Ni Zhao; Jinny S. Ha; David R. Jones; Kristen A. Marrone; Jarushka Naidoo; Edward Gabrielson; Janis M. Taube; Victor E. Velculescu; Julie R. Brahmer; Franck Housseau; Matthew D. Hellmann; Patrick M. Forde; Drew M. Pardoll; Hongkai Ji; Kellie N. Smith

    Purpose: Neoadjuvant PD-1 blockade is a promising treatment for resectable non–small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial ([NCT02259621][1]), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade. Experimental Design: T-cell receptor (TCR) sequencing was performed on serial peripheral blood, tumor, and normal lung samples from resectable NSCLC patients treated with neoadjuvant PD-1 blockade. We explored the temporal dynamics of the T-cell repertoire in the peripheral and tumoral compartments in response to neoadjuvant PD-1 blockade by using the TCR as a molecular barcode. Results: Higher intratumoral TCR clonality was associated with reduced percent residual tumor at the time of surgery, and the TCR repertoire of tumors with major pathologic response (MPR; <10% residual tumor after neoadjuvant therapy) had a higher clonality and greater sharing of tumor-infiltrating clonotypes with the peripheral blood relative to tumors without MPR. Additionally, the posttreatment tumor bed of patients with MPR was enriched with T-cell clones that had peripherally expanded between weeks 2 and 4 after anti–PD-1 initiation and the intratumoral space occupied by these clonotypes was inversely correlated with percent residual tumor. Conclusions: Our study suggests that exchange of T-cell clones between tumor and blood represents a key correlate of pathologic response to neoadjuvant immunotherapy and shows that the periphery may be a previously underappreciated originating compartment for effective antitumor immunity. See related commentary by XXX, p. XXX [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02259621&atom=%2Fclincanres%2Fearly%2F2020%2F01%2F13%2F1078-0432.CCR-19-2931.atom

    更新日期:2020-01-14
  • Targeting PD-L1 Initiates Effective Antitumor Immunity in a Murine Model of Cushing Disease
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Hanna R. Kemeny; Aladine A. Elsamadicy; S. Harrison Farber; Cosette D. Champion; Selena J. Lorrey; Pakawat Chongsathidkiet; Karolina I. Woroniecka; Xiuyu Cui; Steven H. Shen; Kristen E. Rhodin; Vadim Tsvankin; Jeffrey Everitt; Luis Sanchez-Perez; Patrick Healy; Roger E. McLendon; Patrick J. Codd; Ian F. Dunn; Peter E. Fecci

    Purpose: Although pituitary adenoma is classified as benign, Cushing disease is associated with significant morbidity due to the numerous sequelae of elevated cortisol levels. Successful therapy for Cushing disease remains elusive due to high rates of treatment-refractory recurrence. The frequent emergence of lymphocytic hypophysitis following checkpoint blockade for other cancers, as well as the expression of PD-L1 on pituitary adenomas, suggest a role for immunotherapy. Experimental Design: This study confirms PD-L1 expression on functioning pituitary adenomas and is the first to evaluate the efficacy of checkpoint blockade (anti–PD-L1) therapy in a preclinical model of Cushing disease. Results: Herein, treatment with anti–PD-L1 was successful in reducing adrenocorticotropic hormone plasma levels, decreasing tumor growth, and increasing survival in our model. Furthermore, tumor-infiltrating T cells demonstrated a pattern of checkpoint expression similar to other checkpoint blockade–susceptible tumors. Conclusions: This suggests that immunotherapy, particularly blockade of the PD1/PD-L1 axis, may be a novel therapeutic option for refractory Cushing disease. Clinical investigation is encouraged.

    更新日期:2020-01-14
  • AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Justin Cidado; Scott Boiko; Theresa Proia; Douglas Ferguson; Steven W. Criscione; Maryann San Martin; Petar Pop-Damkov; Nancy Su; Valar Nila Roamio Franklin; Chandra Sekhar Reddy Chilamakuri; Clive S. D'Santos; Wenlin Shao; Jamal C. Saeh; Raphael Koch; David M. Weinstock; Michael Zinda; Stephen E. Fawell; Lisa Drew

    Purpose: Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many cancers. Multiple nonselective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573. Experimental Design: The antitumor activity of AZD4573 was determined across broad cancer cell line panels in vitro as well as cell line- and patient-derived xenograft models in vivo . Multiple approaches, including integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacologic comparisons, were employed to further understand the major mechanism driving AZD4573 activity and to establish an exposure/effect relationship. Results: AZD4573 is a highly selective and potent CDK9 inhibitor. It demonstrated rapid induction of apoptosis and subsequent cell death broadly across hematologic cancer models in vitro , and MCL-1 depletion in a dose- and time-dependent manner was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. This pharmacodynamic (PD) response was also observed in vivo , which led to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses both as monotherapy or in combination with venetoclax. This understanding of the mechanism, exposure, and antitumor activity of AZD4573 facilitated development of a robust pharmacokinetic/PD/efficacy model used to inform the clinical trial design. Conclusions: Selective targeting of CDK9 enables the indirect inhibition of MCL-1, providing a therapeutic option for MCL-1–dependent diseases. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematologic malignancies (clinicaltrials.gov identifier: [NCT03263637][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03263637&atom=%2Fclincanres%2Fearly%2F2020%2F01%2F13%2F1078-0432.CCR-19-1853.atom

    更新日期:2020-01-14
  • Functional Genomics Identifies Hepatitis-Induced STAT3–TYRO3–STAT3 Signaling as a Potential Therapeutic Target of Hepatoma
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Chia-Liang Tsai; Jeng-Shou Chang; Ming-Chin Yu; Chern-Horng Lee; Tse-Ching Chen; Wen-Yu Chuang; Wei-Liang Kuo; Chen-Chun Lin; Shi-Ming Lin; Sen-Yung Hsieh

    Purpose: Hepatitis promotes the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTK) play critical roles in the development of many cancers. We explored the potential roles of RTKs in hepatitis-related liver cancers. Experimental Design: We conducted loss-of-function screening to elucidate the roles of RTKs in the development of HCC in vitro and in vivo . Results: Many RTKs were coexpressed in HCC and were involved in tumor development and growth. Of these, TYRO3 promoted tumor growth and was clinically associated with hepatitis activity and poor prognosis. In mice, chemical-induced hepatitis transcriptionally activated Tyro3 expression via IL-6/IL6R–STAT3 signaling. Moreover, hepatitis-associated apoptotic cells facilitated the presentation of GAS6, a TYRO3 ligand, to further activate TYRO3-mediated signaling. Furthermore, TYRO3 activation elicited intracellular SRC- and STAT3 signaling. In mice, hepatitis and Tyro3 synergistically promoted HCC development. Silencing TYRO3 expression or inhibiting its kinase activity suppressed xenograft HCC growth in nude mice. Conclusions: Many RTKs are simultaneously involved in HCC development. Hepatitis exerts dual effects on the activation of TYRO3-mediated signaling in HCC cells, which further elicits the “TYRO3–STAT3–TYRO3” signaling loop to facilitate tumor growth. Our findings unveil a previously unrecognized link between RTKs and hepatitis-associated HCC and suggest TYRO3 as a marker and therapeutic target for the HCCs with higher hepatitis activity.

    更新日期:2020-01-14
  • Genomic Determinants of Clinical Outcomes in Rhabdomyosarcoma
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-14
    Dana L. Casey; Leonard H. Wexler; Kenneth L. Pitter; Robert M. Samstein; Emily K. Slotkin; Suzanne L. Wolden

    Purpose: Increased availability of next-generation sequencing has allowed for the genomic characterization of a variety of pediatric tumors, although genomic determinants of response to treatment remain largely unknown. We sought to evaluate the genomic landscape and genomic determinants of clinical outcomes in rhabdomyosarcoma (RMS). Experimental Design: Of 29,067 patients who underwent genomic profiling at our institution using a 468-gene oncopanel with complete records, 87 had RMS, of whom 22 were fusion positive. The 10 most common genetic alterations were associated with locoregional control (LC), disease-free survival (DFS), and overall survival (OS). Tumor mutational burden (TMB), defined as the total number of somatic nonsynonymous mutations normalized to the number of sequenced megabases, was also associated with clinical outcomes. Results: Median age at diagnosis was 16.4 years and median follow-up, 2.1 years. Patients with fusion-negative RMS had more genomic alterations and a higher TMB than those with fusion-positive RMS (mean number of genomic alterations, 6.0 vs. 2.9; P = 0.007 and mean TMB, 2.6 vs. 1.0; P = 0.01). Genetic alterations in TP53 were associated with worse OS ( P = 0.03). High TMB (defined as the top quartile ≥ 2.8) was associated with worse LC ( P = 0.05), DFS ( P = 0.04), and OS ( P = 0.01), with significance retained on multivariable analysis after controlling for risk group, fusion status, and receipt of chemotherapy as per pediatric protocols. Conclusions: High TMB was associated with worse clinical outcomes in patients with RMS. With further validation, TMB and other genomic classifiers may be combined with traditional clinicopathologic risk factors to guide risk stratification and ultimately treatment decisions.

    更新日期:2020-01-14
  • A small hypoxia signature predicted pCR response to bevacizumab in the neoadjuvant GeparQuinto breast cancer trial
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-13
    Thomas Karn; Tobias Meissner; Karsten Weber; Christine Solbach; Carsten Denkert; Knut Engels; Peter A. Fasching; Bruno V Sinn; Iris Schrader; Jan Budczies; Frederik Marmé; Volkmar Müller; Uwe Holtrich; Bernd Gerber; Christian Schem; Brandon Young; Claus A Hanusch; Elmar Stickeler; Jens Huober; Marion van Mackelenbergh; Brian Leyland-Jones; Tanja Fehm; Valentina Nekljudova; Michael Untch; Sibylle Loibl

    Purpose:In breast cancer bevacizumab increased pCR rate but not long term survival and no predictive markers are available to identify patients with long term benefit from the drug. Experimental Design:We profiled 289 pre-therapeutic FFPE biopsies of HER2 negative patients from the GeparQuinto trial of neoadjuvant chemotherapy +/- bevacizumab by exome-capture RNA-Seq. In a prospectively planned study we tested molecular signatures for response prediction. Immunohistochemical validation was performed using tissue microarrays. Results:We found strong agreement of molecular and pathological parameters as hormone receptors, grading, and lymphocyte infiltration in 221 high quality samples. Response rates (49.3% pCR overall) were higher in basal-like (68.9%) and HER2-enriched (45.5%) than in luminal B (35.7%), luminal A (17.9%), and normal-like (20.0%) subtypes. T cell- (OR 1.60, 95%CI 1.21-2.12, P=0.001), proliferation- (OR 2.88, 95%CI 2.00-4.15, P<0.001), and hypoxia-signatures (OR 1.92, 95%CI 1.41-2.60, P<0.001) significantly predicted pCR in univariate analysis. In a pre-specified multivariate logistic regression a small hypoxia signature predicted pCR (OR 2.40, 95%CI 1.28-4.51, P=0.006) with a significant interaction with bevacizumab treatment (P=0.020). Immunohistochemical validation using NDRG1 as marker revealed highly heterogenous expression within tissue leading to profound loss of sensitivity in TMA analysis, still a significant predictive value for pCR was detected (P=0.025). Conclusions:Exome-capture RNA-Seq characterizes small FFPE core biopsies by reliably detecting factors as e.g. ER status, grade, and TIL levels. Beside molecular subtypes and immune signatures, a small hypoxiasignature predicted pCR to bevacizumab, which could be validated by IHC. The signature can have important applications for bevacizumab treatment in different cancer types and might also have a role for novel combination therapies of bevacizumab with immune checkpoint inhibition.

    更新日期:2020-01-13
  • Predominance of central memory T cells with high T-cell receptor repertoire diversity is associated with response to PD-1/PD-L1 inhibition in Merkel cell carcinoma
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-13
    Ivelina Spassova; Selma Ugurel; Patrick Terheyden; Antje Sucker; Jessica C Hassel; Cathrin Ritter; Linda Kubat; Daniel Habermann; Farnoush Farahpour; Mohammadkarim Saeedghalati; Lukas Peiffer; Rajiv Kumar; David Schrama; Daniel Hoffmann; Dirk Schadendorf; Jurgen C Becker

    Purpose: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer, which can be effectively controlled by immunotherapy with PD-1/PD-L1 checkpoint inhibitors. However, a significant proportion of patients are characterized by primary therapy resistance. Predictive biomarker for response to immunotherapy are lacking. Experimental Design: We applied Bayesian inference analyses on 41 MCC patients testing various clinical and biomolecular characteristics to predict treatment response. Further, we performed a comprehensive analysis of tumor tissue-based immunological parameters including multiplexed immunofluorescence for T-cell activation and differentiation markers, expression of immune-related genes and T-cell receptor (TCR) repertoire analyses in 18 patients, seven objective responders and eleven non-responders. Results: Bayesian inference analyses demonstrated that among currently discussed biomarkers only unimpaired overall performance status and absence of immunosuppression were associated with response to therapy. However, in responders, a predominance of central memory T cells and expression of genes associated with lymphocyte attraction and activation was evident. Additionally, TCR repertoire usage of tumor-infiltrating lymphocytes (TIL) demonstrated low T-cell clonality, but high TCR diversity in responding patients. In non-responders, terminally differentiated effector T cells with a constrained TCR repertoire prevailed. Sequential analyses of tumor tissue obtained during immunotherapy revealed a more pronounced and diverse clonal expansion of TIL in responders indicating an impaired proliferative capacity among TIL of non-responders upon checkpoint blockade. Conclusions: Our explorative study identified new tumor tissue-based molecular characteristics associated with response to anti-PD-1/PD-L1 therapy in MCC. These observations warrant further investigations in larger patient cohorts to confirm their potential value as predictive markers.

    更新日期:2020-01-13
  • Investigating PSMA-targeted radioligand therapy efficacy as a function of cellular PSMA levels and intra-tumoral PSMA heterogeneity
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-13
    Kyle Current; Catherine Meyer; Clara E Magyar; Christine E Mona; Joel Almajano; Roger Slavik; Andreea D Stuparu; Chloe Cheng; David W. Dawson; Caius G. Radu; Johannes Czernin; Katharina Lueckerath

    Purpose: Prostate specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA expressingcells. However, the relationship between PSMA levels and intra-lesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA-positive cells in a tumor. Experimental design: RM1 cells expressing different levels of PSMA (PSMA-, PSMA+, PSMA++,PSMA+++; study 1) or a mix of PSMA-positive and -negativeRM1 (study 2, 4) or PC-3/ PC-3-PIP (study 3)cells at various ratios were injected into mice. Mice received 177Lu- (studies 1-3) or 225Ac- (study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified. Results: 177Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2, 3) in both, the RM1 and PC-3-PIP models. In tumors resected two days post-RLT, PSMA expression correlated with 177Lu-PSMA617 uptake and the degree of DNA damage. Compared to 177Lu-PSMA617, 225Ac-PSMA617 improved overall anti-tumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups. Conclusion: In the current models both the degree of PSMA expression and the fraction of PSMA-positive cells correlate with 177Lu-/225Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT.

    更新日期:2020-01-13
  • Diverse AR Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-13
    Yingming Li; Rendong Yang; Christine M Henzler; Yeung Ho; Courtney Passow; Benjamin Auch; Suzanne Carreira; Daniel Nava Rodrigues; Claudia Bertan; Tae Hyun Hwang; David A Quigley; Ha X. Dang; Colm Morrissey; Michael Fraser; Stephen R Plymate; Christopher A Maher; Felix Y. Feng; Johann S. de Bono; Scott M. Dehm

    Purpose: Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to development and progression of CRPC. Experimental Design: We used whole genome and targeted DNA sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA-sequencing to analyze effects on expression of AR and truncated AR variants (AR-Vs). Results: AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally-derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide. Conclusions: AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.

    更新日期:2020-01-13
  • Cannabinoids promote progression of HPV positive head and neck squamous cell carcinoma via p38 MAPK activation
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-13
    Chao Liu; Sayed H Sadat; Koji Ebisumoto; Akihiro Sakai; Bharat A Panuganti; Shuling Ren; Yusuke Goto; Sunny Haft; Takahito Fukusumi; Mizuo Ando; Yuki Saito; Theresa Guo; Pablo Tamayo; Huwate Yeerna; William Kim; Jacqueline Hubbard; Andrew B Sharabi; J. Silvio Gutkind; Joseph A. Califano

    Purpose: Human papilloma virus (HPV) related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV positive HNSCC. Experimental Design: The expression of cannabinoid receptors CNR1 and CNR2 was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs or shRNA based models to explore the roles of CNR1 and CNR2 in HPV positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS). Results: In TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV positive HNSCC compared with HPV negative HNSCC, and knockdown of CNR1/CNR2 expression inhibited proliferation in HPV positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as non-selective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration, and induced apoptosis. Using whole genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure. Conclusion: Cannabinoids can promote progression of HPV positive HNSCC through p38 MAPK pathway activation.

    更新日期:2020-01-13
  • Romidepsin Plus Liposomal Doxorubicin Is Safe and Effective in Patients with Relapsed or Refractory T-Cell Lymphoma: Results of a Phase I Dose-Escalation Study
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-10
    Khoan Vu; Chi-Heng Wu; Chen-Yen Yang; Aaron Zhan; Erika Cavallone; Wade Berry; Pamela Heeter; Laura Pincus; Matthew J. Wieduwilt; Basem M. William; Charalambos Andreadis; Lawrence K. Kaplan; Frank McCormick; Pierluigi Porcu; Jonathan E. Brammer; Weiyun Z. Ai

    Purpose: The histone deacetylase (HDAC) inhibitor romidepsin and the anthracycline liposomal doxorubicin (LD) have modest single-agent activity in cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). We investigated the safety and efficacy of the combination of these two agents in CTCL and PTCL. Patients and Methods: Using CTCL cell lines and primary CTCL tumor cells, we demonstrated synergistic antitumor activity with romidepsin plus doxorubicin. We then conducted a phase I dose-escalation study of the romidepsin/LD combination in relapsed/refractory CTCL and PTCL. The primary objective was to determine the MTD of romidepsin in combination with LD at 20 mg/m2 i.v., once every 28 days. Results: Eleven patients with CTCL and 12 patients with PTCL were treated. The MTD of romidepsin was determined to be 12 mg/m2. Grade 3/4 hematologic toxicities included thrombocytopenia (17%), anemia (13%), and neutropenia (9%). The most frequent treatment-related nonhematologic adverse events were fatigue (48%), nausea (48%), vomiting (35%), and anorexia (30%). Among 21 evaluable patients, the overall response rate was 70% [1 complete response (CR), 6 partial responses (PR)] in CTCL and 27% (3 CR, 0 PR) in PTCL. Of the patients with CTCL, 8 of 10 had skin response, including 6 patients (60%) achieving skin involvement less than 10% of their body surface area at time of best response. Conclusions: Romidepsin plus LD demonstrated an acceptable safety profile and promising clinical efficacy with deep skin responses in relapsed/refractory CTCL. Thus, this combination could be considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in patients with aggressive CTCL.

    更新日期:2020-01-10
  • Coaltered Ras/B-raf and TP53 Is Associated with Extremes of Survivorship and Distinct Patterns of Metastasis in Patients with Metastatic Colorectal Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-10
    Jashodeep Datta; J. Joshua Smith; Walid K. Chatila; John C. McAuliffe; Cyriac Kandoth; Efsevia Vakiani; Timothy L. Frankel; Karuna Ganesh; Isaac Wasserman; Marla Lipsyc-Sharf; Jose Guillem; Garrett M. Nash; Philip B. Paty; Martin R. Weiser; Leonard B. Saltz; Michael F. Berger; William R. Jarnagin; Vinod Balachandran; T. Peter Kingham; Nancy E. Kemeny; Andrea Cercek; Julio Garcia-Aguilar; Barry S. Taylor; Agnes Viale; Rona Yaeger; David B. Solit; Nikolaus Schultz; Michael I. D’Angelica

    Purpose: We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer. Experimental Design: We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year ( n = 17) and ≥10-year ( n = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I–IV patients. Results: In the extremes-of-survivorship cohort, significant co-occurrence of KRAS hotspot mutations and TP53 alterations was observed in ≤2-year survivors ( P < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic Ras/B-raf (i.e., either KRAS, NRAS , or BRAF ) and TP53 alteration generated three prognostic clusters: (i) TP53 -altered alone (median OS, 132 months); (ii) Ras/B-raf –altered alone (65 months) or Ras/B-raf - and TP53 pan-wild-type (60 months); and (iii) coaltered Ras/B-raf – TP53 (40 months; P < 0.0001). Coaltered Ras/B-raf – TP53 was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91–3.21; P < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I–IV patients. Coaltered Ras/B-raf – TP53 was associated with worse OS in patients with liver ( n = 490) and lung ( n = 172) but not peritoneal surface ( n = 149) metastases. Moreover, coaltered Ras/B-raf – TP53 tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options. Conclusions: Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered Ras/B-raf – TP53 and its association with distinct patterns of colorectal cancer metastasis.

    更新日期:2020-01-10
  • Statin Use Is Associated with Lower Risk of PTEN-Null and Lethal Prostate Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-10
    Emma H. Allott; Ericka M. Ebot; Konrad H. Stopsack; Amparo G. Gonzalez-Feliciano; Sarah C. Markt; Kathryn M. Wilson; Thomas U. Ahearn; Travis A. Gerke; Mary K. Downer; Jennifer R. Rider; Stephen J. Freedland; Tamara L. Lotan; Philip W. Kantoff; Elizabeth A. Platz; Massimo Loda; Meir J. Stampfer; Edward Giovannucci; Christopher J. Sweeney; Stephen P. Finn; Lorelei A. Mucci

    Purpose: Statins are associated with lower risk of aggressive prostate cancer, but lethal prostate cancer is understudied and contributing mechanisms are unclear. We prospectively examined statins and lethal prostate cancer risk in the Health Professionals Follow-up Study (HPFS), tested associations with molecular subtypes, and integrated gene expression profiling to identify putative mechanisms. Experimental Design: Our study included 44,126 men cancer-free in 1990, followed for prostate cancer incidence through 2014, with statin use recorded on biennial questionnaires. We used multivariable Cox regression to examine associations between statins and prostate cancer risk overall, by measures of clinically significant disease, and by ERG and PTEN status. In an exploratory analysis, age-adjusted gene set enrichment analysis identified statin-associated pathways enriched in tumor and adjacent normal prostate tissue. Results: During 24 years of follow-up, 6,305 prostate cancers were diagnosed and 801 (13%) were lethal (metastatic at diagnosis or metastatic/fatal during follow-up). Relative to never/past use, current statin use was inversely associated with risk of lethal prostate cancer [HR, 0.76; 95% confidence interval (CI), 0.60–0.96] but not overall disease. We found a strong inverse association for risk of PTEN-null cancers (HR, 0.40; 95% CI, 0.19–0.87) but not PTEN-intact cancers (HR, 1.18; 95% CI, 0.95–1.48; P heterogeneity = 0.01). Associations did not differ by ERG. Inflammation and immune pathways were enriched in normal prostate tissue of statin ever ( n = 10) versus never users ( n = 103). Conclusions: Molecular tumor classification identified PTEN and inflammation/immune activation as potential mechanisms linking statins with lower lethal prostate cancer risk. These findings support a potential causal association and could inform selection of relevant biomarkers for statin clinical trials.

    更新日期:2020-01-10
  • Proteomic analysis of CSF from patients with leptomeningeal melanoma metastases identifies signatures associated with disease progression and therapeutic resistance
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-10
    Inna Smalley; Vincent Law; Clayton Wyatt; Brittany Evernden; Bin Fang; John M. Koomen; Eric A Welsh; Robert J. B. Macaulay; Peter A. Forsyth; Keiran S.M. Smalley

    Purpose: The development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. Here, we performed a multi-omics analysis of the CSF from LMM patients to determine how the leptomeningeal microenvironment shapes the biology and therapeutic responses of melanoma cells. Patients and Methods: A total of 45 serial CSF samples were collected from 16 patients, 8 of these with confirmed LMM. Of those with LMM, 7 had poor survival (<4 months) and one was an extraordinary responder (still alive with survival >35 months). CSF samples were analyzed by mass spectrometry and incubated with melanoma cells, that were subjected to RNA-Seq analysis. Functional assays were performed to validate the pathways identified. Results: Mass spectrometry analyses showed the CSF of most LMM patients to be enriched for pathways involved in innate immunity, protease-mediated damage, and IGF-related signaling. All of these were anti-correlated in the extraordinary responder. RNA-Seq analysis showed CSF to induce PI3K/AKT, integrin, B-cell activation, S-phase entry, TNFR2, TGF-band oxidative stress responses in the melanoma cells. ELISA assays confirmed that TGF-bexpression increased in the CSF of patients progressing with LMM. CSF from poorly responding patients conferred tolerance to BRAF inhibitor therapy in apoptosis assays. Conclusions: These analyses identified proteomic/transcriptional signatures in the CSF of patients who succumbed to LMM. We further showed that the CSF from LMM patients has the potential to modulate BRAF inhibitor responses and may contribute to drug resistance.

    更新日期:2020-01-10
  • Efficacy of affibody-based ultrasound molecular imaging of vascular B7-H3 for breast cancer detection
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-10
    Rakesh Bam; Patrick S Lown; Lawrence A Stern; Karina Sharma; Katheryne E. Wilson; Gregory R Bean; Amelie M Lutz; Ramasamy Paulmurugan; Benjamin J. Hackel; Jeremy Dahl; Lotfi Abou-Elkacem

    Purpose: Human B7-H3 (hB7-H3) is a promising molecular imaging target differentially expressed on the neovasculature of breast cancer and has been validated for pre-clinical ultrasound (US) imaging with anti-B7-H3-antibody functionalized microbubbles (MB). However, smaller ligands such as affibodies (ABY) are more suitable for the design of clinical-grade targeted-MB. Experimental Design: Binding of ABYB7-H3 was confirmed with soluble and cell-surface B7-H3 by flow-cytometry. MB were functionalized with ABYB7-H3 or anti-B7-H3-antibody (AbB7-H3). Control and targeted-MB were tested for binding to hB7-H3-expressing cells (MS1hB7-H3) under shear stress conditions. US imaging was performed with MBABY-B7-H3 in an orthotopic mouse model of human MDA-MB-231 co-implanted with MS1hB7-H3 or control MS1WT cells and a transgenic mouse model of breast cancer development. Results: ABYB7-H3 specifically binds to MS1hB7-H3 and murine-B7-H3-expressing monocytes. MBABY-B7-H3 (8.5 ± 1.4 MB/cell) and MBAb-B7-H3 (9.8 ± 1.3 MB/cell) showedsignificantly higher (p<0.0001) binding to the MS1hB7-H3 cells compared to control MBNon-targeted (0.5 ± 0.1 MB/cell)under shear stress conditions. In vivo , MBABY-B7-H3 produced significantly higher (p<0.04) imaging signal in orthotopic tumors co-engrafted with MS1hB7-H3 (8.4 ± 3.3 a.u.)compared to tumors with MS1WT cells (1.4 ± 1.0 a.u.). In the transgenic mouse tumors, MBABY-B7-H3 (9.6 ± 2.0 a.u.) produced higher (p<0.0002) imaging signal compared to MBNon-targeted (1.3 ± 0.3 a.u.), while MBABY-B7-H3 signal in normal mammary glands and tumors with B7-H3-blocking significantly reduced (p<0.02) imaging signal. Conclusions: MBABY-B7-H3 enhances B7-H3 molecular signal in breast tumors, improving cancer detection, while offering the advantages of a small size ligand and easier production for clinical imaging.

    更新日期:2020-01-10
  • Radiological evaluation of newly diagnosed non-brainstem pediatric high-grade glioma in the HERBY phase II trial
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-10
    Daniel Rodriguez Gutierrez; Chris Jones; Pascale Varlet; Alan Mackay; Daniel Warren; Monika Warmuth-Metz; Esther Sánchez Aliaga; Raphael Calmon; Darren R. Hargrave; Adela Cañete; Maura Massimino; Amedeo A Azizi; Marie-Cécile Le Deley; Frank Saran; Raphael F Rousseau; Gudrun Zahlmann; Josep Garcia; Gilles Vassal; Jacques Grill; Paul S Morgan; Tim Jaspan

    Background: The HERBY trial evaluated the benefit of the addition of the antiangiogenic agent Bevacizumab (BEV) to radiotherapy/Temozolomide (RT/TMZ) in pediatric patients with newly diagnosed non-brainstem high-grade glioma (HGG). The work presented here aims to correlate imaging characteristics and outcome measures with pathological and molecular data. Methods: Radiological, pathological and molecular data were correlated with trial clinical information to retrospectively re-evaluate event free and overall survival. Results: One-hundred thirteen patients were randomized to the RT/TMZ arm (n =54) or the RT/TMZ+BEV (BEV arm; n =59). The tumor arose in the cerebral hemispheres in 68 patients (Cerebral group) and a midline location in 45 cases (Midline group). Pathological diagnosis was available in all cases and molecular data in 86/113. H3 K27M histone mutations were present in 23/32 Midline cases and H3 G34R/V mutations in 7/54 Cerebral cases. Total/near-total resection occurred in 44/68 (65%) Cerebral cases but only 5/45 (11%) Midline cases (p <0.05). Leptomeningeal metastases (27 cases, 13 with subependymal spread) at relapse were more frequent in Midline (17/45) than Cerebral tumors (10/68, p <0.05). Mean OS (14.1 months) and EFS (9.0 months) in Midline tumors were significantly lower than mean OS (20.7 months) and EFS (14.9 months) in Cerebral tumors (p <0.05). Pseudoprogression occurred in 8/111 (6.2%) cases. Conclusions: This study has shown that the poor outcome of midline tumors (compared to cerebral) may be related to 1) lesser surgical resection, 2) H3 K27M histone mutations, and 3) higher leptomeningeal dissemination.

    更新日期:2020-01-10
  • Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-10
    Anna M. Varghese; Dana B. Cardin; Jonathan Hersch; Al Benson; Howard S. Hochster; Lukas Makris; Kensuke Hamada; Jordan Berlin; Leonard B Saltz

    Purpose: This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). Experimental Design: Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20-35 mg/m2 twice daily [BID]; days 1-5 of a 14-day cycle) and irinotecan (120-180 mg/m2; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered. Results: Fifty patients (26 across 6 dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m2 BIDplus irinotecan 180 mg/m2. In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1-13.4 months). Conclusions:Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI-irinotecan-bevacizumab combination in previously treated mCRC.

    更新日期:2020-01-10
  • Trametinib activity in patients with solid tumors and lymphomas harboring BRAF non-V600 mutations or fusions: results from NCI-MATCH (EAY131)
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-10
    Douglas B. Johnson; Fengmin Zhao; Marcus S Noel; Gregory J. Riely; Edith P. Mitchell; John J. Wright; Helen X. Chen; Robert J Gray; Shuli Li; Lisa M McShane; Lawrence Rubinstein; David Patton; Mickey Williams; Stanley R. Hamilton; Barbara A Conley; Carlos L. Arteaga; Lyndsay N. Harris; Peter J. O'Dwyer; Alice P Chen; Keith T Flaherty

    Purpose: Substantial preclinical evidence and case reports suggest that MEK inhibition is an active approach in tumors with BRAF mutations outside the V600 locus, and in BRAF fusions. Thus, Subprotocol R of the NCI-MATCH study tested the MEK inhibitor trametinib in this population. Methods: The NCI-MATCH study performed genomic profiling on tumor samples from patients with solid tumors and lymphomas progressing on standard therapies or with no standard treatments. Patients with pre-specified fusions and non-V600 mutations in BRAF were assigned to Subprotocol R using the NCI-MATCHBOX algorithm. The primary endpoint was objective response rate (ORR). Results: Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Of these, 1 had a BRAF fusion and 31 had BRAF mutations (13 and 19 with class 2 and 3 mutations, respectively). There were no complete responses; 1 patient (3%) had a confirmed partial response (patient with breast ductal adenocarcinoma with BRAF G469E mutation) and 10 patients had stable disease as best response (clinical benefit rate 34%). Median progression free survival was 1.8 months and median overall survival was 5.7 months. Exploratory subgroup analyses showed that patients with colorectal adenocarcinoma (n=8) had particularly poor PFS. No new toxicity signals were identified. Conclusions: Trametinib did not show promising clinical activity in patients with tumors harboring non-V600 BRAF mutations, and the subprotocol did not meet its primary endpoint.

    更新日期:2020-01-10
  • Elite Intratumoral T-cell Clonotypes (The 1%) Effect "Trickle-Down Cytotoxicity"
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Brian S Henick

    Careful study of T cell clonal dynamics in non-small cell lung cancer patients treated with neoadjuvant nivolumab suggests that successful trafficking of clones from a proliferative burst in the periphery to the tumor associates with major pathologic response. Integration of these findings with functional analysis may augment current therapeutic strategies.

    更新日期:2020-01-09
  • A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Newly Diagnosed Stage IV Squamous Cell Lung Cancers
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Paul K. Paik; Rachel K. Kim; Linda Ahn; Andrew J. Plodkowski; Ai Ni; Mark T.A. Donoghue; Philip Jonsson; Miguel Villalona-Calero; Kenneth Ng; Daniel McFarland; John J. Fiore; Afsheen Iqbal; Juliana Eng; Mark G. Kris; Charles M. Rudin

    Purpose: Gemcitabine and albumin-bound paclitaxel (ABP) exhibit synergistic anti-tumor efficacy, with ABP serving to increase the intratumoral gemcitabine concentration. Both drugs are active in squamous cell lung cancers (SQCLCs) and are conventional partners for carboplatin. We hypothesized that combining gemcitabine and ABP would enhance the anti-tumor activity in patients with advanced SQCLCs. Experimental Design: This was a Simon two-stage, open-label, single-arm, multicenter phase II study that enrolled patients between August 1, 2015 and June 1, 2018. We enrolled 37 patients with chemotherapy-naïve, PD-L1 low/unknown advanced stage IV SQCLC. Patients were administered weekly intravenous gemcitabine (1000 mg/m2) plus ABP (100 mg/m2) in a 3 week on, 1 week off schedule during Stage 1 and a 2 week on, 1 week off schedule in Stage 2. The primary endpoint was best objective response rate (ORR). Next-generation sequencing by MSK-IMPACT was used to calculate tumor mutation burden and genome doubling and assess somatic variants for correlations with efficacy. Results: Thirty-two patients were evaluable for response assessment. The study satisfied its primary endpoint, with confirmed partial responses in 18 of 32 patients and a complete response in 1 patient (ORR 59%, 95% CI 42% to 74%). Median progression-free survival (PFS), a secondary endpoint, was 7.5 (95% CI 6.7 to 10.5) months. There were no unexpected toxicities. Conclusions: Gemcitabine plus ABP was a safe, tolerable, and effective first-line therapy for patients with chemotherapy-naïve SQCLCs, with an ORR and median PFS substantially higher than carboplatin doublet regimens and efficacy comparable to carboplatin plus taxane plus pembrolizumab.

    更新日期:2020-01-09
  • A Phase II Trial of Pembrolizumab and Vorinostat in Recurrent Metastatic Head and Neck Squamous Cell Carcinomas and Salivary Gland Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Cristina P. Rodriguez; Qian (Vicky) Wu; Jenna Voutsinas; Jonathan R. Fromm; Xiuyun Jiang; Venu G. Pillarisetty; Sylvia M. Lee; Rafael Santana-Davila; Bernardo Goulart; Christina S. Baik; Laura Q.M. Chow; Keith Eaton; Renato Martins

    Background: This clinical trial combined pembrolizumab and vorinostat in recurrent/metastatic squamous cell carcinomas of the head and neck (HN), and salivary gland cancer (SGC). Patients and Methods: Patients with progressing incurable HN and SGC, Eastern Cooperative Oncology Group (ECOG) ≤1, no prior immunotherapy, RECIST1.1 measurable disease, and normal organ function were eligible. Pembrolizumab 200 mg was given intravenous every 21 days, and vorinostat 400 mg given orally 5 days on and 2 days off during each 21-day cycle. Primary endpoints were safety and objective response rates. Results: From November 2015 to August 2017, 25 patients with HN and 25 SGC were enrolled. Median age was 61 (range, 33–86) years, 39 (78%) were male, 21 (62%) were never smokers, and 27 (54%) had ECOG 0. In HN, 13 (52%) were p16+ oropharynx. Most common SGC histologies were adenoid cystic 12 (48%), acinic cell 3 (12%), and mucoepidermoid 3 (12%). Adverse events (AEs) in all patients were: 27 (54%) with grade ≥ 1 and 18 (36%) with grade ≥ 3. The most common AEs in all patients were renal insufficiency in seven, (14%), fatigue in six, (12%), and nausea in three (6%). There were three (12%) deaths on study. Responses in HN were complete response (CR) 0, partial response (PR) eight (32%), and stable disease (SD) five (20%). Efficacy in SGCs was CR 0, PR four (16%) in one lymphoepithelioma-like carcinoma, two acinic cell, one adenoid cystic, and SD 14 (56%). In the HN group, median follow-up (mFUP) was 12.6 months, median overall survival (mOS) was 12.6 months, and median progression-free survival (mPFS) was 4.5 months. In SGC, mFUP was 13.1 months, mOS was 14.0 months, and mPFS was 6.9 months. Conclusions: This combination demonstrated activity in HN, with fewer responses in SGC. Toxicities were higher than reported with pembrolizumab alone.

    更新日期:2020-01-09
  • HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Kevin D. Courtney; Yuanqing Ma; Alberto Diaz de Leon; Alana Christie; Zhiqun Xie; Layton Woolford; Nirmish Singla; Allison Joyce; Haley Hill; Ananth J. Madhuranthakam; Qing Yuan; Yin Xi; Yue Zhang; Jenny Chang; Oluwatomilade Fatunde; Yull Arriaga; Arthur E. Frankel; Sanjeeva Kalva; Song Zhang; Tiffani McKenzie; Oscar Reig Torras; Robert A. Figlin; Brian I. Rini; Renée M. McKay; Payal Kapur; Tao Wang; Ivan Pedrosa; James Brugarolas

    Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1β, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients. Experimental Design: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW ( n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies. Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance. Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).

    更新日期:2020-01-09
  • Adaptive Immune Resistance to Intravesical BCG in Non–Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Max Kates; Andres Matoso; Woonyoung Choi; Alexander S. Baras; Marcus J. Daniels; Kara Lombardo; Aaron Brant; Nina Mikkilineni; David J. McConkey; Ashish M. Kamat; Robert S. Svatek; Sima P. Porten; Joshua J. Meeks; Seth P. Lerner; Colin P. Dinney; Peter C. Black; James M. McKiernan; Chris Anderson; Charles G. Drake; Trinity J. Bivalacqua

    Purpose: To characterize immune cell expression among patients with non–muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG). Experimental Design: Patients with NMIBC treated with intravesical BCG (2008–2015) were identified, and a tissue microarray was constructed using paired pre- and post-BCG bladder samples. Among patients undergoing BCG, cystoscopic evaluation began 3 months after initiating BCG treatment to determine therapeutic response. IHC was performed for CD8, CD4, FoxP3, PD-L1 (SP-142 and 22C3), and PD-1. A full slide review of PD-L1+ staining tumors was performed to characterize PD-L1 and CD8 colocalization. RNA-seq was performed on cored tumors from available specimens. We compared immune cell populations between BCG responders and nonresponders, and between pretreatment and postreatment tumor samples. Baseline PD-L1 staining in the BCG naïve population was then validated in a separate cohort. Results: The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG nonresponders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and nonresponders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25% to 28% of nonresponders and 0% to 4% of responders ( P < 0.01). PD-L1+ cells in BCG nonresponders colocalized with CD8+ T cells. In addition, BCG therapy did not increase PD-L1 gene expression (RNA-seq) or protein levels (IHC). The number of pretreatment CD4+ T cells was very low among PD-L1+ nonresponders (12%) and high among PD-L1− nonresponders (50%, P < 0.01). In a separate cohort of 57 patients with NMIBC undergoing BCG, baseline PD-L1 (22C3) staining was similar (26%). Conclusions: One mechanism of BCG failure may be adaptive immune resistance. Baseline tumor PD-L1 expression predicts an unfavorable response to BCG and if validated, could be used to guide therapeutic decisions.

    更新日期:2020-01-09
  • Exploitation of CD133 for the Targeted Imaging of Lethal Prostate Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Paige M. Glumac; Joseph P. Gallant; Mariya Shapovalova; Yingming Li; Paari Murugan; Shilpa Gupta; Ilsa M. Coleman; Peter S. Nelson; Scott M. Dehm; Aaron M. LeBeau

    Purpose: Aggressive variant prostate cancer (AVPC) is a nonandrogen receptor–driven form of disease that arises in men in whom standard-of-care therapies have failed. Therapeutic options for AVPC are limited, and the development of novel therapeutics is significantly hindered by the inability to accurately quantify patient response to therapy by imaging. Imaging modalities that accurately and sensitively detect the bone and visceral metastases associated with AVPC do not exist. Experimental Design: This study investigated the transmembrane protein CD133 as a targetable cell surface antigen in AVPC. We evaluated the expression of CD133 by microarray and IHC analysis. The imaging potential of the CD133-targeted IgG (HA10 IgG) was evaluated in preclinical prostate cancer models using two different imaging modalities: near-infrared and PET imaging. Results: Evaluation of the patient data demonstrated that CD133 is overexpressed in a specific phenotype of AVPC that is androgen receptor indifferent and neuroendocrine differentiated. In addition, HA10 IgG was selective for CD133-expressing tumors in all preclinical imaging studies. PET imaging with [89Zr]Zr-HA10 IgG revealed a mean %ID/g of 24.30 ± 3.19 in CD133-positive metastatic lesions as compared with 11.82 ± 0.57 in CD133-negative lesions after 72 hours ( P = 0.0069). Ex vivo biodistribution showed similar trends as signals were increased by nearly 3-fold in CD133-positive tumors ( P < 0.0001). Conclusions: To our knowledge, this is the first study to define CD133 as a targetable marker of AVPC. Similarly, we have developed a novel imaging agent, which is selective for CD133-expressing tumors, resulting in a noninvasive PET imaging approach to more effectively detect and monitor AVPC.

    更新日期:2020-01-09
  • Transient Sox9 Expression Facilitates Progression to Castrate Resistant Prostate Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Mannan Nouri; Shabnam Massah; Josselin Caradec; Amy A Lubik; Na Li; Sarah Truong; Ahn R Lee; Ladan Fazli; Varune Rohan Ramnarine; Jessica M Lovnicki; Jackson Moore; Mike Wang; Jane Foo; Martin E. Gleave; Brett G. Hollier; Colleen C. Nelson; Xuesen Dong; Colin C. Collins; Ralph Buttyan

    Purpose: Metastatic prostate cancer (PCa) patients are increasingly presenting with treatment-resistant, androgen receptor-Negative/Low (AR-/Low) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here we explore the role of the developmental transcription factor Sox9 in the process of PCa therapy response and tumor progression. Experimental Design: Unique PCa cell models that capture AR-/Low stem cell-like intermediates were analyzed for features of plasticity and the functional role of Sox9. Human PCa xenografts and tissue microarrays were evaluated for temporal alterations in Sox9 expression. The role of NF-κB pathway activity in Sox9 overexpression was explored. Results: PCa stem cell-like intermediates have reduced Rb1 and p53 protein expression and overexpress Sox2 as well as Sox9. Sox9 was required for spheroid growth, and overexpression increased invasiveness and neural features of PCa cells. Sox9 was transiently upregulated in castration-induced progression of PCa xenografts and was specifically overexpressed in neoadjuvant hormone therapy (NHT) treated patient tumors. High Sox9 expression in NHT-treated patients predicts biochemical recurrence. Finally, we link Sox9 induction to NF-κB dimer activation in PCa cells. Conclusions: Developmentally reprogrammed PCa cell models recapitulate features of clinically-advanced prostate tumors including downregulated Rb1/p53 and overexpression of Sox2 with Sox9. Sox9 is a marker of a transitional state that identifies PCa cells under the stress of therapeutic assault and facilitates progression to therapy resistance. Its expression may index the relative activity of the NF-κB pathway.

    更新日期:2020-01-09
  • The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Christian Brieghel; Caspar da Cunha-Bang; Christina Westmose Yde; Ane Yde Schmidt; Savvas Kinalis; Ferran Nadeu; Michael Asger Andersen; Line Offenbach Jacobsen; Mette Klarskov Andersen; Lone Bredo Pedersen; Julio Delgado; Tycho Baumann; Mattias Mattsson; Larry Mansouri; Richard Rosenquist; Elias Campo; Finn Cilius Nielsen; Carsten U Niemann

    Purpose: Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at time of diagnosis remains unclear. Experimental Design: We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing. Results: Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refine prognostication in CLL; in particular for CLL-IPI low and intermediate risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways. Conclusions: We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.

    更新日期:2020-01-09
  • Targeting the Complement Alternative Pathway Permits Graft Versus Leukemia Activity while Preventing Graft Versus Host Disease
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Hung Nguyen; Ali Alawieh; David Bastian; Sandeepkumar Kuril; Min Dai; Anusara Daenthanasanmak; Mengmeng Zhang; Supinya Iamsawat; Steven D Schutt; Yongxia Wu; M. Mahdi Sleiman; Akshay Shetty; Carl Atkinson; Shaoli Sun; Juan Carlos Varela; Stephen Tomlinson; Xue-Zhong Yu

    Purpose: Application of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with hematological disorders is limited by the development of graft-versus-host-disease (GVHD). Separation of GVHD and graft-versus-leukemia (GVL) remains a great challenge in the field. We investigated the contribution of individual pathways involved in the complement cascade in GVH and GVL responses in order to identify specific targets by which to separate these two processes. Experimental Design: We used multiple preclinical murine and human-to-mouse xenograft models involving allo-HCT recipients lacking components of the AP or CP/LP to dissect the role of each individual pathway in GVHD pathogenesis and the GVL effect. For translational purposes, we used the AP-specific complement inhibitor, CR2-fH, which localizes in injured target organs to allow specific blockade of complement activation at sites of inflammation. Results: Complement deposition was evident in intestines of mice and patients with GVHD. In a preclinical setting, ablation of the AP, but not the CL/LP, significantly improved GVHD outcomes. Complement activation through the AP in host hematopoietic cells, and specifically dendritic cells (DCs), was required for GVHD progression. AP-deficiency in recipients decreased donor T-cell migration and Th1/Th2 differentiation, while increasing the generation of regulatory T-cells. This was due to decreased activation and stimulatory activity of recipient DCs in GVHD target organs. Treatment with CR2-fH effectively prevented GVHD while preserving GVL activity. Conclusions: This study highlights the AP as a new therapeutic target to prevent GVHD and tumor relapse after allo-HCT. Targeting the AP by CR2-fH represents a promising therapeutic approach for GVHD treatment.

    更新日期:2020-01-09
  • Analysis of pre- and post-treatment tissues from the SWOG S0800 trial reveals an effect of neoadjuvant chemotherapy on the breast cancer genome
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Ryan L. Powles; Vikram B. Wali; Xiaotong Li; William E. Barlow; Zeina Nahleh; Alastair M Thompson; Andrew K. Godwin; Christos Hatzis; Lajos Pusztai

    Purpose: We performed whole exome sequencing of pre- and post-treatment cancer tissues to assess the somatic mutation landscape of tumors before and after neoadjuvant taxane and anthracycline chemotherapy with or without bevacizumab. Experimental Design: 29 pre-treatment biopsies from the SWOG S0800 trial were subjected to whole exome sequencing to identify mutational patterns associated with response to neoadjuvant chemotherapy. Nine matching samples with residual cancer after therapy were also analyzed to assess changes in mutational patterns in response to therapy. Results: In pre-treatment samples, a higher proportion of mutation signature 3, a BRCA-mediated DNA repair deficiency mutational signature, was associated with higher rate of pathologic complete response (pCR) (median signature weight 24%, range 0-38% in oCR vs. median weight 0%, range 0-19% in residual disease, Wilcoxon rank sum, Bonferroni p = 0.007). We found no biological pathway level mutations associated with pCR or enriched in post treatment samples. We observed statistically significant enrichment of high functional impact mutations in the "E2F Targets" and "G2M Checkpoint" pathways in residual cancer samples implicating these pathways in resistance to therapy and a significant depletion of mutations in the "Myogenesis pathway" suggesting the cells harboring these variants were effectively eradicated by therapy. Conclusion: These results suggest that genomic disturbances in BRCA-related DNA repair mechanisms, reflected by a dominant mutational signature 3, confer increased chemotherapy sensitivity. Cancers that survive neoadjuvant chemotherapy, frequently have alterations in cell cycle regulating genes but different genes of the same pathways are affected in different patients.

    更新日期:2020-01-09
  • Predictive blood-based biomarkers in epithelial ovarian cancer patients treated with carboplatin and paclitaxel with or without bevacizumab: Results from GOG-0218
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Angeles Alvarez Secord; Kirsten Bell Burdett; Kouros Owzar; David Tritchler; Alexander B Sibley; Yingmiao Liu; Mark D Starr; John C Brady; Heather A Lankes; Herbert I. Hurwitz; Robert S Mannel; Krishnansu S. Tewari; David M. O'Malley; Heidi Gray; Jamie N. Bakkum-Gamez; Keiichi Fujiwara; Matthew Boente; Wei Deng; Robert A Burger; Michael J Birrer; Andrew B. Nixon

    Purpose: GOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses. Experimental Design: Plasma samples were analyzed via multiplex ELISA technology for seven pre-specified biomarkers (IL6, Ang-2, osteopontin (OPN), stromal cell-derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130). The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates. Results: Baseline samples were available from 751 patients. According to our pre-specified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS (p=0.007) and OS (p=0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS (p<0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared to placebo. Conclusions: The inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in renal cancer patients treated with anti-angiogenic therapies, it appears plasma IL6 may also define those EOC patients more or less likely to benefit from the addition of bevacizumab to standard chemotherapy.

    更新日期:2020-01-09
  • Organoid Cultures as Preclinical Models of Non–Small Cell Lung Cancer
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-09
    Ruoshi Shi; Nikolina Radulovich; Christine Ng; Ni Liu; Hirotsugu Notsuda; Michael Cabanero; Sebastiao N. Martins-Filho; Vibha Raghavan; Quan Li; Arvind Singh Mer; Joshua C. Rosen; Ming Li; Yu-Hui Wang; Laura Tamblyn; Nhu-An Pham; Benjamin Haibe-Kains; Geoffrey Liu; Nadeem Moghal; Ming-Sound Tsao

    Purpose: Non–small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide. There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease. Experimental Design: Thirty surgically resected NSCLC primary patient tissue and 35 previously established patient-derived xenograft (PDX) models were processed for organoid culture establishment. Organoids were histologically and molecularly characterized by cytology and histology, exome sequencing, and RNA-sequencing analysis. Tumorigenicity was assessed through subcutaneous injection of organoids in NOD/SCID mice. Organoids were subjected to drug testing using EGFR, FGFR, and MEK-targeted therapies. Results: We have identified cell culture conditions favoring the establishment of short-term and long-term expansion of NSCLC organoids derived from primary lung patient and PDX tumor tissue. The NSCLC organoids recapitulated the histology of the patient and PDX tumor. They also retained tumorigenicity, as evidenced by cytologic features of malignancy, xenograft formation, preservation of mutations, copy number aberrations, and gene expression profiles between the organoid and matched parental tumor tissue by whole-exome and RNA sequencing. NSCLC organoid models also preserved the sensitivity of the matched parental tumor to targeted therapeutics, and could be used to validate or discover biomarker–drug combinations. Conclusions: Our panel of NSCLC organoids closely recapitulates the genomics and biology of patient tumors, and is a potential platform for drug testing and biomarker validation.

    更新日期:2020-01-09
  • Racial Differences in the Association between Luminal Master Regulator Gene Expression Levels and Breast Cancer Survival
    Clin. Cancer Res. (IF 8.911) Pub Date : 2020-01-07
    Jung S Byun; Sandeep Singhal; Samson Park; Dae Ik Yi; Tingfen Yan; Ambar Caban; Alana Jones; Partha Mukhopadhyay; Sara M Gil; Stephen M. Hewitt; Lisa Newman; Melissa B. Davis; Brittany D Jenkins; Jorge L Sepulveda; Adriana De Siervi; Anna María Nápoles; Nasreen A Vohra; Kevin Gardner

    Purpose: Compared to their European American (EA) counterparts, African American (AA) women are more likely to die from breast cancer in the United States. This disparity is greatest in hormone receptor-positive subtypes. Here we uncover biological factors underlying this disparity by comparing functional expression and prognostic significance of master transcriptional regulators of luminal differentiation. Experimental Design: Data and biospecimens from 262 (AA) and 293 (EA) patients diagnosed with breast cancer from 2001-2010 at a major medical center, were analyzed by immunohistochemistry (IHC) for functional biomarkers of luminal differentiation including estrogen receptor ( ESR1 ), and its pioneer factors FOXA1 and GATA3 . Integrated comparison of protein levels with network-level gene expression analysis uncovered predictive correlations with race and survival. Results: Univariate or multivariate hazard ratios (HRs) for overall survival, estimated from digital IHC scoring of nuclear antigen, show distinct differences in the magnitude and significance of these biomarkers to predict survival based on race: ESR1 (EA HR= 0.47, 95% CI: 0.31-0.72; AA HR= 0.77, CI: 0.48-1.18); FOXA1 (EA HR= 0.38, CI: 0.23-0.63; AA HR = 0.53, CI: 0.31-0.88); and GATA3 (EA HR= 0.36, CI: 0.23-0.56; AA HR= 0.57, CI: 0.56-1.4). Additionally, we identify genes in the downstream regulons of these biomarkers highly correlated with race and survival. Conclusions: Even within clinically homogeneous tumor groups, regulatory networks that drive mammary luminal differentiation reveal race-specific differences in their association with clinical outcome. Understanding these biomarkers and their downstream regulons will elucidate the intrinsic mechanisms that drive racial disparities in breast cancer survival.

    更新日期:2020-01-07
Contents have been reproduced by permission of the publishers.
导出
全部期刊列表>>
2020新春特辑
限时免费阅读临床医学内容
ACS材料视界
科学报告最新纳米科学与技术研究
清华大学化学系段昊泓
自然科研论文编辑服务
中国科学院大学楚甲祥
中国科学院微生物研究所潘国辉
中国科学院化学研究所
课题组网站
X-MOL
北京大学分子工程苏南研究院
华东师范大学分子机器及功能材料
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug