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  • Phyllanthusmin derivatives induce apoptosis and reduce tumor burden in high grade serous ovarian cancer by late-stage autophagy inhibition
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-17
    Alexandria N. Young, Denisse Herrera, Andrew C. Huntsman, Melissa A. Korkmaz, Daniel D Lantvit, Sarmistha Mazumder, Shamalatha Kolli, Christopher C Coss, Salane King, Hongyan Wang, Steven M Swanson, A. Douglas Kinghorn, Xiaoli Zhang, Mitch A. Phelps, Leslie N. Aldrich, James R. Fuchs, Joanna E. Burdette

    High grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutics. Many of the most widely used chemotherapeutic drugs are derived from natural products or their semi-synthetic derivatives. We have developed potent synthetic analogues of a class of compounds known as phyllanthusmins, inspired by natural products isolated from Phyllanthus poilanei Beille. The most potent analogue, PHY34, had the highest potency in HGSOC cell lines in vitro and displayed cytotoxic activity through activation of apoptosis. PHY34 exerts its cytotoxic effects by inhibiting autophagy at a late stage in the pathway, involving the disruption of lysosomal function. The autophagy activator, rapamycin, combined with PHY34 eliminated apoptosis, suggesting that autophagy inhibition was required for apoptosis. PHY34 was readily bioavailable through intraperitoneal administration in vivo where it significantly inhibited the growth of cancer cell lines in hollow fibers, as well as reduced ovarian tumor burden in a xenograft model. We demonstrate that PHY34 acts as a late-stage autophagy inhibitor with nanomolar potency and significant antitumor efficacy as a single-agent against HGSOC in vivo. This class of compounds holds promise as a potential, novel chemotherapeutic and demonstrates the effectiveness of targeting the autophagic pathway as a viable strategy for combating ovarian cancer.

    更新日期:2018-07-18
  • The Protein Tyrosine Phosphatase Activity of Eyes Absent Contributes to Tumor Angiogenesis and Tumor Growth
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Yuhua Wang, Ram Naresh Pandey, Stephen Riffle, Hemabindu Chintala, Kathryn A. Wikenheiser-Brokamp, Rashmi S. Hegde

    DNA damage repair capacity is required for cells to survive catastrophic DNA damage and proliferate under conditions of intratumoral stress. The ability of the minor histone protein H2AX to serve as a hub for the assembly of a productive DNA damage repair complex is a necessary step in preventing DNA damage–induced cell death. The Eyes Absent (EYA) proteins dephosphorylate the terminal tyrosine residue of H2AX, thus permitting assembly of a productive DNA repair complex. Here, we use genetic and chemical biology approaches to separately query the roles of host vascular endothelial cell and tumor cell EYA in tumor growth. Deletion of Eya3 in host endothelial cells significantly reduced tumor angiogenesis and limited tumor growth in xenografts. Deletion of Eya3 in tumor cells reduced tumor cell proliferation and tumor growth without affecting tumor angiogenesis. A chemical inhibitor of the EYA tyrosine phosphatase activity inhibited both tumor angiogenesis and tumor growth. Simultaneously targeting the tumor vasculature and tumor cells is an attractive therapeutic strategy because it could counter the development of the more aggressive phenotype known to emerge from conventional antiangiogenic agents. Mol Cancer Ther; 17(8); 1–11. ©2018 AACR.

    更新日期:2018-07-14
  • Novel Trifluoromethylated Enobosarm Analogues with Potent Anti-androgenic Activity in vitro and Tissue Selectivity in vivo.
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    D. Alwyn Dart, Sahar Kandil, Serena Tommasini-Ghelfi, Gilberto Serrano de Almeida, Charlotte L Bevan, Wenguo Jiang, Andrew D Westwell

    Prostate cancer often develops anti‐androgen resistance, possibly via androgen receptor (AR) mutations which change antagonists to agonists. Novel therapies with increased anticancer activity, whilst overcoming current drug resistance are urgently needed. Enobosarm has anabolic effects on muscle and bone whilst having no effect on the prostate. Here we describe the activity of novel chemically modified enobosarm analogues. The rational addition of bis‐trifluoromethyl groups into ring B of enobosarm, profoundly modified their activity, pharmacokinetic and tissue distribution profiles. These chemical structural modifications resulted in an improved AR binding affinity ‐ by increasing the molecular occupational volume near helix 12 of AR. In vitro, the analogues SK33 and SK51 showed very potent antiandrogenic activity, monitored using LNCaP/AR‐Luciferase cells where growth, PSA and luciferase activity were used as AR activity measurements. These compounds were 10-fold more potent than bicalutamide and 100-fold more potent than enobosarm within the LNCaP model. These compounds were also active in LNCaP/BicR cells with acquired bicalutamide resistance. In vivo, using the AR‐Luc reporter mice, these drugs showed potent AR inhibitory activity in the prostate and other AR‐expressing tissues e.g. testes, seminal vesicles and brain. These compounds do not inhibit AR activity in the skeletal muscle, and spleen ‐ thus indicating a selective tissue inhibitory profile. These compounds were also active in vivo in the Pb-PTen deletion model. SK33 and SK51 have significantly different and enhanced activity profiles compared to enobosarm, and are ideal candidates for further development for prostate cancer therapy with potentially fewer side effects.

    更新日期:2018-07-14
  • The ATR Inhibitor AZD6738 Synergizes with Gemcitabine In Vitro and In Vivo to Induce Pancreatic Ductal Adenocarcinoma Regression
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Yann Wallez, Charles R. Dunlop, Timothy Isaac Johnson, Siang-Boon Koh, Chiara Fornari, James W.T. Yates, Sandra Bernaldo de Quirós Fernández, Alan Lau, Frances M. Richards, Duncan I. Jodrell

    Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, and overall survival rates have barely improved over the past five decades. The antimetabolite gemcitabine remains part of the standard of care but shows very limited antitumor efficacy. Ataxia telangiectasia and Rad3-related protein (ATR), the apical kinase of the intra–S-phase DNA damage response, plays a central role in safeguarding cells from replication stress and can therefore limit the efficacy of antimetabolite drug therapies. We investigated the ability of the ATR inhibitor, AZD6738, to prevent the gemcitabine-induced intra–S-phase checkpoint activation and evaluated the antitumor potential of this combination in vitro and in vivo . In PDAC cell lines, AZD6738 inhibited gemcitabine-induced Chk1 activation, prevented cell-cycle arrest, and restrained RRM2 accumulation, leading to the strong induction of replication stress markers only with the combination. Moreover, synergistic growth inhibition was identified in a panel of 5 mouse and 7 human PDAC cell lines using both Bliss Independence and Loewe models. In clonogenic assays, the combination abrogated survival at concentrations for which single agents had minor effects. In vivo , AZD6738 in combination with gemcitabine was well tolerated and induced tumor regression in a subcutaneous allograft model of a KrasG12D; Trp53R172H; Pdx-Cre (KPC) mouse cancer cell line, significantly extending survival. Remarkably, the combination also induced regression of a subgroup of KPC autochthonous tumors, which generally do not respond well to conventional chemotherapy. Altogether, our data suggest that AZD6738 in combination with gemcitabine merits evaluation in a clinical trial in patients with PDAC. Mol Cancer Ther; 17(8); 1–13. ©2018 AACR.

    更新日期:2018-07-14
  • The XPO1 Inhibitor Selinexor Inhibits Translation and Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and In Vivo
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Amy Wahba, Barbara H. Rath, John W. O'Neill, Kevin Camphausen, Philip J. Tofilon

    Analysis of the radiation-induced translatome of glioblastoma stem-like cells (GSC) identified an interacting network in which XPO1 serves as a major hub protein. To determine whether this nuclear export protein provides a target for radiosensitization, we defined the effects of clinically relevant XPO1 inhibitor selinexor on the radiosensitivity of glioblastoma cells. As determined by clonogenic survival analysis, selinexor enhanced the radiosensitivity of GSCs but not normal fibroblast cell lines. On the basis of γH2AX foci and neutral comet analyses, selinexor inhibited the repair of radiation-induced DNA double-strand breaks in GSCs, suggesting that the selinexor-induced radiosensitization is mediated by an inhibition of DNA repair. Consistent with a role for XPO1 in the nuclear to cytoplasm export of rRNA, selinexor reduced 5S and 18S rRNA nuclear export in GSCs, which was accompanied by a decrease in gene translation efficiency, as determined from polysome profiles, as well as in protein synthesis. In contrast, rRNA nuclear export and protein synthesis were not reduced in normal cells treated with selinexor. Orthotopic xenografts initiated from a GSC line were then used to define the in vivo response to selinexor and radiation. Treatment of mice bearing orthotopic xenografts with selinexor decreased tumor translational efficiency as determined from polysome profiles. Although selinexor treatment alone had no effect on the survival of mice with brain tumors, it significantly enhanced the radiation-induced prolongation of survival. These results indicate that selinexor enhances the radiosensitivity of glioblastoma cells and suggest that this effect involves the global inhibition of gene translation. Mol Cancer Ther; 17(8); 1–10. ©2018 AACR.

    更新日期:2018-07-14
  • TAS6417, A Novel EGFR Inhibitor Targeting Exon 20 Insertion Mutations
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Shinichi Hasako, Miki Terasaka, Naomi Abe, Takao Uno, Hirokazu Ohsawa, Akihiro Hashimoto, Ryoto Fujita, Kenji Tanaka, Takashige Okayama, Renu Wadhwa, Kazutaka Miyadera, Yoshimi Aoyagi, Kazuhiko Yonekura, Kenichi Matsuo

    Activating mutations in the EGFR gene are important targets in cancer therapy because they are key drivers of non–small cell lung cancer (NSCLC). Although almost all common EGFR mutations, such as exon 19 deletions and the L858R point mutation in exon 21, are sensitive to EGFR-tyrosine kinase inhibitor (TKI) therapies, NSCLC driven by EGFR exon 20 insertion mutations is associated with poor clinical outcomes due to dose-limiting toxicity, demonstrating the need for a novel therapy. TAS6417 is a novel EGFR inhibitor that targets EGFR exon 20 insertion mutations while sparing wild-type (WT) EGFR. In cell viability assays using Ba/F3 cells engineered to express human EGFR, TAS6417 inhibited EGFR with various exon 20 insertion mutations more potently than it inhibited the WT. Western blot analysis revealed that TAS6417 inhibited EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, resulting in caspase activation. These characteristics led to marked tumor regression in vivo in both a genetically engineered model and in a patient-derived xenograft model. Furthermore, TAS6417 provided a survival benefit with good tolerability in a lung orthotopic implantation mouse model. These findings support the clinical evaluation of TAS6417 as an efficacious drug candidate for patients with NSCLC harboring EGFR exon 20 insertion mutations. Mol Cancer Ther; 17(8); 1–11. ©2018 AACR.

    更新日期:2018-07-14
  • A Raf-Competitive K-Ras Binder Can Fail to Functionally Antagonize Signaling
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-13
    Monique J. Kauke, Alison W. Tisdale, Ryan L. Kelly, Christian J. Braun, Michael T. Hemann, K. Dane Wittrup

    Mutated in approximately 30% of human cancers, Ras GTPases are the most common drivers of oncogenesis and render tumors unresponsive to many standard therapies. Despite decades of research, no drugs directly targeting Ras are currently available. We have previously characterized a small protein antagonist of K-Ras, R11.1.6, and demonstrated its direct competition with Raf for Ras binding. Here we evaluate the effects of R11.1.6 on Ras signaling and cellular proliferation in a panel of human cancer cell lines. Through lentiviral transduction, we generated cell lines that constitutively or through induction with doxycycline express R11.1.6 or a control protein YW1 and show specific binding by R11.1.6 to endogenous Ras through microscopy and co-immunoprecipitation experiments. Genetically encoded intracellular expression of this high-affinity Ras antagonist, however, fails to measurably disrupt signaling through either the MAPK or PI3K pathway. Consistently, cellular proliferation was unaffected as well. To understand this lack of signaling inhibition, we quantified the number of molecules of R11.1.6 expressed by the inducible cell lines and developed a simple mathematical model describing the competitive binding of Ras by R11.1.6 and Raf. This model supports a potential mechanism for the lack of biological effects that we observed, suggesting stoichiometric and thermodynamic barriers that should be overcome in pharmacologic efforts to directly compete with downstream effector proteins localized to membranes at very high effective concentrations. Mol Cancer Ther; 17(8); 1–8. ©2018 AACR.

    更新日期:2018-07-14
  • Therapeutic targeting of KDM1A/LSD1 in Ewing sarcoma with SP-2509 engages the endoplasmic reticulum stress response
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-11
    Kathleen I. Pishas, Christina D Drenberg, Cenny Taslim, Emily R Theisen, Kirsten M Johnson, Ranajeet S Saund, Ioana L Pop, Brian D Crompton, Elizabeth R Lawlor, Franck Tirode, Jaume Mora, Olivier Delattre, Mary C. Beckerle, David F. Callen, Sunil Sharma, Stephen L Lessnick

    Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/LSD1 (Lysine Specific Demethylase 1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P=0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (n=17)( IC50 range 81nM-1593nM), in contrast resistance to the next generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50>300μM). Although TP53/STAG2/CDKN2A status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hyper-sensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum (ER) stress pathway. In addition, ETS1/ HIST1H2BM were specifically induced/repressed respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma.

    更新日期:2018-07-12
  • Targeted Sequencing of Circulating Tumor DNA to Monitor Genetic Variants and Therapeutic Response in Metastatic Colorectal Cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-11
    Hung-Chih Hsu, Nina Lapke, Chuang-Wei Wang, Pei-Yi Lin, Jeng-Fu You, Chien-Yuh Yeh, Wen-Sy Tsai, Hsin-Yuan Hung, Sum-Fu Chang, Hua-Chien Chen, Shu-Jen Chen, An Hsu, Tsai-Sheng Yang

    Substantial improvements have been made in the management of metastatic colorectal cancer (mCRC) in the last two decades, but disease monitoring remains underdeveloped. Circulating tumor DNA (ctDNA) is a promising prognostic and predictive biomarker, however, ctDNA as a marker for mCRC patients is not well-established, and there is still no consensus about how to utilize it most cost-effectively. In this study, we aim to investigate plasma ctDNA levels as a biomarker for therapeutic response of mCRC patients. We performed next generation sequencing (NGS) by using a 12-gene panel to identify genetic variants in 136 tumor tissue and ctDNA samples from 32 mCRC patients. Genetic variants were detected in approximately 70% of samples, and there was a high concordance (85%) between tumor tissue and plasma ctDNA. We observed ctDNA changes in 18 follow-up patients, including the emergence of new variants. Changes in ctDNA levels significantly correlated with tumor shrinkage (P=0.041), and patients with a ctDNA decrease >80% after treatment had a longer progression-free survival compared to patients with a ctDNA decrease <80% (HR=0.22; P=0.015). The objective response rate among patients with a ctDNA decrease >80% was better compared to those with a ctDNA decrease <80% (OR=0.026; P=0.007). In conclusion, this study demonstrates that monitoring of genetic ctDNA variants can serve as a valuable biomarker for therapeutic efficacy in mCRC patients, and that using a moderate-sized 12-gene NGS panel may be suitable for such clinical monitoring.

    更新日期:2018-07-12
  • Modulation of Circulating Protein Biomarkers in Cancer Patients Receiving Bevacizumab and the Anti-Endoglin Antibody TRC105
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-11
    Yingmiao Liu, Mark D Starr, John C Brady, Christel Rushing, Herbert Pang, Bonne Adams, Delia Alvarez, Charles P. Theuer, Herbert I. Hurwitz, Andrew B. Nixon

    TRC105 is an anti-endoglin antibody currently being tested in combination with VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both TRC105 and bevacizumab (BEV) and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-VEGF therapy. Plasma samples were tested for angiogenic and inflammatory biomarkers at baseline and on-treatment. To provide broader context of this combination biomarker study, direct cross-study comparisons were made to biomarker studies previously conducted in patients treated with either BEV or TRC105 monotherapy. Upon treatment with BEV and TRC105, pharmacodynamic changes in response to both BEV (PlGF increase) and TRC105 (soluble endoglin increase) were noted. Additionally, distinct patterns of change were identified (similar, opposing, neutralizing). Similar patterns were observed when the combination elicited similar effects to those observed with monotherapy treatment, (i.e., decreases of Ang-2, increases of IL-6 and VCAM-1). Opposing patterns were observed when the combination led to opposing effects compared to monotherapy treatment (i.e., TGF-1, PDGF-AA and PDGF-BB, PAI-1). Lastly, neutralizing patterns were observed when one drug led to increase, while the other drug led to decrease, and the combination elicited no overall effect on the marker (i.e., VEGF-A, VEGF-D and IGFBP-3). Patients achieving partial responses or stable disease from the combination exhibited significantly lower expression of E-Cadherin, HGF, ICAM-1 and TSP-2 at baseline. Taken together, the novel biomarker modulations identified may deepen our understanding of the underlying biology in patients treated with BEV and TRC105 compared to either drug alone.

    更新日期:2018-07-12
  • A Chemosensitivity Study of Colorectal Cancer Using Xenografts of Patient-Derived Tumor Initiating Cells
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-03
    Hisatsugu Maekawa, Hiroyuki Miyoshi, Tadayoshi Yamaura, Yoshiro Itatani, Kenji Kawada, Yoshiharu Sakai, M. Mark Taketo

    Current genomic and gene expression analyses provide versatile tools to improve cancer chemotherapy. However, it is still difficult to predict whether each patient responds to a particular regimen or not. To predict chemosensitivity in each colorectal cancer patient, we developed an evaluation method using the primary tumor initiating cells (TIC, aka cancer stem cells) xenografted in nude mice subcutaneously (patient-derived spheroid xenografts; PDSXs). Simultaneously, we also prepared the conventional patient-derived xenografts (PDXs) from the same patients' tumors, and compared the dosing results with those of PDSXs. We further compared the chemosensitivities of PDSXs with those of seven patients who had been given regimens such as FOLFOX and FOLFIRI to treat their metastatic lesions. As the results, the PDSX method provided much more precise and predictable tumor growth with less variance than conventional PDX, although both retained the epithelial characteristics of the primary tumors. Likewise, drug-dosing tests showed essentially the same results in PDXs and PDSXs, with stronger statistical power in PDSXs. Notably, the cancer chemosensitivity in each patient was precisely reflected in that of the PDSX mice along the clinical course until the resistance emerged at the terminal stage. This "paraclinical" xenograft trials using PDSXs may help selection of chemotherapy regimens efficacious for each patient, and more importantly, avoiding inefficient ones by which the patient can lose precious time and QOL. Furthermore, the PDSX method may be employed for evaluations of off-label uses of cancer chemotherapeutics and compassionate uses of yet-unapproved new drugs in personalized therapies.

    更新日期:2018-07-04
  • Role of EphB3 receptor in mediating head and neck tumor growth, cell migration, and response to PI3K inhibitor
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-03
    Shilpa Bhatia, Anastacia Griego, Shelby Lennon, Ayman Oweida, Jaspreet Sharma, Christina Rohmer, Nomin Uyanga, Sanjana Bukkapatnam, Benjamin Van Court, David Raben, Christian Young, Lynn Heasley, Sana D. Karam

    Eph proteins have emerged as critical drivers affecting tumor growth and progression in human malignancies. Our TCGA data analysis showed that EphB3, a receptor tyrosine kinase, is frequently co-amplified with PIK3CA in head and neck squamous cell carcinoma (HNSCC). We therefore hypothesized that EphB3 amplification plays a pro-tumorigenic role in HNSCC and that EphB3 and PIK3CA are co-operating oncogenes that contribute toward its pathogenesis. This hypothesis was not experimentally supported since EphB3 knockdown failed to alter HNSCC tumor cell growth in vitro or in vivo with an orthotopic model. However, responsiveness of EphB3 knockdown tumors to the PI3K inhibitor, BKM120, was significantly decreased in terms of both tumor growth delay and survival. This is correlated with an increase in pro-survival proteins, S6 and Bcl-XL in the EphB3 shRNA tumors treated with BKM120 compared to controls. We further observed that EphB3 knockdown resulted in increased migration in vitro and increased EMT gene signature in vivo. To explain these results, we examined EphB3 phosphorylation levels in HNSCC at baseline. While total EphB3 levels were high, we found low phospho-EphB3 levels in HNSCCs. Forced EphB3 phosphorylation with an ephrin-B2-Fc fusion protein resulted in decreased HNSCC migration and cell growth and enhanced response to BKM120 in vitro. These data collectively indicate that progression of HNSCC selects for low/inhibited EphB3 activity to enhance their survival and migratory abilities and decrease response to PI3K signaling. Therefore, strategies focused on activating EphB3 might be helpful to inhibit tumor growth and enhance sensitivity to PI3K inhibitors in HNSCC.

    更新日期:2018-07-04
  • Inhibition of Parp1 by BMN673 effectively sensitizes cells to radiotherapy by upsetting the balance of repair pathways processing DNA double-strand breaks
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-03
    Aashish Soni, Fanghua Li, You Wang, Martha Grabos, Lisa Marie Krieger, Shipra Chaudhary, Mohammad Sharif Mortoga Hasan, Mansoor M. Ahmed, C. Norman Coleman, Beverly A Teicher, Richard L Piekarz, Dian Wang, George E Iliakis

    Parp inhibitors (Parpi) are commonly used as single agents for the management of tumors with homologous recombination repair (HRR) deficiencies, but combination with radiotherapy is not widely considered due to the modest radiosensitization typically observed. BMN673 is one of the most recently developed Parpi and has been shown to mediate strong cell sensitization to methylating agents. Here we explore the mechanisms of BMN673 radiosensitization to killing, aiming to combine it with radiotherapy (RT). We demonstrate markedly stronger radiosensitization by BMN673 at concentrations substantially lower (50nM) than Olaparib (3µM) or AG14361 (0.4µM) and dramatically lower as compared to second generation inhibitors such as PJ34 (5µM). Notably, BMN673 radiosensitization peaks after surprisingly short contact times (~1h) and at pharmacologically achievable concentrations in vivo. BMN673 exerts a complex set of effects on DNA-double strand break (DSB) processing including inhibition of classical non-homologous end joining (cNHEJ) and alternative end joining pathway (altEJ) at high doses of ionizing radiation (IR). BMN673 enhances resection at DSB and favors HRR and altEJ at low clinically relevant IR doses. The combined outcome of these effects is an abrogation in the inherent balance of DSB processing culminating in the formation of chromosomal translocations that underpin radiosensitization. Our observations pave the way to clinical trials exploring inherent benefits in combining BMN673 with RT for the treatment of various forms of cancer.

    更新日期:2018-07-04
  • Drug sensitivity screening and genomic characterization of 45 HPV-negative head and neck carcinoma cell lines for novel biomarkers of drug efficacy
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-03
    Tatiana Lepikhova, Piia-Riitta Karhemo, Riku Louhimo, Bhagwan Yadav, Astrid Murumägi, Evgeny Kulesskiy, Mikko Kivento, Harri Sihto, Reidar Grénman, Stina M Syrjänen, Olli Kallioniemi, Tero Aittokallio, Krister Wennerberg, Heikki Joensuu, Outi Monni

    There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers and point mutations in 45 human papillomavirus negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to EGFR inhibitor erlotinib was validated by gene silencing and from the dataset at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series.

    更新日期:2018-07-04
  • Efficacy of the MDM2 inhibitor SAR405838 in glioblastoma is limited by poor distribution across the blood-brain barrier
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-03
    Minjee Kim, Daniel J Ma, David Calligaris, Shuangling Zhang, Ryan W Feathers, Rachael A Vaubel, Isabelle Meaux, Ann C. Mladek, Karen E. Parrish, Fang Jin, Cedric Barriere, Laurent Debussche, James Watters, Shulan Tian, Paul A. Decker, Jeanette E. Eckel-Passow, Gaspar J. Kitange, Aaron J Johnson, Ian F Parney, Panos Z Anastasiadis, Nathalie Y. R. Agar, William F. Elmquist, Jann N. Sarkaria

    Controversy exists surrounding whether heterogeneous disruption of the blood-brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. In vitro efficacy of SAR405838 was evaluated in PDX models with varying MDM2-expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy. BBB permeability, evaluated using TexasRed-3kDa dextran, was significantly increased in GBM108 through VEGFA over-expression. Drug delivery, magnetic resonance imaging (MRI), and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-amplified PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison to MDM2 control lines in both in vitro and heterotopic models. In contrast to profound efficacy observed in flank xenografts, SAR405838 was ineffective in orthotopic tumors. Although both GBM108-vector and GBM108-VEGFA readily imaged on MRI following gadolinium contrast administration, GBM108-VEGFA tumors had a significantly enhanced drug and gadolinium accumulation, as determined by MALDI-MSI. Enhanced drug delivery in GBM108-VEGFA translated into a marked improvement in orthotopic efficacy. This study clearly shows that limited drug distribution across a partially intact BBB may limit the efficacy of targeted agents in GBM. Brain penetration of targeted agents is a critical consideration in any precision medicine strategy for GBM.

    更新日期:2018-07-04
  • Identification of FDA-approved oncology drugs with selective potency in high-risk childhood ependymoma
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-02
    Andrew M Donson, Vladimir Amani, Elliot A Warner, Andrea M Griesinger, Davis A. Witt, Jean M Mulcahy Levy, Lindsey M Hoffman, Todd C Hankinson, Michael H Handler, Rajeev Vibhakar, Kathleen Dorris, Nicholas K Foreman

    Children with ependymoma are cured in less than 50% of cases, with little improvement in outcome over the last several decades. Chemotherapy has not impacted survival in ependymoma, due in part to a lack of preclinical models that has precluded comprehensive drug testing. We recently developed two human ependymoma cell lines harboring high-risk phenotypes which provided us with an opportunity to execute translational studies. ependymoma and other pediatric brain tumor cell lines were subject to a large-scale comparative drug screen of ependymoma -approved oncology drugs for rapid clinical application. The results of this in vitro study were combined with in silico prediction of drug sensitivity to identify ependymoma -selective compounds, which were validated by dose curve and time course modelling. Mechanisms of ependymoma -selective antitumor effect were further investigated using transcriptome and proteome analyses. We identified three classes of oncology drugs that showed ependymoma -selective anti-tumor effect, namely (i) fluorinated pyrimidines (5-fluorouracil, carmofur and floxuridine), (ii) retinoids (bexarotene, tretinoin and isotretinoin), and (iii) a subset of small-molecule multi-receptor tyrosine kinase inhibitors (axitinib, imatinib and pazopanib). Axitinib's anti-tumor mechanism in ependymoma cell lines involved inhibition of PDGFR-alpha and PDGFR-beta and was associated with reduced mitosis-related gene expression and cellular senescence. The clinically available, ependymoma -selective oncology drugs identified by our study have the potential to critically inform design of upcoming clinical studies in ependymoma, in particular for those children with recurrent ependymoma who are in the greatest need of novel therapeutic approaches.

    更新日期:2018-07-03
  • Highlights of This Issue
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    American Association for Cancer Research

    ### [Chen et al. Page 1575][1] Chen and colleagues analyzed next generation sequencing of 216 advanced thyroid carcinomas identifying prevalent targetable MAPK pathway activating mutations. Secondary mutations in PIK3CA which may confer resistant to single agent targeted therapy were 8x more

    更新日期:2018-07-02
  • Resistance to Systemic Therapies in Clear Cell Renal Cell Carcinoma: Mechanisms and Management Strategies
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Peter Makhov, Shreyas Joshi, Pooja Ghatalia, Alexander Kutikov, Robert G. Uzzo, Vladimir M. Kolenko

    Renal cell carcinoma (RCC) is the most common form of kidney cancer. It is categorized into various subtypes, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. The lack of sensitivity to chemotherapy and radiation therapy prompted research efforts into novel treatment options. The development of targeted therapeutics, including multi-targeted tyrosine kinase inhibitors (TKI) and mTOR inhibitors, has been a major breakthrough in ccRCC therapy. More recently, other therapeutic strategies, including immune checkpoint inhibitors, have emerged as effective treatment options against advanced ccRCC. Furthermore, recent advances in disease biology, tumor microenvironment, and mechanisms of resistance formed the basis for attempts to combine targeted therapies with newer generation immunotherapies to take advantage of possible synergy. This review focuses on the current status of basic, translational, and clinical studies on mechanisms of resistance to systemic therapies in ccRCC. Mol Cancer Ther; 17(7); 1355–64. ©2018 AACR .

    更新日期:2018-07-02
  • Targeted Therapy-based Combination Treatment in Rhabdomyosarcoma
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Anke E.M. van Erp, Yvonne M.H. Versleijen-Jonkers, Winette T.A. van der Graaf, Emmy D.G. Fleuren

    Targeted therapies have revolutionized cancer treatment; however, progress lags behind in alveolar (ARMS) and embryonal rhabdomyosarcoma (ERMS), a soft-tissue sarcoma mainly occurring at pediatric and young adult age. Insulin-like growth factor 1 receptor (IGF1R)-directed targeted therapy is one of the few single-agent treatments with clinical activity in these diseases. However, clinical effects only occur in a small subset of patients and are often of short duration due to treatment resistance. Rational selection of combination treatments of either multiple targeted therapies or targeted therapies with chemotherapy could hypothetically circumvent treatment resistance mechanisms and enhance clinical efficacy. Simultaneous targeting of distinct mechanisms might be of particular interest in this regard, as this affects multiple hallmarks of cancer at once. To determine the most promising and clinically relevant targeted therapy–based combination treatments for ARMS and ERMS, we provide an extensive overview of preclinical and (early) clinical data concerning a variety of targeted therapy–based combination treatments. We concentrated on the most common classes of targeted therapies investigated in rhabdomyosarcoma to date, including those directed against receptor tyrosine kinases and associated downstream signaling pathways, the Hedgehog signaling pathway, apoptosis pathway, DNA damage response, cell-cycle regulators, oncogenic fusion proteins, and epigenetic modifiers. Mol Cancer Ther; 17(7); 1365–80. ©2018 AACR .

    更新日期:2018-07-02
  • ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNF{alpha}-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    George A. Ward, Edward J. Lewis, Jong Sook Ahn, Christopher N. Johnson, John F. Lyons, Vanessa Martins, Joanne M. Munck, Sharna J. Rich, Tomoko Smyth, Neil T. Thompson, Pamela A. Williams, Nicola E. Wilsher, Nicola G. Wallis, Gianni Chessari

    Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue, direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of noncanonical NF-κB signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNFα-dependent induction of apoptosis in various cancer cell lines in vitro , whereas dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase I–II clinical trial ([NCT02503423][1]), and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective. Mol Cancer Ther; 17(7); 1381–91. ©2018 AACR . [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02503423&atom=%2Fmolcanther%2F17%2F7%2F1381.atom

    更新日期:2018-07-02
  • A Short BRCA2-Derived Cell-Penetrating Peptide Targets RAD51 Function and Confers Hypersensitivity toward PARP Inhibition
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Anika Trenner, Julia Godau, Alessandro A. Sartori

    Under conditions of genotoxic stress, cancer cells strongly rely on efficient DNA repair to survive and proliferate. The human BRCA2 tumor suppressor protein is indispensable for the repair of DNA double-strand breaks by homologous recombination (HR) by virtue of its ability to promote RAD51 loading onto single-stranded DNA. Therefore, blocking the interaction between BRCA2 and RAD51 could significantly improve the efficacy of conventional anticancer therapies. However, targeting protein–protein interaction (PPI) interfaces has proven challenging because flat and large PPI surfaces generally do not support binding of small-molecule inhibitors. In contrast, peptides are more potent for targeting PPIs but are otherwise difficult to deliver into cells. Here, we report that a synthetic 16-mer peptide derived from the BRC4 repeat motif of BRCA2 is capable of blocking RAD51 binding to BRCA2. Efficient noncytotoxic cellular uptake of a nona-arginine (R9)-conjugated version of the BRC4 peptide interferes with DNA damage–induced RAD51 foci formation and HR. Moreover, transduction of the BRC4 peptide impairs replication fork–protective function of BRCA2 and triggers MRE11-dependent degradation of nascent DNA in response to DNA replication stress. Finally, the BRC4 cell-penetrating peptide (CPP) confers selective hypersensitivity to PARP inhibition in cancer cells but spares noncancerous cells. Taken together, our data highlight an innovative approach to develop novel peptide-based DNA repair inhibitors and establish BRCA2-derived CPPs as promising anticancer agents. Mol Cancer Ther; 17(7); 1392–404. ©2018 AACR .

    更新日期:2018-07-02
  • A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Viktoryia Sidarovich, Marilena De Mariano, Sanja Aveic, Michael Pancher, Valentina Adami, Pamela Gatto, Silvia Pizzini, Luigi Pasini, Michela Croce, Federica Parodi, Flora Cimmino, Marianna Avitabile, Laura Emionite, Michele Cilli, Silvano Ferrini, Aldo Pagano, Mario Capasso, Alessandro Quattrone, Gian Paolo Tonini, Luca Longo

    Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anticancer compounds library. In the primary screening, we employed three NB cell lines, grown as three-dimensional (3D) multicellular spheroids, which were treated with 10 μmol/L of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high-content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in two-dimensional and 3D models. Dose-response curves were then supplemented with the data on side effects, therapeutic index, and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell-cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy. Mol Cancer Ther; 17(7); 1405–15. ©2018 AACR .

    更新日期:2018-07-02
  • Targeting the Proteasome-Associated Deubiquitinating Enzyme USP14 Impairs Melanoma Cell Survival and Overcomes Resistance to MAPK-Targeting Therapies
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Robin Didier, Aude Mallavialle, Rania Ben Jouira, Marie Angela Domdom, Mélanie Tichet, Patrick Auberger, Frédéric Luciano, Mickael Ohanna, Sophie Tartare-Deckert, Marcel Deckert

    Advanced cutaneous melanoma is one of the most challenging cancers to treat because of its high plasticity, metastatic potential, and resistance to treatment. New targeted therapies and immunotherapies have shown remarkable clinical efficacy. However, such treatments are limited to a subset of patients and relapses often occur, warranting validation of novel targeted therapies. Posttranslational modification of proteins by ubiquitin coordinates essential cellular functions, including ubiquitin-proteasome system (UPS) function and protein homeostasis. Deubiquitinating enzymes (DUB) have been associated to multiple diseases, including cancer. However, their exact involvement in melanoma development and therapeutic resistance remains poorly understood. Using a DUB trap assay to label cellular active DUBs, we have observed an increased activity of the proteasome-associated DUB, USP14 (Ubiquitin-specific peptidase 14) in melanoma cells compared with melanocytes. Our survey of public gene expression databases indicates that high expression of USP14 correlates with melanoma progression and with a poorer survival rate in metastatic melanoma patients. Knockdown or pharmacologic inhibition of USP14 dramatically impairs viability of melanoma cells irrespective of the mutational status of BRAF, NRAS , or TP53 and their transcriptional cell state, and overcomes resistance to MAPK-targeting therapies both in vitro and in human melanoma xenografted mice. At the molecular level, we find that inhibition of USP14 rapidly triggers accumulation of poly-ubiquitinated proteins and chaperones, mitochondrial dysfunction, ER stress, and a ROS production leading to a caspase-independent cell death. Our results provide a rationale for targeting the proteasome-associated DUB USP14 to treat and combat melanomas. Mol Cancer Ther; 17(7); 1416–29. ©2018 AACR .

    更新日期:2018-07-02
  • MKAD-21 Suppresses the Oncogenic Activity of the miR-21/PPP2R2A/ERK Molecular Network in Bladder Cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Marina Koutsioumpa, Hsiao-Wang Chen, Neil O'Brien, Filippos Koinis, Swapna Mahurkar-Joshi, Christina Vorvis, Artin Soroosh, Tong Luo, Shawnt Issakhanian, Allan J. Pantuck, Vassilis Georgoulias, Dimitrios Iliopoulos, Dennis J. Slamon, Alexandra Drakaki

    Bladder cancer represents a disease associated with significant morbidity and mortality. MiR-21 has been found to have oncogenic activity in multiple cancers, including bladder cancer, whereas inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in bladder cancer and evaluate the effects of i.v. and i.p. administration of a novel miR-21 chemical inhibitor in vivo . LNA miR-21 reduced the oncogenic potential of bladder cancer cells, whereas the MKAD-21 chemically modified antisense oligo against miR-21 dose-dependently blocked xenograft growth. I.v. administration of LNA miR-21 was more effective in suppressing tumor growth than was i.p. administration. Integration of computational and transcriptomic analyses in a panel of 28 bladder cancer lines revealed a 15-gene signature that correlates with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit Balpha ( PPP2R2A) was one of these 15 genes and was experimentally validated as a novel miR-21 direct target gene. Gene network and molecular analyses showed that PPP2R2A is a potent negative regulator of the ERK pathway activation and bladder cancer cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21–induced oncogenic effects in bladder cancer. Integrative analysis of human bladder cancer tumors and a large panel of human bladder cancer cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. Importantly, we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and bladder cancer cell growth. Furthermore, i.v. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A–ERK network in mice. Mol Cancer Ther; 17(7); 1430–40. ©2018 AACR .

    更新日期:2018-07-02
  • Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Guangmin Li, Jun Guo, Ben-Quan Shen, Daniela Bumbaca Yadav, Mark X. Sliwkowski, Lisa M. Crocker, Jennifer A. Lacap, Gail D. Lewis Phillips

    The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla, T-DM1), an antibody–drug conjugate that is comprised of trastuzumab covalently linked to the antimitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1–resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and upregulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1–resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1–resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss–induced resistance in T-DM1–resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. Mol Cancer Ther; 17(7); 1441–53. ©2018 AACR . This article is featured in Highlights of This Issue, [p. 1353][1] [1]: /lookup/volpage/17/1353?iss=7

    更新日期:2018-07-02
  • Antibody-Dependent Cellular Phagocytosis by Macrophages is a Novel Mechanism of Action of Elotuzumab
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Ahmed T. Kurdi, Siobhan V. Glavey, Natalie A. Bezman, Amy Jhatakia, Jennifer L. Guerriero, Salomon Manier, Michele Moschetta, Yuji Mishima, Aldo Roccaro, Alexandre Detappe, Chia-Jen Liu, Antonio Sacco, Daisy Huynh, Yu-Tzu Tai, Michael D. Robbins, Jamil Azzi, Irene M. Ghobrial

    Elotuzumab, a recently approved antibody for the treatment of multiple myeloma, has been shown to stimulate Fcγ receptor (FcγR)-mediated antibody-dependent cellular cytotoxicity by natural killer (NK) cells toward myeloma cells. The modulatory effects of elotuzumab on other effector cells in the tumor microenvironment, however, has not been fully explored. Antibody-dependent cellular phagocytosis (ADCP) is a mechanism by which macrophages contribute to antitumor potency of monoclonal antibodies. Herein, we studied the NK cell independent effect of elotuzumab on tumor-associated macrophages using a xenograft tumor model deficient in NK and adaptive immune cells. We demonstrate significant antitumor efficacy of single-agent elotuzumab in immunocompromised xenograft models of multiple myeloma, which is in part mediated by Fc–FcγR interaction of elotuzumab with macrophages. Elotuzumab is shown in this study to induce phenotypic activation of macrophages in vivo and mediates ADCP of myeloma cells though a FcγR-dependent manner in vitro . Together, these findings propose a novel immune-mediated mechanism by which elotuzumab exerts anti-myeloma activity and helps to provide rationale for combination therapies that can enhance macrophage activity. Mol Cancer Ther; 17(7); 1454–63. ©2018 AACR .

    更新日期:2018-07-02
  • Mechanistic Investigations of Diarrhea Toxicity Induced by Anti-HER2/3 Combination Therapy
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Annie Moisan, Francesca Michielin, Wolfgang Jacob, Sven Kronenberg, Sabine Wilson, Blandine Avignon, Régine Gérard, Fethallah Benmansour, Christine McIntyre, Georgina Meneses-Lorente, Max Hasmann, Andreas Schneeweiss, Martin Weisser, Céline Adessi

    Combination of targeted therapies is expected to provide superior efficacy in the treatment of cancer either by enhanced antitumor activity or by preventing or delaying the development of resistance. Common challenges in developing combination therapies include the potential of additive and aggravated toxicities associated with pharmacologically related adverse effects. We have recently reported that combination of anti-HER2 and anti-HER3 antibodies, pertuzumab and lumretuzumab, along with paclitaxel chemotherapy in metastatic breast cancer, resulted in a high incidence of diarrhea that ultimately limited further clinical development of this combination. Here, we further dissected the diarrhea profile of the various patient dose cohorts and carried out in vitro investigations in human colon cell lines and explants to decipher the contribution and the mechanism of anti-HER2/3 therapeutic antibodies to intestinal epithelium malfunction. Our clinical investigations in patients revealed that while dose reduction of lumretuzumab, omission of pertuzumab loading dose, and introduction of a prophylactic antidiarrheal treatment reduced most severe adverse events, patients still suffered from persistent diarrhea during the treatment. Our in vitro investigations showed that pertuzumab and lumretuzumab combination treatment resulted in upregulation of chloride channel activity without indication of intestinal barrier disruption. Overall, our findings provide a mechanistic rationale to explore alternative of conventional antigut motility using medication targeting chloride channel activity to mitigate diarrhea of HER combination therapies. Mol Cancer Ther; 17(7); 1464–74. ©2018 AACR .

    更新日期:2018-07-02
  • Selective Targeting and Eradication of LGR5+ Cancer Stem Cells Using RSPO-Conjugated Doxorubicin Liposomes
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Jing Cao, Chong Li, Xiaohui Wei, Meiqing Tu, Yan Zhang, Fengwei Xu, Yuhong Xu

    Cancer stem cells (CSC) that may account for only a small fraction of tumor mass were found to play crucial roles during tumor initiating, progression, and metastasis. However, they are usually difficult to be treated and notoriously resilient to drug eradication. In this study, we aimed at the Wnt signaling characteristic of CSCs and designed a liposomal drug delivery system to target CSCs. Liposomes decorated with RSPO1 on the surface were constructed for specific interactions with the Wnt pathway coreceptor LGR5. Doxorubicin carried by the RSPO1-liposomes was more effective at lower concentrations than the same drug loaded in PEG-liposomes. More importantly, we showed using a patient-derived xenograft tumor model where LGR5+ CSCs coexisted with LGR5− cells, the RSPO1-liposomes were able to access more CSC cells and deliver the drug specifically and efficiently. Such a focused effect in eradicating LGR5+ cells led to massive tumor tissue necrosis and growth inhibition even when only a fraction of the conventional drug dose was used. These data clearly demonstrated the advantages of CSC-targeted drug delivery and would support the development of such approaches as a new cancer treatment strategy. Mol Cancer Ther; 17(7); 1475–85. ©2018 AACR .

    更新日期:2018-07-02
  • Improving the In Vivo Efficacy of an Anti-Tac (CD25) Immunotoxin by Pseudomonas Exotoxin A Domain II Engineering
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Gilad Kaplan, Ronit Mazor, Fred Lee, Youjin Jang, Yasmin Leshem, Ira Pastan

    Tac (CD25) is expressed on multiple hematologic malignancies and is a target for cancer therapies. LMB-2 is an extremely active anti-Tac recombinant immunotoxin composed of an Fv that binds to Tac and a 38-kDa fragment of Pseudomonas exotoxin A (PE38). Although LMB-2 has shown high cytotoxicity toward Tac-expressing cancer cells in clinical trials, its efficacy was hampered by the formation of anti-drug antibodies against the immunogenic bacterial toxin and by dose-limiting off-target toxicity. To reduce toxin immunogenicity and nonspecific toxicity, we introduced six point mutations into domain III that were previously shown to reduce T-cell immunogenicity and deleted domain II from the toxin, leaving only the 11aa furin cleavage site, which is required for cytotoxic activity. Although this strategy has been successfully implemented for mesothelin and CD22-targeting immunotoxins, we found that removal of domain II significantly lowered the cytotoxic activity of anti-Tac immunotoxins. To restore cytotoxic activity in the absence of PE domain II, we implemented a combined rational design and screening approach to isolate highly active domain II–deleted toxin variants. The domain II–deleted variant with the highest activity contained an engineered disulfide-bridged furin cleavage site designed to mimic its native conformation within domain II. We found that this approach restored 5-fold of the cytotoxic activity and dramatically improved the MTD. Both of these improvements led to significantly increased antitumor efficacy in vivo . We conclude that the next-generation anti-Tac immunotoxin is an improved candidate for targeting Tac-expressing malignancies. Mol Cancer Ther; 17(7); 1486–93. ©2018 AACR .

    更新日期:2018-07-02
  • A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Tomomi Nakayama Iwata, Chiaki Ishii, Saori Ishida, Yusuke Ogitani, Teiji Wada, Toshinori Agatsuma

    Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system–activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only rechallenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd upregulated CD86 expression on bone marrow–derived dendritic cells (DC) in vitro and that DS-8201a increased tumor-infiltrating DCs and upregulated their CD86 expression in vivo . DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti–PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of rechallenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti–PD-1 antibody, possibly due to increased T-cell activity and upregulated PD-L1 expression induced by DS-8201a. Mol Cancer Ther; 17(7); 1494–503. ©2018 AACR .

    更新日期:2018-07-02
  • Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Satarupa Sengupta, Matthew Sobo, Kyungwoo Lee, Shiva Senthil Kumar, Angela R. White, Ilgen Mender, Christine Fuller, Lionel M.L. Chow, Maryam Fouladi, Jerry W. Shay, Rachid Drissi

    Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Hence, there is an urgent need to identify actionable targets and to develop more effective therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), and high-risk medulloblastoma. We have previously shown that DIPG, HGG, and medulloblastoma frequently express telomerase activity. Here, we show that the telomerase-dependent incorporation of 6-thio-2′deoxyguanosine (6-thio-dG), a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction–induced foci (TIF) along with extensive genomic DNA damage, cell growth inhibition, and cell death of primary stem-like cells derived from patients with DIPG, HGG, and medulloblastoma. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G2–M arrest. In vivo treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood–brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, our findings suggest that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors. Mol Cancer Ther; 17(7); 1504–14. ©2018 AACR . This article is featured in Highlights of This Issue, [p. 1353][1] [1]: /lookup/volpage/17/1353?iss=7

    更新日期:2018-07-02
  • Involvement of Prokineticin 2-expressing Neutrophil Infiltration in 5-Fluorouracil-induced Aggravation of Breast Cancer Metastasis to Lung
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Soichiro Sasaki, Tomohisa Baba, Hayato Muranaka, Yamato Tanabe, Chiaki Takahashi, Seiichi Matsugo, Naofumi Mukaida

    Adjuvant chemotherapy is used for human breast cancer patients, even after curative surgery of primary tumor, to prevent tumor recurrence primarily as a form of metastasis. However, anticancer drugs can accelerate metastasis in several mouse metastasis models. Hence, we examined the effects of postsurgical administration with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide, on lung metastasis process, which developed after the resection of the primary tumor arising from the orthotopic injection of a mouse triple-negative breast cancer cell line, 4T1. Only 5-FU markedly increased the numbers and sizes of lung metastasis foci, with enhanced tumor cell proliferation and angiogenesis as evidenced by increases in Ki67-positive cell numbers and CD31-positive areas, respectively. 5-FU–mediated augmented lung metastasis was associated with increases in intrapulmonary neutrophil numbers and expression of neutrophilic chemokines, Cxcl1 and Cxcl2 in tumor cells, with few effects on intrapulmonary T-cell or macrophage numbers. 5-FU enhanced Cxcl1 and Cxcl2 expression in 4T1 cells in a NFκB-dependent manner. Moreover, the administration of a neutrophil-depleting antibody or a Cxcr2 antagonist, SB225002, significantly attenuated 5-FU–mediated enhanced lung metastasis with depressed neutrophil infiltration. Furthermore, infiltrating neutrophils and 4T1 cells abundantly expressed prokineticin-2 ( Prok2 ) and its receptor, Prokr1 , respectively. Finally, the administration of 5-FU after the resection of the primary tumor failed to augment lung metastasis in the mice receiving Prokr1 -deleted 4T1 cells. Collectively, 5-FU can enhance lung metastasis by inducing tumor cells to produce Cxcl1 and Cxcl2, which induced the migration of neutrophils expressing Prok2 with a capacity to enhance 4T1 cell proliferation. Mol Cancer Ther; 17(7); 1515–25. ©2018 AACR . This article is featured in Highlights of This Issue, [p. 1353][1] [1]: /lookup/volpage/17/1353?iss=7

    更新日期:2018-07-02
  • RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Bruno Bockorny, Maria Rusan, Wankun Chen, Rachel G. Liao, Yvonne Li, Federica Piccioni, Jun Wang, Li Tan, Aaron R. Thorner, Tianxia Li, Yanxi Zhang, Changhong Miao, Therese Ovesen, Geoffrey I. Shapiro, David J. Kwiatkowski, Nathanael S. Gray, Matthew Meyerson, Peter S. Hammerman, Adam J. Bass

    The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a FGFR1 -dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRK), the TAM family of tyrosine kinases (TYRO3, MERTK, AXL), and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1- and FGFR3-dependent cellular models and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, coinhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant reactivation of RAS–MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR dependencies and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers. Mol Cancer Ther; 17(7); 1526–39. ©2018 AACR .

    更新日期:2018-07-02
  • Targeting AKT with Oridonin Inhibits Growth of Esophageal Squamous Cell Carcinoma In Vitro and Patient-Derived Xenografts In Vivo
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Mengqiu Song, Xuejiao Liu, Kangdong Liu, Ran Zhao, Hai Huang, Yuanyuan Shi, Man Zhang, Silei Zhou, Hua Xie, Hanyong Chen, Yin Li, Yan Zheng, Qiong Wu, Fangfang Liu, Enmin Li, Ann M. Bode, Zigang Dong, Mee-Hyun Lee

    Overexpression or activation of AKT is very well known to control cell growth, survival, and gene expression in solid tumors. Oridonin, an inflammatory medical and diterpenoid compound isolated from Rabdosia rubescens , has exhibited various pharmacologic and physiologic properties, including antitumor, antibacterial, and anti-inflammatory effects. In this study, we demonstrated that oridonin is an inhibitor of AKT and suppresses proliferation of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo . The role of AKT in ESCC was studied using immuno-histochemical analysis of a tumor microarray, the effect of AKT knockdown on cell growth, and treatment of cells with MK-2206, an AKT inhibitor. Oridonin blocked AKT kinase activity and interacted with the ATP-binding pocket of AKT. It inhibited growth of KYSE70, KYSE410, and KYSE450 esophageal cancer cells in a time- and concentration-dependent manner. Oridonin induced arrest of cells in the G2–M cell-cycle phase, stimulated apoptosis, and increased expression of apoptotic biomarkers, including cleaved PARP, caspase-3, caspase-7, and Bims in ESCC cell lines. Mechanistically, we found that oridonin diminished the phosphorylation and activation of AKT signaling. Furthermore, a combination of oridonin and 5-fluorouracil or cisplatin (clinical chemotherapeutic agents) enhanced the inhibition of ESCC cell growth. The effects of oridonin were verified in patient-derived xenograft tumors expressing high levels of AKT. In summary, our results indicate that oridonin acts as an AKT inhibitor to suppress the growth of ESCC by attenuating AKT signaling. Mol Cancer Ther; 17(7); 1540–53. ©2018 AACR .

    更新日期:2018-07-02
  • Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Fengyi Mao, Jie Li, Qian Luo, Ruixin Wang, Yifan Kong, Colin Carlock, Zian Liu, Bennet D. Elzey, Xiaoqi Liu

    Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of β-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling. Mol Cancer Ther; 17(7); 1554–65. ©2018 AACR .

    更新日期:2018-07-02
  • Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Hiroki Ide, Satoshi Inoue, Taichi Mizushima, Guiyang Jiang, Kuang-Hsiang Chuang, Mototsugu Oya, Hiroshi Miyamoto

    Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, dihydrotestosterone treatment lowered the effects of irradiation. Meanwhile, an antiandrogen hydroxyflutamide enhanced them in AR-positive cells cultured in the presence of androgens. AR knockdown or hydroxyflutamide treatment also resulted in a delay in DNA double-strand break repair 4–24 hours after irradiation. We then established “radiation-resistant” sublines and found considerable elevation of the expression of AR as well as DNA repair genes, such as ATR, CHEK1 , and PARP-1 , in these sublines, compared with respective controls. Furthermore, dihydrotestosterone induced the expression of these DNA repair genes in irradiated AR-positive cells, and hydroxyflutamide antagonized the androgen effects. Finally, in a mouse xenograft model, low-dose flutamide was found to enhance the inhibitory effects of irradiation, and its tumor size was similar to that of AR knockdown line with radiation alone. These findings suggest that AR activity inversely correlates with radiosensitivity in bladder cancer. Accordingly, antiandrogenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer. Mol Cancer Ther; 17(7); 1566–74. ©2018 AACR .

    更新日期:2018-07-02
  • Molecular Profile of Advanced Thyroid Carcinomas by Next-Generation Sequencing: Characterizing Tumors Beyond Diagnosis for Targeted Therapy
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Hui Chen, Rajyalakshmi Luthra, Mark J. Routbort, Keyur P. Patel, Maria E. Cabanillas, Russell R. Broaddus, Michelle D. Williams

    Next-generation sequencing (NGS) for molecular diagnostics allows simultaneous testing of activating oncogenes and tumor suppressor mutations in multiple signal pathways. Extended mutational profiling of advanced thyroid cancers may enhance considerations for targeted therapies. We analyzed clinically derived molecular profiling of 216 patients with advanced thyroid carcinoma using NGS (Ion Torrent Personal Genome Machine) from April 2012 to February 2014. We examined substitutions and small indels in 46 or 50 cancer-related genes using Ampliseq Cancer Hotspot panel in respect to tumor diagnosis and clinical correlations. Mutations were common in advanced thyroid carcinomas 154 (71%) predominately in targetable MAPK pathway (146/216, 68%), and several PI3K/AKT pathway (8, 4%; six as comutations). BRAF V600E mutation associated with papillary (94/139, 68%), poorly differentiated (4/39, 10%), and anaplastic (3/12, 25%) carcinomas. NRAS mutations occurred in follicular (5/12, 42%) and poorly differentiated thyroid carcinoma (12/39, 31%). Tumor suppressor mutations (16, 7%) occurred predominantly in TP53 in Hurthle cell (2/5, 40%, the only mutation), in anaplastic (3/12, 25%) and poorly differentiated thyroid carcinoma (4/39, 10%) some as comutations and in papillary thyroid carcinoma (5/139, 4%) always a comutation. Kaplan–Meier analysis of patients with poorly differentiated thyroid carcinoma containing activating mutations who received targeted therapeutics showed improved survival compared to similarly treated patients without mutations in targetable pathways ( P = 0.02). In conclusion, MAPK pathway is the predominant target for therapy in advance thyroid carcinomas; adding NGS enables the identification of comutations associated with resistance ( PI3K/AKT ). Within poorly differentiated thyroid carcinoma, the molecular profile may hold prognostic value in the era of targeted therapy. Mol Cancer Ther; 17(7); 1575–84. ©2018 AACR . This article is featured in Highlights of This Issue, [p. 1353][1] [1]: /lookup/volpage/17/1353?iss=7

    更新日期:2018-07-02
  • Disruption of NSD1 in Head and Neck Cancer Promotes Favorable Chemotherapeutic Responses Linked to Hypomethylation
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Nam Bui, Justin K. Huang, Ana Bojorquez-Gomez, Katherine Licon, Kyle S. Sanchez, Sean N. Tang, Alex N. Beckett, Tina Wang, Wei Zhang, John Paul Shen, Jason F. Kreisberg, Trey Ideker

    Human papillomavirus (HPV)–negative head and neck squamous cell carcinoma (HNSCC) represents a distinct classification of cancer with worse expected outcomes. Of the 11 genes recurrently mutated in HNSCC, we identify a singular and substantial survival advantage for mutations in the gene encoding Nuclear Set Domain Containing Protein 1 ( NSD1 ), a histone methyltransferase altered in approximately 10% of patients. This effect, a 55% decrease in risk of death in NSD1 -mutated versus non-mutated patients, can be validated in an independent cohort. NSD1 alterations are strongly associated with widespread genome hypomethylation in the same tumors, to a degree not observed for any other mutated gene. To address whether NSD1 plays a causal role in these associations, we use CRISPR-Cas9 to disrupt NSD1 in HNSCC cell lines and find that this leads to substantial CpG hypomethylation and sensitivity to cisplatin, a standard chemotherapy in head and neck cancer, with a 40% to 50% decrease in the IC50 value. Such results are reinforced by a survey of 1,001 cancer cell lines, in which loss-of-function NSD1 mutations have an average 23% decrease in cisplatin IC50 value compared with cell lines with wild-type NSD1 . Significance: This study identifies a favorable subtype of HPV–negative HNSCC linked to NSD1 mutation, hypomethylation, and cisplatin sensitivity. Mol Cancer Ther; 17(7); 1585–94. ©2018 AACR .

    更新日期:2018-07-02
  • Clinical Next-Generation Sequencing for Precision Oncology in Rare Cancers
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Roman Groisberg, David S. Hong, Jason Roszik, Filip Janku, Apostolia M. Tsimberidou, Milind Javle, Funda Meric-Bernstam, Vivek Subbiah

    The European Society for Medical Oncology defines rare cancers as 5 or fewer cases per 100,000 persons per year. For many rare cancers, no standard of care exists, and treatment is often extrapolated. Identifying potentially targetable genomic alterations in rare tumors is a rational approach to improving treatment options. We sought to catalog these mutations in rare tumors and to assess their clinical utility. For this retrospective analysis, we selected rare tumor patients from a dataset of patients who underwent clinical tumor genomic profiling. Sarcomas were excluded. To index potentially actionable alterations, patients' reports were reviewed for mutations in cancer-associated genes and pathways. Respective clinical records were abstracted to appraise the benefit of using a targeted therapy approach. Actionable alterations were defined as targeted by a drug available on-label, off-label, or in clinical trials. The 95 patients analyzed had 40 different tumor subtypes, most common being adenoid cystic (13%), cholangiocarcinoma (7%), and metaplastic breast (6%). At least one genomic alteration was identified in 87 patients (92%). The most common identifiable mutations were in TP53 (23%), KRAS (10%), PIK3CA (9%), CDKN2A/B (8%), BRAF (7%), MLL (7%), and ARID1A (6%). Thirty-six patients (38%) with 21 different tumors had at least one potentially actionable alteration. Thirteen patients received targeted therapy. Of these, 4 had a partial response, 6 had stable disease, and 3 had progressive disease as the best response. The addition of genomic profiling to management of rare cancers adds a potential line of therapy for cancers that have little or no standard of care. In our analysis, tumors with a BRAF alteration responded well to BRAF inhibitors. Mol Cancer Ther; 17(7); 1595–601. ©2018 AACR .

    更新日期:2018-07-02
  • Tumor-Independent Host Secretomes Induced By Angiogenesis and Immune-Checkpoint Inhibitors
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Michalis Mastri, Christina R. Lee, Amanda Tracz, Robert S. Kerbel, Melissa Dolan, Yuhao Shi, John M.L. Ebos

    The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. Although TIS can derive from tumor cells directly, nontumor “host” treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral “side effects” of treatment. Here, we describe a comparative transcriptomic and proteomic analysis of host TIS in tissues and plasma from cancer-free mice treated with antibody and receptor tyrosine kinase inhibitors (RTKI) of the VEGF, cMet/ALK, and PD-1 pathways. We found that all cancer therapies elicit TIS independent of tumor growth, with systemic secretory gene change intensity higher in RTKIs compared with antibodies. Our results show that host TIS signatures differ between drug target, drug class, and dose. Notably, protein and gene host TIS signatures were not always predictive for each other, suggesting limitations to transcriptomic-only approaches to clinical biomarker development for circulating proteins. Together, these are the first studies to assess and compare “off-target” host secretory effects of VEGF and PD-1 pathway inhibition that occur independent of tumor stage or tumor response to therapy. Testing treatment impact on normal tissues to establish host-mediated TIS signatures (or “therasomes”) may be important for identifying disease agnostic biomarkers to predict benefits (or limitations) of drug combinatory approaches. Mol Cancer Ther; 17(7); 1602–12. ©2018 AACR .

    更新日期:2018-07-02
  • Photodynamic Therapy Using Indocyanine Green Loaded on Super Carbonate Apatite as Minimally Invasive Cancer Treatment
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-07-01
    Koki Tamai, Tsunekazu Mizushima, Xin Wu, Akira Inoue, Minori Ota, Yuhki Yokoyama, Norikatsu Miyoshi, Naotsugu Haraguchi, Hidekazu Takahashi, Junichi Nishimura, Taishi Hata, Chu Matsuda, Yuichiro Doki, Masaki Mori, Hirofumi Yamamoto

    Minimally invasive treatment is getting more and more important in an aging society. The purpose of this study was to explore the possibility of ICG loaded on super carbonate apatite (sCA) nanoparticles as a novel photodynamic therapy (PDT) against cancers. Using colon cancer cells, ICG uptake and anti-tumor effects were examined between the treatments of ICG and sCA-ICG. Reactive oxygen species (ROS) production and temperature rise were also evaluated to explore the underlying mechanism. Atomic force microscopy revealed that the size of sCA-ICG ranged from 10 to 20 nm. In aqueous solution with 0.5% albumin, the temperature increase after laser irradiation was 27.1°C and 23.1°C in sCA-ICG and ICG, respectively (control DW: 5.7°C). A significant increase in ROS generation was noted in cell cultures treated with sCA-ICG plus irradiation compared with those treated with ICG plus irradiation ( P < 0.01). Uptake of ICG in the tumor cells significantly increased in sCA-ICG compared with ICG in vitro and in vivo . The fluorescence signals of ICG in the tumor, liver, and kidney faded away in both treatments by 24 hours. Finally, the HT29 tumors treated with sCA-ICG followed by irradiation exhibited drastic tumor growth retardation ( P < 0.01), whereas irradiation of tumors after injection of ICG did not inhibit tumor growth. This study shows that sCA is a useful vehicle for ICG-based PDT. Quick withdrawal of ICG from normal organs is unique to sCA-ICG and contrasts with the other nanoparticles remaining in normal organs for a long time. Mol Cancer Ther; 17(7); 1613–22. ©2018 AACR .

    更新日期:2018-07-02
  • Dual targeting of ErbB2/ErbB3 for treatment of SLC3A2-NRG1-mediated lung cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-29
    Dong Hoon Shin, Jeong Yeon Jo, Ji-Youn Han

    We characterized the SLC3A2-NRG1 fusion gene in non-small cell lung cancer (NSCLC) and established an effective therapy for patients with SLC3A2-NRG1 fusion-positive cancer. The SLC3A2-NRG1 fusion product was composed of the SLC3A2 transmembrane domain and the epidermal growth factor (EGF)-like domain of the neuregulin 1 (NRG1) protein. The NRG1 family is classified as a ligand of the ERBB family. We identified ERBB3 and ERBB4 in the ERBB family as binding partners of the SLC3A2-NRG1 fusion protein via ligand and receptor binding assays. We confirmed that SLC3A2-NRG1 increased formation of a heterocomplex of ERBB3 with ERBB2. Activation of the ERBB2-ERBB3 heterocomplex by SLC3A2-NRG1 increased colony formation and tumor growth through PI3K-AKT and MAP kinase. The specific siRNAs for ERBB2 and ERBB3, pertuzumab, lumretuzumab, and afatinib all decreased ERBB2-ERBB3 heterocomplex formation, phosphorylation of each protein, and their downstream signaling. In addition, single treatment with pertuzumab, lumretuzumab, or afatinib decreased tumor volume and weight, whereas combination treatment with these drugs and taxol enhanced generation of cleaved-caspase 3, PARP, and TUNEL-positive cells compared with each single treatment. Thus, the SLC3A2-NRG1 fusion gene plays an important role in lung cancer cell proliferation and tumor growth by promoting generation of the ERBB2-ERBB3 heterocomplex, its phosphorylation, and activation of the PI3K/ERK/mTOR signaling pathway. Inhibition of either ERBB2 or ERBB3 alone did not completely shut down downstream signaling of ERBB2 and ERBB3; however, inhibition of both ERBB2 and ERBB3 blocked downstream signaling activated by SLC3A2-NRG1 fusion. ERBB2 and ERBB3 might be promising targets for treatment of SLC3A2-NRG1-positive tumors.

    更新日期:2018-07-01
  • A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-29
    Maria Cristina Manara, Sergio Valente, Camilla Cristalli, Giordano Nicoletti, Lorena Landuzzi, Clemens Zwergel, Roberta Mazzone, Giulia Stazi, Paola B Arimondo, Michela Pasello, Clara Guerzoni, Piero Picci, Patrizia Nanni, Pier-Luigi Lollini, Antonello Mai, Katia Scotlandi

    The identification of new therapeutic strategies against osteosarcoma (OS), the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. OS originates from the transformation of mesenchymal stem cells (MSCs) and/or osteoblast progenitors, and the loss of differentiation is a common biological OS feature which strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel non-nucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking OS cells in G1 or G2/M phases and induced osteoblastic differentiation through the specific re-expression of genes regulating this physiological process. While MC3343 has a similar antiproliferative effect as 5azadC, the conventional FDA-approved nucleoside inhibitor of DNA methylation, its effects on cell differentiation are distinct. Induction of the mature osteoblast phenotype coupled with a sustained cytostatic response was also confirmed in vivo when MC3343 was used against a patient-derived xenograft (PDX). In addition, MC3343 displayed synergistic effects with doxorubicin (DXR) and cisplatin (CDDP), two major chemotherapeutic agents used to treat OS. Specifically, MC3343 increased stable DXR bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this non-nucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for OS patients who respond poorly to pre-adjuvant chemotherapy.

    更新日期:2018-07-01
  • Targeting Notch1 and IKKa enhanced NF-{kappa}B activation in CD133+ Skin Cancer Stem Cells
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-29
    Xin Xin Quan, Nga Voong Hawk, Weiping Chen, Jamie Coupar, Steven Lee, David W. Petersen, Paul S. Meltzer, Andrew Montemarano, Martin Braun, Zhong Chen, Carter Van Waes

    Cancer stem-like cells are hypothesized to be the major tumor initiating cell population of human cutaneous squamous cell carcinoma (cSCC), but the landscape of molecular alterations underpinning their signaling and cellular phenotypes as drug targets remain undefined. In this study, we developed an experimental pipeline to isolate a highly enriched CD133+CD31-CD45-CD61-CD24- (CD133+) cell population from primary cSCC specimens by flow cytometry. The CD133+ cells show enhanced stem-like phenotypes, which were verified by spheroid and colony formation in vitro and tumor generation in vivo. Gene expression profiling of CD133+/- cells was compared and validated, and differentially expressed gene signatures and top pathways were identified. CD133+ cells expressed a repertoire of stemness and cancer related genes, including NOTCH and NOTCH1-mediated NF-kB pathway signaling. Other cancer-related genes from WNT, growth factor receptors, PI3K/mTOR, STAT pathways, and chromatin modifiers were also identified. Pharmacologic and genetic targeting Notch1, IKKa, RELA and RELB modulated NF-kB transactivation, the CD133+ population, and cellular and stemness phenotypes. Immunofluorescent staining confirmed co-localization of CD133+ and IKKa expression in SCC tumor specimens. Our functional, genetic and pharmacologic studies uncovered a novel linkage between Notch1, IKKα and NF-κB pathway activation in maintaining the CD133+ stem SCC phenotypes. Studies investigating markers of activation and modulators of NOTCH, IKK/NF-kB and other pathways regulating these cancer stem gene signatures could further accelerate the development of effective therapeutic strategies to treat cSCC recurrence and metastasis.

    更新日期:2018-07-01
  • Arsenic trioxide and sorafenib induce synthetic lethality of FLT3-ITD acute myeloid leukemia cells
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-29
    Rui Wang, Ying Li, Ping Gong, Janice Gabrilove, Samuel Waxman, Yongkui Jing

    Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity, produces an impressive but short-lived remission in FLT3-ITD AML patients. The second, arsenic trioxide (ATO), at therapeutically achievable concentrations, reduces the level of FLT3-ITD and Mcl-1 proteins, and induces apoptosis in leukemic cell lines and in primary cells expressing FLT3-ITD. We linked this relative sensitivity to ATO to low levels of reduced glutathione. While producing proapoptotic effects, ATO treatment also has an unwanted effect whereby it causes the accumulation of the phosphorylated (inactive) form of glycogen synthase kinase 3β (GSK-3β), a kinase necessary for apoptosis. When ATO is combined with Sorafenib, GSK-3β is activated, Mcl-1 is further reduced, and proapoptotic proteins Bak and Bax are activated. Mice xenografted with FLT3-ITD MOLM13 cell line treated with the Sorafenib/ATO combination have significantly improved survival. This combination has potential to improve the therapeutic outcome of FLT3-ITD targeted therapy of AML patients.

    更新日期:2018-07-01
  • Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-26
    Francis P Roche, Ilkka Pietilä, Hiroshi Kaito, Elisabet O Sjöström, Nadine Sobotzki, Oriol Noguer, Tor Persson Skare, Magnus Essand, Bernd Wollscheid, Michael Welsh, Lena Claesson-Welsh

    The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and anti-tumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and co-localization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG treated gliomas displayed decreased numbers of Interleukin-35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control anti-tumor immunity.

    更新日期:2018-06-27
  • Induction of Thioredoxin-Interacting Protein by Histone Deacetylase Inhibitor, Entinostat, Is Associated with DNA Damage and Apoptosis in Esophageal Adenocarcinoma
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-22
    Paul L. Feingold, Deborah R. Surman, Kate Brown, Yuan Xu, Lucas A. McDuffie, Vivek Shukla, Emily S. Reardon, Daniel R. Crooks, Jane B. Trepel, Sunmin Lee, Min-Jung Lee, Shaojian Gao, Sichuan Xi, Kaitlin C McLoughlin, Laurence P. Diggs, David G. Beer, Derek J. Nancarrow, Leonard M Neckers, Jeremy L Davis, Chuong D Hoang, Jonathan M. Hernandez, David S Schrump, R. Taylor Ripley

    In 2017, an estimated 17,000 individuals were diagnosed with esophageal adenocarcinoma (EAC) and less than 20% will survive 5 years. PET-avidity is indicative of high glucose utilization and is nearly universal in EAC. TXNIP blocks glucose uptake and exhibits pro-apoptotic functions. Higher expression in EAC has been associated with improved disease-specific survival, lack of lymph node involvement, reduced perineural invasion, and increased tumor differentiation. We hypothesized that TXNIP may act as a tumor suppressor that sensitizes EAC cells to standard chemotherapeutics. EAC cell lines and a Barrett's epithelial cell line were used. qRT-PCR, immunoblot, and immunofluorescence techniques evaluated gene expression. TXNIP was stably over-expressed or knocked down using lentiviral RNA transduction techniques. Murine xenograft methods examined growth following over-expression of TXNIP. Apoptosis and DNA damage were measured by Annexin V and ɣH2AX assays. Activation of the intrinsic apoptosis was quantitated with green fluorescence protein-caspase 3 reporter assay. In cultured cells and an esophageal tissue array, TXNIP expression was higher in Barrett's epithelia and normal tissue compared to EAC. Constitutive over-expression of TXNIP decreased proliferation, clonogenicity, and tumor xenograft growth. TXNIP overexpression increased whereas knockdown abrogated DNA damage and apoptosis following cisplatin treatment. An HDAC-inhibitor, entinostat (currently in clinical trials), upregulated TXNIP and synergistically increased cisplatin-mediated DNA damage and apoptosis. TXNIP is a tumor suppressor that is down-regulated in EACC. Its re-expression dramatically sensitizes these cells to cisplatin. Our findings support phase I/II evaluation of 'priming' strategies to enhance the efficacy of conventional chemotherapeutics in EAC.

    更新日期:2018-06-25
  • Recombinant MDA-7/IL-24 suppresses prostate cancer bone metastasis through down regulation of the Akt/Mcl-1 pathway
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-22
    Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Luni Emdad, Swadesh K Das, Devanand Sarkar, Paul B Fisher

    Prostate cancer (PC) is a principal cause of cancer-associated morbidity in men. Although 5-year survival of patients with localized PC approaches 100 percent, survival decreases precipitously after metastasis. Bone is the preferred site for disseminated PC cell colonization, altering the equilibrium of bone homeostasis resulting in weak and fragile bones. Currently, no curative options are available for PC bone metastasis. MDA-7/IL-24 is a well-studied cytokine established as a therapeutic in a wide-array of cancers upon delivery as a gene therapy. In this study, we explored the potential anti-cancer properties of MDA-7/IL-24 delivered as a recombinant protein. Using bone metastasis experimental models, animals treated with recombinant MDA-7/IL-24 had significantly less metastatic lesions in their femurs as compared to controls. The inhibitory effects of MDA-7/IL-24 on bone metastasis resulted from PC-selective killing and inhibition of osteoclast differentiation, which is necessary for bone resorption. Gain- and loss-of-function genetic approaches document that pro-survival Akt and Mcl-1 pathways are critically important in the anti-bone metastatic activity of MDA-7/IL-24. Our previous findings showed that MDA-7/IL-24 gene therapy plus Mcl-1 inhibitors cooperate synergistically. Similarly, an Mcl-1 small molecule inhibitor synergized with MDA-7/IL-24 and induced robust anti-bone metastatic activity. These results expand the potential applications of MDA-7/IL-24 as an anti-cancer molecule and demonstrate that purified recombinant protein is non-toxic in pre-clinical animal models and has profound inhibitory effects on bone metastasis, which can be enhanced further when combined with an Mcl-1 inhibitory small molecule.

    更新日期:2018-06-25
  • KDM6B counteracts EZH2-mediated suppression of IGFBP5 to confer resistance to PI3K/AKT inhibitor treatment in breast cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-20
    Wenyu Wang, Keng Gat Lim, Min Feng, Yi Bao, Puay Leng Lee, Cai Yu, Yufeng Chen, Hao Zhang, Diego Marzese, Dave SB Hoon, Qiang Yu

    Despite showing promise against PIK3CA-mutant breast cancers in preclinical studies, phosphatidylinositol-3-kinase (PI3K)/AKT pathway inhibitors demonstrate limited clinical efficacy as monotherapy. Here, we found that histone H3K27me3 demethylase KDM6B-targeted IGFBP5 expression provides a protective mechanism for PI3K/AKT inhibitor-induced apoptosis in breast cancer cells. We found that overexpression of KDM6B and IGFBP5 in luminal breast cancer are positively associated with poorer disease outcomes. Mechanistically, KDM6B promotes IGFBP5 expression by antagonizing EZH2-mediated repression, and pharmacologic inhibition of KDM6B augments apoptotic response to PI3K/AKT inhibitor treatment. Moreover, the IGFBP5 expression is upregulated upon acquired resistance to the PI3K inhibitor GDC-0941, which is associated with an epigenetic switch from H3K27me3 to H3K27Ac at the IGFBP5 gene promoter. Intriguingly, GDC-0941-resistant breast cancer cells remained sensitive to KDM6B or IGFBP5 inhibition, indicating the dependency on KDM6B-IGFBP5 axis to confer the survival advantage in GDC-0941-resistant cells. Our study reveals an epigenetic mechanism associated with resistance to targeted therapy and demonstrates that therapeutic targeting of KDM6B-mediated IGFBP5 expression may provide a useful approach to mitigate both intrinsic and acquired resistance to the PI3K inhibitor in breast cancer.

    更新日期:2018-06-22
  • The Role of Pyruvate Dehydrogenase Kinase-4 (PDK4) in Bladder Cancer and Chemoresistance
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-15
    Benjamin L Woolbright, Dharamainder Choudhary, Andrew Mikhalyuk, Cassandra Trammel, Sambantham Shanmugam, Erika Abbott, Carol C Pilbeam, John A Taylor

    Advanced bladder cancer (BCa) remains a major source of mortality, with poor treatment options. Cisplatin based chemotherapy is the standard treatment, however many patients are or become resistant. One potential cause of chemoresistance is the Warburg Effect, a metabolic switch to aerobic glycolysis that occurs in many cancers. Upregulation of the pyruvate dehydrogenase kinase family (PDK1-4) is associated with aerobic glycolysis and chemoresistance through inhibition of the pyruvate dehydrogenase complex (PDH). We have previously observed upregulation of PDK4 in high grade compared to low grade bladder cancers. We initiated this study to determine if inhibition of PDK4 could reduce tumor growth rates or sensitize BCa cells to cisplatin. Upregulation of PDK4 in malignant BCa cell lines as compared to benign transformed urothelial cells was confirmed using qPCR. Inhibition of PDK4 with dichloroacetate (DCA) resulted in increased PDH activity, reduced cell growth, and G0/G1 phase arrest in BCa cells. Similarly, siRNA knockdown of PDK4 inhibited BCa cell proliferation. Co-treatment of BCa cells with cisplatin and DCA did not increase caspase-3 activity but did enhance overall cell death in vitro. While daily treatment with 200mg/kg DCA alone did not reduce tumor volumes in a xenograft model, combination treatment with cisplatin resulted in dramatically reduced tumor volumes as compared to either DCA or cisplatin alone. This was attributed to substantial intra-tumoral necrosis. These findings indicate inhibition of PDK4 may potentiate cisplatin induced cell death and warrant further studies investigating the mechanism through which this occurs.

    更新日期:2018-06-16
  • Repositioning Dopamine D2 Receptor Agonist Bromocriptine to Enhance Docetaxel Chemotherapy and Treat Bone Metastatic Prostate Cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-15
    Yang Yang, Kenza Mamouni, Xin Li, Yanhua Chen, Sravan Kavuri, Yuhong Du, Haian Fu, Omer Kucuk, Daqing Wu

    Docetaxel resistance remains a major obstacle in the treatment of prostate cancer (PCa) bone metastasis. In this study, we demonstrate that the dopamine D2 receptor (DRD2) agonist bromocriptine effectively enhances docetaxel efficacy and suppresses skeletal growth of PCa in preclinical models. DRD2 is ubiquitously expressed in PCa cell lines, and DRD2 is significantly reduced in PCa tissues with high Gleason score. Bromocriptine has weak to moderate cytotoxicity in PCa cells, but effectively induces cell cycle arrest. At the molecular level, bromocriptine inhibits the expression of c-Myc, E2F-1 and survivin, and increases the expression of p53, p21 and p27. Intriguingly, bromocriptine markedly reduces androgen receptor (AR) levels, partially through heat-shock protein 90 (Hsp90)-mediated protein degradation. The combination of bromocriptine and docetaxel demonstrates enhanced in vitro cytotoxicity in PCa cells and significantly retards the skeletal growth of C4-2-Luc tumors in mice. Collectively, these results provide the first experimental evidence for repurposing bromocriptine as an effective adjunct therapy to enhance docetaxel efficacy in PCa.

    更新日期:2018-06-16
  • Nuclear PTEN localization contributes to DNA damage repair in Endometrial cancer and could have a diagnostic benefit for therapeutic management of the disease.
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-13
    Ananda Mukherjee, Amanda L Patterson, Jitu W George, Tyler J. Carpenter, Zachary B Madaj, Galen Hostetter, John I. Risinger, Jose M. Teixeira

    Endometrial adenocarcinoma (EndoCA) is the most common gynecological cancer type in the US, and its incidence is increasing. The majority of patients are disease-free after surgical resection of stage I tumors, which is often followed by radiation therapy, but most patients with advanced disease recur and have a poor prognosis, largely because the tumors become refractory to cytotoxic chemotherapies. PTEN, a commonly mutated tumor suppressor in EndoCAs, is well known for its ability to inhibit the AKT/mTOR signaling pathway. Nuclear functions for PTEN have been proposed as well, but whether those affect EndoCA development, progression, or outcomes is not well understood. Using immunohistochemistry, nuclear PTEN expression was observed in approximately half of EndoCA patient tumors, independent of grade and cytoplasmic PTEN expression. Higher levels of the DNA damage response (DDR) marker, yH2AX, were observed by immunohistochemistry and immunofluorescence in human EndoCA tumor sections that were PTEN-negative, in murine EndoCA tissues that were genetically modified to be PTEN-null, and in Ishikawa EndoCA cells, which do not express endogenous PTEN. Over-expression of exogenous PTEN-WT or PTEN-NLS, a modified PTEN with an added nuclear localization signal, significantly improved both DDR and G2/M transition in Ishikawa cells treated with a DNA damaging agent. Whereas PARP inhibition with Olaparib was not as effective in Ishikawa cells expressing native or PTEN-NLS, inhibition with Talazoparib was not affected by PTEN overexpression. These results suggest that nuclear PTEN subcellular localization in human EndoCA could be diagnostic when considering DDR therapeutic intervention.

    更新日期:2018-06-14
  • Intra vs Inter Cross-Resistance Determines Treatment Sequence between Taxane and AR-Targeting Therapies in Advanced Prostate Cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-11
    Alan P. Lombard, Liangren Liu, Vito Cucchiara, Chengfei Liu, Cameron M. Armstrong, Ruining Zhao, Joy C Yang, Wei Lou, Christopher P. Evans, Allen C. Gao

    Current treatments for castration resistant prostate cancer (CRPC) largely fall into two major classes; AR-targeted therapies such as the next-generation anti-androgen therapies (NGATs), enzalutamide and abiraterone, and taxanes such as docetaxel and cabazitaxel. Despite improvements in outcomes, patients still succumb to the disease due to the development of resistance. Further complicating the situation is lack of a well-defined treatment sequence and potential for cross-resistance between therapies. We have developed several models representing CRPC with acquired therapeutic resistance. Here, we utilized these models to assess putative cross-resistance between treatments. We find that resistance to enzalutamide induces resistance to abiraterone and vice versa but resistance to neither alters sensitivity to taxanes. Acquired resistance to docetaxel induces cross-resistance to cabazitaxel but not to enzalutamide or abiraterone. Correlating responses with known mechanisms of resistance indicates that androgen receptor (AR) variants are associated with resistance to NGATs while the membrane efflux protein ABCB1 is associated with taxane resistance. Mechanistic studies show that AR variant-7 (AR-v7) is involved in NGAT resistance but not resistance to taxanes. Our findings suggest the existence of intra cross-resistance within a drug class (i.e., within NGATs or within taxanes), while inter cross-resistance between drug classes does not develop. Furthermore, our data suggests resistance mechanisms differ between drug classes. These results may have clinical implications by showing that treatments of one class can be sequenced with those of another, but caution should be taken when sequencing similar classed drugs. Additionally, the development and use of biomarkers indicating resistance will improve patient stratification for treatment.

    更新日期:2018-06-12
  • STAT3 Cyclic Decoy Demonstrates Robust Antitumor Effects in Non-Small Cell Lung Cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-11
    Christian Njatcha, Mariya Farooqui, Adam Kornberg, Daniel E Johnson, Jennifer R. Grandis, Jill M. Siegfried

    Constitutively activated STAT3 plays a critical role in non-small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT 3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type (WT) EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975). These cells are resistant to EGFR inhibitors and require an alternate therapeutic approach. CS3D activity was compared to an inactive cyclic control oligonucleotide (CS3M) that differs by a single base pair, rendering it unable to bind to STAT3 protein. Transfection of 0.3 µM of CS3D caused a 50% inhibition in proliferation in 201T and H1975 cells, relative to CS3M, and a 2-fold increase in apoptotic cells. Toxicity was minimal in normal cells. CS3D treatment caused a significant reduction of mRNA and protein expression of the STAT3 target gene c-Myc, and inhibited colony formation by 70%. The active decoy decreased the nuclear pool of STAT3 compared to the mutant. In a xenograft model, treatments with CS3D (5 mg/kg) caused a potent 96.5% and 81.7% reduction in tumor growth in 201T (P<0.007) and H1975 models (P<.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC.

    更新日期:2018-06-12
  • Anti-PSMA/CD3 Bispecific Antibody Delivery And Anti-Tumor Activity Using A Polymeric Depot Formulation
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-11
    Wilhem Leconet, He Liu, Ming Guo, Sophie Le Lamer-Déchamps, Charlotte Molinier, Sae Kim, Tjasa Vrlinic, Murielle Oster, Fang Liu, Vincent Navarro, Jaspreet S Batra, Adolfo Lopez-Noriega, Sylvestre Grizot, Neil H. Bander

    Small therapeutic proteins represent a promising novel approach to treat cancer. Nevertheless, their clinical application is often adversely impacted by their short plasma half-life. Controlled long-term delivery of small biologicals has become a challenge because of their hydrophilic properties and in some cases their limited stability. Here, an in-situ forming depot injectable polymeric system was used to deliver BiJ591, a Bispecific T-cell Engager (BiTE) targeting both prostate-specific membrane antigen (PSMA) and the CD3 T-cell receptor in prostate cancer. BiJ591 induced T-cell activation, prostate cancer directed cell lysis and tumor growth inhibition. The use of diblock and triblock biodegradable polyethylene glycol - poly(lactic acid) (PEG-PLA) copolymers solubilized in tripropionin, a small chain triglyceride, allowed maintenance of BiJ591 stability and functionality in the formed depot and controlled its release. In mice, after a single subcutaneous injection, one of the polymeric candidates, TB1/DB4, provided the most sustained release of BiJ591 for up to 21 days. Moreover, the use of BiJ591-TB1/DB4 formulation in prostate cancer xenograft models showed significant therapeutic activity in both low and high PSMA expressing tumors whereas daily intravenous administration of BiJ591 was less efficient. Collectively, the present data provide new insights into the development of controlled delivery of small therapeutic proteins in cancer.

    更新日期:2018-06-12
  • AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-11
    Kshitij Verma, Nehal Gupta, Tianzhu Zang, Phumvadee Wangtrakuldee, Sanjay K Srivastava, Trevor M. Penning, Paul C Trippier

    Aldo-keto reductase 1C3 (AKR1C3) also known as type 5 17 β-hydroxysteroid dehydrogenase is responsible for intratumoral androgen biosynthesis, contributing to the development of castration-resistant prostate cancer (CRPC) and eventual chemotherapeutic failure. Significant upregulation of AKR1C3 is observed in CRPC patient samples and derived CRPC cell lines. As AKR1C3 is a downstream steroidogenic enzyme synthesizing intratumoral testosterone (T) and 5α-dihydrotestosterone (DHT), the enzyme represents a promising therapeutic target to manage CRPC and combat the emergence of resistance to clinically employed androgen deprivation therapy. Herein, we demonstrate the antineoplastic activity of a potent, isoform selective and hydrolytically stable AKR1C3 inhibitor (E)-3-(4-(3-methylbut-2-en-1-yl)-3-(3-phenylpropanamido)phenyl)acrylic acid (KV-37) which reduces prostate cancer cell growth in vitro and in vivo, and sensitizes CRPC cell lines (22Rv1 and LNCaP1C3) towards the anti-tumor effects of enzalutamide. Crucially, KV-37 does not induce toxicity in non-malignant WPMY-1 prostate cells nor does it induce weight loss in mouse xenografts. Moreover, KV-37 reduces androgen receptor (AR) transactivation and prostate specific antigen (PSA) expression levels in CRPC cells lines indicative of a therapeutic effect in prostate cancer. Combination studies of KV-37 with enzalutamide reveal a very high degree of synergistic drug interaction that induces significant reduction in prostate cancer cell viability via apoptosis, resulting in >200-fold potentiation of enzalutamide action in drug resistant 22Rv1 cells. These results demonstrate a promising therapeutic strategy for the treatment of drug resistant CRPC that invariably develops in prostate cancer patients following initial treatment with AR antagonists such as enzalutamide.

    更新日期:2018-06-12
  • Intratumoral delivery of an adenoviral vector carrying the SOCS-1 gene enhances T cell-mediated anti-tumor immunity by suppressing PD-L1
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-11
    Satoshi Nakagawa, Satoshi Serada, Reisa Kakubari, Kosuke Hiramatsu, Takahito Sugase, Shinya Matsuzaki, Satoko Matsuzaki, Yutaka Ueda, Kiyoshi Yoshino, Tomoharu Ohkawara, Minoru Fujimoto, Tadamitsu Kishimoto, Tadashi Kimura, Tetsuji Naka

    Ovarian cancer (OvCa) is the leading cause of gynecological cancer-related deaths and novel therapeutic strategies are required. Programmed cell death 1 and programmed cell death ligand 1 (PD-L1), which are key mediators of host immune tolerance, are associated with OvCa progression. Recent evidence indicates the importance of IFN-γ-induced PD-L1 for immune tolerance in OvCa. This study aimed to reveal the therapeutic potential of suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, for the treatment of OvCa. Immunohistochemical assessment revealed that OvCa patients with high intratumoral STAT1 activation exhibited poor prognosis compared with patients with low STAT1 activation (P < 0.05). Stimulation of OVISE, OVTOKO, OV2944-HM-1 (HM-1) and CT26 cell lines with IFN-γ induced STAT1 phosphorylation and PD-L1 expression. Adenovirus-mediated SOCS-1 gene delivery (AdSOCS-1) in HM-1 and CT26 cells in vitro potently inhibited IFN-γ-induced STAT1 phosphorylation and PD-L1 upregulation, similar to the addition of JAK inhibitor I, but failed to inhibit their proliferation. Notably, intratumoral injection of AdSOCS-1, but not AdLacZ, significantly inhibited the tumor growth of HM-1 and CT26 cells subcutaneously transplanted in immunocompetent syngeneic mice. AdSOCS-1 reduced PD-L1 expression on tumors and restored the activation of tumor-infiltrating CD8 T cells. Moreover, the anti-tumor effect of AdSOCS-1 was significantly attenuated by PD-L1 Fc-fusion protein administration in vivo, suggesting that the effect of AdSOCS-1 is mainly attributable to enhancement of tumor immunity. This study highlights the potential clinical utility of SOCS-1 as an immune checkpoint inhibitor.

    更新日期:2018-06-12
  • Glucuronide-linked antibody-tubulysin conjugates display activity in MDR+ and heterogeneous tumor models
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-04
    Patrick J. Burke, Joseph Z Hamilton, Thomas A Pires, Holden W. H. Lai, Christopher I Leiske, Kim K Emmerton, Andrew B Waight, Peter D. Senter, Robert P. Lyon, Scott C. Jeffrey

    While antibody-drug conjugates (ADCs) find increasing applications in cancer treatment, de novo or treatment-emergent resistance mechanisms may impair clinical benefit. Two resistance mechanisms that emerge under prolonged exposure include upregulation of transporter proteins that confer multidrug resistance (MDR+) and loss of cognate antigen expression. New technologies that circumvent these resistance mechanisms may serve to extend the utility of next generation ADCs. Recently, we developed the quaternary ammonium linker system to expand the scope of conjugatable payloads to include tertiary amines and applied the linker to tubulysins, a highly potent class of tubulin binders that maintain activity in MDR+ cell lines. In this work, tubulysin M, which contains an unstable acetate susceptible to enzymatic hydrolysis, and two stabilized tubulysin analogues, were prepared as quaternary ammonium-linked glucuronide-linkers and assessed as ADC payloads in preclinical models. The conjugates were potent across a panel of cancer cell lines and active in tumor xenografts, including those displaying the MDR+ phenotype. The ADCs also demonstrated potent bystander activity in a co-culture model comprised of a mixture of antigen-positive and -negative cell lines, and in an antigen-heterogeneous tumor model. Thus, the glucuronide-tubulysin drug-linkers represent a promising ADC payload class, combining conjugate potency in the presence of the MDR+ phenotype and robust activity in models of tumor heterogeneity in a structure-dependent manner.

    更新日期:2018-06-05
  • Development of MGD007, a gpA33 x CD3 bispecific DART(R) protein for T-cell immunotherapy of metastatic colorectal cancer
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-04
    Paul A Moore, Kalpana Shah, Yinhua Yang, Ralph Alderson, Penny Roberts, Vatana Long, Daorong Liu, Jonathan C Li, Steve Burke, Valentina Ciccarone, Hua Li, Claudia B Fieger, Jeff Hooley, Ann Easton, Monica Licea, Sergey Gorlatov, Kathleen L. King, Peter Young, Arash Adami, Deryk Loo, Gurunadh R Chichili, Liqin Liu, Douglas H. Smith, Jennifer G Brown, Francine Z Chen, Scott Koenig, Jennie Mather, Ezio Bonvini, Syd Johnson

    We have developed MGD007 (anti-glycoprotein A33 x anti-CD3), a DART® protein designed to redirect T-cells to target gpA33 expressing colon cancer. The gpA33 target was selected based on an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic CRC specimens, including putative cancer stem cell populations. MGD007 displays the anticipated bispecific binding properties and mediates potent lysis of gpA33-positive cancer cell lines, including models of colorectal cancer stem cells, through recruitment of T-cells. Xenograft studies showed tumor growth inhibition at doses as low as 4 µg/kg. Both CD8 and CD4 T cells mediated lysis of gpA33-expressing tumor cells, with activity accompanied by increases in granzyme and perforin. Notably, suppressive T-cell populations could also be leveraged to mediate lysis of gpA33 expressing tumor cells. Concomitant with CTL activity, both T-cell activation and expansion are observed in a gpA33-dependent manner. No cytokine activation was observed with human PBMC alone, consistent with the absence of gpA33 expression on peripheral blood cell populations. Following prolonged exposure to MGD007 and gpA33 positive tumor cells, T cells express PD 1 and LAG-3 and acquire a memory phenotype but retain ability to support potent cell killing. In cynomolgus monkeys, 4 weekly doses of 100 µg/kg were well tolerated, with prolonged PK consistent with that of an Fc-containing molecule. Taken together MGD007 displays potent activity against colorectal cancer cells consistent with a mechanism of action endowed in its design and support further investigation of MGD007 as a potential novel therapeutic treatment for colorectal cancer.

    更新日期:2018-06-05
  • Synthetic Lethal Strategy Identifies a Potent and Selective TTK and CLK2 Inhibitor for Treatment of Triple-negative Breast Cancer with a Compromised G1/S Checkpoint
    Mol. Cancer Ther. (IF 5.365) Pub Date : 2018-06-04
    Dan Zhu, Shuichan Xu, Gordafaried Deyanat-Yazdi, Sophie X. Peng, Leo A Barnes, Rama Krishna Narla, Tam Tran, David Mikolon, Yuhong Ning, Tao Shi, Ning Jiang, Heather K Raymon, Jennifer R Riggs, John F. Boylan

    Historically, phenotypic-based drug discovery has yielded a high percentage of novel drugs while uncovering new tumor biology. CC-671 was discovered using a phenotypic screen for compounds that preferentially induced apoptosis in triple negative breast cancer cell lines while sparing luminal breast cancer cell lines. Detailed in vitro kinase profiling shows CC-671 potently and selectively inhibits two kinases-TTK and CLK2. Cellular mechanism of action studies demonstrate that CC-671 potently inhibits the phosphorylation of KNL1 and SRp75, direct TTK and CLK2 substrates, respectively. Furthermore, CC-671 causes mitotic acceleration and modification of pre-mRNA splicing leading to apoptosis, consistent with cellular TTK and CLK inhibition. Correlative analysis of genomic and potency data against a large panel of breast cancer cell lines identifies breast cancer cells with a dysfunctional G1/S checkpoint as more sensitive to CC-671, suggesting synthetic lethality between G1/S checkpoint and TTK/CLK2 inhibition. Furthermore, significant in vivo CC-671 efficacy was demonstrated in two cell line-derived and one patient tumor-derived xenograft models of TNBC following weekly dosing. These findings are the first to demonstrate the unique inhibitory combination activity of a dual TTK/CLK2 inhibitor that preferably kills TNBC cells and shows synthetic lethality with a compromised G1/S checkpoint in breast cancer cell lines. Based on these data, CC-671 was moved forward for clinical development as a potent and selective TTK/CLK2 inhibitor in a subset of TNBC patients.

    更新日期:2018-06-05
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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