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  • Highlights of This Issue
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    American Association for Cancer Research

    ### [Couts et al. Page 222][1] Anaplastic lymphoma kinase (ALK) is an oncogenic kinase which can be expressed and activated in cancers by gene fusions. ALK fusions have not been identified in cutaneous melanomas, but expression of an alternate isoform of ALK (ALKATI) was reported as a potential

    更新日期:2018-01-02
  • Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Anthony W. Tolcher, Wei Peng, Emiliano Calvo

    Molecular characterization of oncogenic mutations within genes in the MAPK and PI3K/AKT/mTOR pathways has led to the rational development of targeted therapies. Combining BRAF and MEK inhibitors to target two steps in the MAPK pathway (vertical inhibition) is now standard of care in advanced-stage melanoma harboring BRAF V600 mutation. Encouraging results have been seen in several tumor types with the same mutation, including BRAF V600–mutant non–small cell lung cancer. Yet similar results in other tumors, such as colorectal cancer, have not been observed, highlighting the unique nature of different tumors. Furthermore, considerable cross talk occurs between signaling pathways, and cancer cells usually harbor multiple aberrations and/or develop compensatory mechanisms that drive resistance. Therefore, it is logical to target multiple pathways simultaneously (horizontal inhibition) by combining selective inhibitors or engineering multitargeted agents. Yet horizontal inhibition has proven to be a significant challenge, primarily due to dose-limiting toxicities. This review focuses on ongoing or completed clinical trials with combination targeted therapies for solid tumors and highlights the successes and ongoing challenges. Novel strategies to overcome these obstacles include new delivery technologies, combinations with emerging agents, and treatment schedule optimization. Mol Cancer Ther; 17(1); 3–16. ©2017 AACR .

    更新日期:2018-01-02
  • Histone Deacetylase Inhibition Enhances the Antitumor Activity of a MEK Inhibitor in Lung Cancer Cells Harboring RAS Mutations
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Tadaaki Yamada, Joseph M. Amann, Azusa Tanimoto, Hirokazu Taniguchi, Takehito Shukuya, Cynthia Timmers, Seiji Yano, Konstantin Shilo, David P. Carbone

    Non–small cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS , and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS–ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle. This is through regulation of apoptotic proteins BIM and FASL and cell-cycle regulators p21Cip1 and p27Kip1. We now show that an HDAC inhibitor affects the expression and localization of FOXO proteins and wanted to determine whether the combination of a MEK inhibitor with an HDAC inhibitor would increase the sensitivity of NSCLC with KRAS mutation. Combined treatment with a MEK inhibitor and an HDAC inhibitor showed synergistic effects on cell metabolic activity of RAS -mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell-cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell-cycle inhibitors p21Cip1 and p27Kip1. These results demonstrate that control of FOXOs localization and expression is critical in RAS -driven lung cancer cells, suggesting that the dual molecular-targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations. Mol Cancer Ther; 17(1); 17–25. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 1][1] [1]: /lookup/volpage/17/1?iss=1

    更新日期:2018-01-02
  • Pharmacologic Inhibition of the Menin-MLL Interaction Leads to Transcriptional Repression of PEG10 and Blocks Hepatocellular Carcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Katarzyna Kempinska, Bhavna Malik, Dmitry Borkin, Szymon Klossowski, Shirish Shukla, Hongzhi Miao, Jingya Wang, Tomasz Cierpicki, Jolanta Grembecka

    Hepatocellular carcinoma (HCC) accounts for approximately 85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein–protein interaction between menin and histone methyltransferase mixed lineage leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients. Here, we demonstrate that the menin–MLL inhibitor MI-503 shows antitumor activity in in vitro and in vivo models of HCC and reveals the potential mechanism of menin contribution to HCC. Treatment with MI-503 selectively kills various HCC cell lines and this effect is significantly enhanced by a combination of MI-503 with sorafenib, the standard-of-care therapy for HCC. Furthermore, MI-503 reduces sphere formation and cell migration in in vitro HCC models. When applied in vivo , MI-503 gives a strong antitumor effect both as a single agent and in combination with sorafenib in mice xenograft models of HCC. Mechanistically, treatment with MI-503 downregulates expression of several genes known to play a critical role in proliferation and migration of HCC cells, including PEG10 , and displaces the menin–MLL1 complex from the PEG10 promoter, resulting in reduced H3K4 methylation and transcriptional repression. Overall, our studies reveal a mechanistic link between menin and genes involved in HCC and demonstrate that pharmacologic inhibition of the menin–MLL interaction might represent a promising therapeutic approach for HCC. Mol Cancer Ther; 17(1); 26–38. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 1][1] [1]: /lookup/volpage/17/1?iss=1

    更新日期:2018-01-02
  • Evaluating the Mechanism and Therapeutic Potential of PTC-028, a Novel Inhibitor of BMI-1 Function in Ovarian Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Anindya Dey, Xunhao Xiong, Aleia Crim, Shailendra Kumar Dhar Dwivedi, Soumyajit Banerjee Mustafi, Priyabrata Mukherjee, Liangxian Cao, Nadiya Sydorenko, Ramil Baiazitov, Young-Choon Moon, Melissa Dumble, Thomas Davis, Resham Bhattacharya

    BMI-1, also known as a stem cell factor, is frequently upregulated in several malignancies. Elevated expression of BMI-1 correlates with poor prognosis and is therefore considered a viable therapeutic target in a number of malignancies including ovarian cancer. Realizing the immense pathologic significance of BMI-1, small-molecule inhibitors against BMI-1 are recently being developed. In this study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by posttranslational modification. We report that PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays, whereas normal cells remain unaffected. Mechanistically, hyperphosphorylation-mediated depletion of cellular BMI-1 by PTC-028 coupled with a concurrent temporal decrease in ATP and a compromised mitochondrial redox balance potentiates caspase-dependent apoptosis. In vivo , orally administered PTC-028, as a single agent, exhibits significant antitumor activity comparable with the standard cisplatin/paclitaxel therapy in an orthotopic mouse model of ovarian cancer. Thus, PTC-028 has the potential to be used as an effective therapeutic agent in patients with epithelial ovarian cancer, where treatment options are limited. Mol Cancer Ther; 17(1); 39–49. ©2017 AACR .

    更新日期:2018-01-02
  • Ceramide Nanoliposomes as a MLKL-Dependent, Necroptosis-Inducing, Chemotherapeutic Reagent in Ovarian Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Xuewei Zhang, Kazuyuki Kitatani, Masafumi Toyoshima, Masumi Ishibashi, Toshinori Usui, Junko Minato, Mahy Egiz, Shogo Shigeta, Todd Fox, Tye Deering, Mark Kester, Nobuo Yaegashi

    Ceramides are bioactive lipids that mediate cell death in cancer cells, and ceramide-based therapy is now being tested in dose-escalating phase I clinical trials as a cancer treatment. Multiple nanoscale delivery systems for ceramide have been proposed to overcome the inherent toxicities, poor pharmacokinetics, and difficult biophysics associated with ceramide. Using the ceramide nanoliposomes (CNL), we now investigate the therapeutic efficacy and signaling mechanisms of this nanoscale delivery platform in refractory ovarian cancer. Treatment of ovarian cancer cells with CNL decreased the number of living cells through necroptosis but not apoptosis. Mechanistically, dying SKOV3 ovarian cancer cells exhibit activation of pseudokinase mixed lineage kinase domain-like (MLKL) as evidenced by oligomerization and relocalization to the blebbing membranes, showing necroptotic characteristics. Knockdown of MLKL, but not its upstream protein kinases such as receptor-interacting protein kinases, with siRNA significantly abolished CNL-induced cell death. Monomeric MLKL protein expression inversely correlated with the IC50 values of CNL in distinct ovarian cancer cell lines, suggesting MLKL as a possible determinant for CNL-induced cell death. Finally, systemic CNL administration suppressed metastatic growth in an ovarian cancer cell xenograft model. Taken together, these results suggest that MLKL is a novel pronecroptotic target for ceramide in ovarian cancer models. Mol Cancer Ther; 17(1); 50–59. ©2017 AACR .

    更新日期:2018-01-02
  • Combinatorial Treatment with mTOR Inhibitors and Streptozotocin Leads to Synergistic In Vitro and In Vivo Antitumor Effects in Insulinoma Cells
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Julien Bollard, Céline Patte, Patrick Massoma, Isabelle Goddard, Nicolas Gadot, Noura Benslama, Valérie Hervieu, Carole Ferraro-Peyret, Martine Cordier-Bussat, Jean-Yves Scoazec, Colette Roche, Thomas Walter, Cécile Vercherat

    Streptozotocin-based chemotherapy is the first-line chemotherapy recommended for advanced pancreatic neuroendocrine tumors (pNETs), whereas targeted therapies, including mTOR inhibitors, are available in second-line treatment. Unfortunately, objective response rates to both treatments are limited. Because mTOR pathway activation, commonly observed in pNETs, has been reported as one of the major mechanisms accounting for chemoresistance, we investigated the potential benefit of mTOR inhibition combined with streptozotocin treatment in a subset of pNETs, namely insulinomas. To evaluate the potential of mTOR inhibition in combination with streptozotocin, we selected four different inhibitors acting at various levels of the pathway (everolimus: inhibition of mTORC1; MK-2206: inhibition of AKT; BKM120: inhibition of PI3K, mTORC1, and mTORC2; and BEZ235: inhibition of mTORC1 and mTORC2). Effects on cell viability and apoptosis were assessed in insulinoma cell lines INS-1E (rat) and MIN6 (mouse) in vitro and were confirmed in vivo by using a mouse model of hepatic tumor dissemination after intrasplenic xenograft. In vitro , all four combinations display synergistic effects. These combinations lead to heterogeneous mTOR pathway inhibition, in agreement with their respective target, and increased apoptosis. In vivo , tumor growth in the liver was significantly inhibited by combining streptozotocin with everolimus ( P = 0.0014), BKM120 ( P = 0.0092), or BEZ235 ( P = 0.008) as compared to each agent alone. These results suggest that targeting the mTOR pathway in combination with streptozotocin could be of potential benefit for insulinomas and pNET patients and thus support further clinical investigations. Mol Cancer Ther; 17(1); 60–72. ©2017 AACR .

    更新日期:2018-01-02
  • Ceritinib Enhances the Efficacy of Trametinib in BRAF/NRAS-Wild-Type Melanoma Cell Lines
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Daniel Verduzco, Brent M. Kuenzi, Fumi Kinose, Vernon K. Sondak, Zeynep Eroglu, Uwe Rix, Keiran S.M. Smalley

    Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (∼35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS -WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single-agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS -WT cell lines, and the combination showed increased cytotoxicity in both three-dimensional spheroid culture and long-term colony formation experiments. Coadministration of ceritinib and trametinib led to robust inhibition of tumor growth in an in vivo xenograft BRAF/NRAS -WT melanoma model; this was not due to ALK inhibition by ceritinib. Mechanistic studies showed the ceritinib–trametinib combination to increase suppression of MAPK and TORC1 signaling. Similar results were seen when BRAF/NRAS -WT melanoma cells were treated with a combination of trametinib and the TORC1/2 inhibitor INK128. We next used mass spectrometry–based chemical proteomics and identified known and new ceritinib targets, such as IGF1R and ACK1, respectively. Validation studies suggested that ceritinib could suppress mTORC1 signaling in the presence of trametinib through inhibition of IGF1R and/or ACK1 in a cell line–dependent manner. Together, our studies demonstrated that combining a specific inhibitor (trametinib) with a more broadly targeted agent (ceritinib) has efficacy against tumors with heterogeneous mutational profiles. Mol Cancer Ther; 17(1); 73–83. ©2017 AACR .

    更新日期:2018-01-02
  • Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas In Vivo and Ex Vivo
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Edward J. Hartsough, Curtis H. Kugel, Michael J. Vido, Adam C. Berger, Timothy J. Purwin, Allison Goldberg, Michael A. Davies, Matthew J. Schiewer, Karen E. Knudsen, Gideon Bollag, Andrew E. Aplin

    FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K–mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib-resistant BRAF splice variant–expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. Mol Cancer Ther; 17(1); 84–95. ©2017 AACR .

    更新日期:2018-01-02
  • Therapeutic Impact of Nanoparticle Therapy Targeting Tumor-Associated Macrophages
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Courtney A. Penn, Kun Yang, Hong Zong, Jae-Young Lim, Alex Cole, Dongli Yang, James Baker, Sascha N. Goonewardena, Ronald J. Buckanovich

    Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest antiangiogenic therapy–induced hypoxia can induce tumor “stemness” as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor-associated macrophages (TAM). As such, TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) nanoparticles deplete TAMs in both solid tumor and ascites models of ovarian cancer. As a therapeutic agent, these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to antiangiogenic therapy, (ii) prevent antiangiogenic therapy–induced increases in cancer stem–like cells in both murine and human tumor cell models, (iii) prevent antiangiogenic therapy–induced increases in VEGF-C, and (iv) prevent antiangiogenic therapy–induced BRCA1 gene expression. Combined, this work strongly supports the development of TAM-targeted nanoparticle therapy. Mol Cancer Ther; 17(1); 96–106. ©2017 AACR .

    更新日期:2018-01-02
  • JQ1 Induces DNA Damage and Apoptosis, and Inhibits Tumor Growth in a Patient-Derived Xenograft Model of Cholangiocarcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Patrick L. Garcia, Aubrey L. Miller, Tracy L. Gamblin, Leona N. Council, John D. Christein, J. Pablo Arnoletti, Marty J. Heslin, Sushanth Reddy, Joseph H. Richardson, Xiangqin Cui, Robert C.A.M. van Waardenburg, James E. Bradner, Eddy S. Yang, Karina J. Yoon

    Cholangiocarcinoma (CCA) is a fatal disease with a 5-year survival of <30%. For a majority of patients, chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the first-line agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ∼8 months. Combining this agent with cisplatin increases survival by ∼3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the antitumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2 and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis and downregulated multiple c-Myc transcriptional targets that regulate cell-cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA. Mol Cancer Ther; 17(1); 107–18. ©2017 AACR .

    更新日期:2018-01-02
  • Targeted Delivery of STAT-3 Modulator to Breast Cancer Stem-Like Cells Downregulates a Series of Stemness Genes
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Santosh K. Misra, Arun De, Dipanjan Pan

    Cancer stem cells are known to be controlled by pathways that are dormant in normal adult cells, for example, PTEN, which is a negative regulator of transcription factor STAT3. STAT3 regulates genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of enormous clinical significance. Studies on breast cancer stem cells (BCSC) have been also significantly correlated with STATs. We describe here for the first time a novel strategy to selectively target CSCs and to induce downregulation of STAT3 downstream target genes reducing expression of series of “stem-ness genes” in treated tumors. In vitro and in vivo experiments were performed to evaluate functional activity with gene and protein expression studies. The results of the study indicate that this targeted delivery approach deactivates STAT3 causing a reduction of CD44+/CD24− CSC populations with aptly tracked gene and protein regulations of “stemness” characteristics. Mol Cancer Ther; 17(1); 119–29. ©2017 AACR .

    更新日期:2018-01-02
  • miR-20a Regulates FAS Expression in Osteosarcoma Cells by Modulating FAS Promoter Activity and Can be Therapeutically Targeted to Inhibit Lung Metastases
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Yuanzheng Yang, Gangxiong Huang, Zhichao Zhou, Jason G. Fewell, Eugenie S. Kleinerman

    The metastatic potential of osteosarcoma cells is inversely correlated to cell surface FAS expression. Downregulation of FAS allows osteosarcoma cells to escape FAS ligand–mediated apoptosis when they enter a FAS ligand–positive microenvironment such as the lung. We have previously demonstrated that miR-20a, encoded by the miR-17-92 cluster, downregulates FAS expression in osteosarcoma. We further demonstrated an inverse correlation between FAS expression and miR-20a expression. However, the mechanism of FAS regulation by miR-20a was still unclear. The purpose of the current study was to evaluate the mechanism of FAS regulation by miR-20a in vitro and test the effect of targeting miR-20a in vivo . We investigated whether miR-20a's downregulation of FAS was mediated by binding to the 3′-untranslated region (3′-UTR) of FAS mRNA with the consequent induction of mRNA degradation or translational suppression. We identified and mutated two miR-20a binding sites on the FAS mRNA 3′-UTR. Using luciferase reporter assays, we demonstrated that miR-20a did not bind to either the wild-type or mutated FAS 3′-UTR. In contrast, overexpression of miR-20a resulted in downregulation of FAS promoter activity. Similarly, the inhibition of miR-20a increased FAS promoter activity. The critical region identified on the FAS promoter was between −240 bp and −150 bp. Delivery of anti-miR-20a in vivo using nanoparticles in mice with established osteosarcoma lung metastases resulted in upregulation of FAS and tumor growth inhibition. Taken together, our data suggest that miR-20a regulates FAS expression through the modulation of the FAS promoter and that targeting miR-20a using anti-miR-20a has therapeutic potential. Mol Cancer Ther; 17(1); 130–9. ©2017 AACR .

    更新日期:2018-01-02
  • HIF2{alpha}-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    So C. Wong, Weijun Cheng, Holly Hamilton, Anthony L. Nicholas, Darren H. Wakefield, Aaron Almeida, Andrei V. Blokhin, Jeffrey Carlson, Zane C. Neal, Vladimir Subbotin, Guofeng Zhang, Julia Hegge, Stephanie Bertin, Vladimir S. Trubetskoy, David B. Rozema, David L. Lewis, Steven B. Kanner

    Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%–90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an overabundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvβ3 and αvβ5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2α-specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model. Mol Cancer Ther; 17(1); 140–9. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 1][1] [1]: /lookup/volpage/17/1?iss=1

    更新日期:2018-01-02
  • IMMU-140, a Novel SN-38 Antibody-Drug Conjugate Targeting HLA-DR, Mediates Dual Cytotoxic Effects in Hematologic Cancers and Malignant Melanoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Thomas M. Cardillo, Serengulam V. Govindan, Maria B. Zalath, Diane L. Rossi, Yang Wang, Chien-Hsing Chang, David M. Goldenberg

    HLA-DR is a member of the MHC class II antigen family expressed on hematologic and solid tumors. Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development. IMMU-140 is an anti–HLA-DR antibody–drug conjugate composed of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti–HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR–expressing tumors. IMMU-140 had dual-therapeutic mechanisms, as evidenced by its retention of nonoverlapping anti–HLA-DR nonclassical apoptotic signaling and classical apoptosis mediated by its SN-38 payload. In seven human disease models [acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and melanoma], IMMU-140 provided significant therapeutic efficacy compared with controls, in vitro , in 3D spheroid models, and in vivo . Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared with parental IMMU-114. Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects, IMMU-140 therapy mediated >80% improvement in survival. Therapy was well tolerated, as demonstrated by no marked loss in body weight. Combined with doxorubicin, IMMU-140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity. The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development. Mol Cancer Ther; 17(1); 150–60. ©2017 AACR .

    更新日期:2018-01-02
  • CAT-02-106, a Site-Specifically Conjugated Anti-CD22 Antibody Bearing an MDR1-Resistant Maytansine Payload Yields Excellent Efficacy and Safety in Preclinical Models
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Penelope M. Drake, Adam Carlson, Jesse M. McFarland, Stefanie Bañas, Robyn M. Barfield, Wesley Zmolek, Yun Cheol Kim, Betty C.B. Huang, Romas Kudirka, David Rabuka

    Hematologically derived tumors make up ∼10% of all newly diagnosed cancer cases in the United States. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1. CD22 is a clinically validated target for the treatment of NHL, but no anti-CD22 agents have yet been approved for this indication. Recent approval of an anti-CD22 antibody–drug conjugate (ADC) for the treatment of relapsed/refractory ALL supports the rationale for targeting this protein. An opportunity exists for a next-generation anti-CD22 antibody–drug conjugate (ADC) to address unmet medical needs in the relapsed/refractory NHL population. We describe a site-specifically conjugated antibody–drug conjugate, made using aldehyde tag technology, targeted against CD22 and bearing a noncleavable maytansine payload that is resistant to MDR1-mediated efflux. The construct was efficacious against CD22+ NHL xenografts and could be repeatedly dosed in cynomolgus monkeys at 60 mg/kg with no observed significantly adverse effects. Exposure to total ADC at these doses (as assessed by AUC0-inf) indicated that the exposure needed to achieve efficacy was below tolerable limits. Together, the data suggest that this drug has the potential to be used effectively in patients with CD22+ tumors that have developed MDR1-related resistance to prior therapies. Mol Cancer Ther; 17(1); 161–8. ©2017 AACR .

    更新日期:2018-01-02
  • Targeting Phosphatidylserine with Calcium-Dependent Protein-Drug Conjugates for the Treatment of Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Ran Li, Srinivas Chiguru, Li Li, Dongyoung Kim, Ramraj Velmurugan, David Kim, Siva Charan Devanaboyina, Hong Tian, Alan Schroit, Ralph P. Mason, Raimund J. Ober, E. Sally Ward

    In response to cellular stress, phosphatidylserine is exposed on the outer membrane leaflet of tumor blood vessels and cancer cells, motivating the development of phosphatidylserine-specific therapies. The generation of drug-conjugated phosphatidylserine-targeting agents represents an unexplored therapeutic approach, for which antitumor effects are critically dependent on efficient internalization and lysosomal delivery of the cytotoxic drug. In the current study, we have generated phosphatidylserine-targeting agents by fusing phosphatidylserine-binding domains to a human IgG1-derived Fc fragment. The tumor localization and pharmacokinetics of several phosphatidylserine-specific Fc fusions have been analyzed in mice and demonstrate that Fc-Syt1, a fusion containing the synaptotagmin 1 C2A domain, effectively targets tumor tissue. Conjugation of Fc-Syt1 to the cytotoxic drug monomethyl auristatin E results in a protein–drug conjugate (PDC) that is internalized into target cells and, due to the Ca2+ dependence of phosphatidylserine binding, dissociates from phosphatidylserine in early endosomes. The released PDC is efficiently delivered to lysosomes and has potent antitumor effects in mouse xenograft tumor models. Interestingly, although an engineered, tetravalent Fc-Syt1 fusion shows increased binding to target cells, this higher avidity variant demonstrates reduced persistence and therapeutic effects compared with bivalent Fc-Syt1. Collectively, these studies show that finely tuned, Ca2+-switched phosphatidylserine-targeting agents can be therapeutically efficacious. Mol Cancer Ther; 17(1); 169–82. ©2017 AACR .

    更新日期:2018-01-02
  • A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin-Drug Conjugate (LDC)
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Osamu Shimomura, Tatsuya Oda, Hiroaki Tateno, Yusuke Ozawa, Sota Kimura, Shingo Sakashita, Masayuki Noguchi, Jun Hirabayashi, Makoto Asashima, Nobuhiro Ohkohchi

    Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin–glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin–drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL = 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg ( P < 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 ( P < 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model ( P < 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments. Mol Cancer Ther; 17(1); 183–95. ©2017 AACR .

    更新日期:2018-01-02
  • Selective and Concentrated Accretion of SN-38 with a CEACAM5-Targeting Antibody-Drug Conjugate (ADC), Labetuzumab Govitecan (IMMU-130)
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Robert M. Sharkey, Serengulam V. Govindan, Thomas M. Cardillo, Jennifer Donnell, Jing Xia, Edmund A. Rossi, Chien-Hsing Chang, David M. Goldenberg

    Labetuzumab govitecan (IMMU-130), an antibody–drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ∼500 or ∼16 μg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1% to 2% injected dose/mL after 5 minutes; overall, approximately 20% was converted to SN-38 and SN-38G. At 1 hour with IMMU-130, 45% to 63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. AUC analysis found that SN-38 levels were approximately 11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130–treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. On the basis of the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared with irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety. Mol Cancer Ther; 17(1); 196–203. ©2017 AACR .

    更新日期:2018-01-02
  • Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Hannah E. Pearson, Mari Iida, Rachel A. Orbuch, Nellie K. McDaniel, Kwangok P. Nickel, Randall J. Kimple, Jack L. Arbiser, Deric L. Wheeler

    Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non–small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo . There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro . Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204–14. ©2017 AACR .

    更新日期:2018-01-02
  • Phase I Study of Enavatuzumab, a First-in-Class Humanized Monoclonal Antibody Targeting the TWEAK Receptor, in Patients with Advanced Solid Tumors
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Elaine T. Lam, S. Gail Eckhardt, Wells Messersmith, Antonio Jimeno, Cindy L. O'Bryant, Ramesh K. Ramanathan, Glen J. Weiss, Manpreet Chadha, Abbie Oey, Han Ting Ding, Patricia A. Culp, Stephan F. Keller, Vivian Y. Zhao, L. Claire Tsao, Anil Singhal, Kyle D. Holen, Daniel Von Hoff

    This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215–21. ©2017 AACR .

    更新日期:2018-01-02
  • ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Kasey L. Couts, Judson Bemis, Jacqueline A. Turner, Stacey M. Bagby, Danielle Murphy, Jason Christiansen, Jennifer D. Hintzsche, Anh Le, Todd M. Pitts, Keith Wells, Allison Applegate, Carol Amato, Pratik Multani, Edna Chow-Maneval, John J. Tentler, Yiqun G. Shellman, Matthew J. Rioth, Aik-Choon Tan, Rene Gonzalez, Theresa Medina, Robert C. Doebele, William A. Robinson

    Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK ( ALKATI ) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 of 45 (24.4%) melanomas. Ten melanomas express wild-type (wt) ALK and/or ALKATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo , the melanomas expressing wt ALK or ALKATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALKATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy, whereas melanomas expressing ALKATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALKATI . Mol Cancer Ther; 17(1); 222–31. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 1][1] [1]: /lookup/volpage/17/1?iss=1

    更新日期:2018-01-02
  • Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3{beta}
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Wen Min Lau, Eileen Teng, Kie Kyon Huang, Jin Wei Tan, Kakoli Das, Zhijiang Zang, Tania Chia, Ming Teh, Koji Kono, Wei Peng Yong, Asim Shabbir, Amy Tay, Niam Sin Phua, Patrick Tan, Shing Leng Chan, Jimmy Bok Yan So

    Preclinical models of diffuse-type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish DGC patient-derived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3β as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with protein kinase C (PKC) inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3β with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multikinase inhibitor with PKC-inhibiting activity, in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo . Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signaling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3β to gain a survival advantage. Mol Cancer Ther; 17(1); 232–42. ©2017 AACR .

    更新日期:2018-01-02
  • Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Matthew Sung, Xingzhi Tan, Bingwen Lu, Jonathan Golas, Christine Hosselet, Fang Wang, Laurie Tylaska, Lindsay King, Dahui Zhou, Russell Dushin, Jeremy S. Myers, Edward Rosfjord, Judy Lucas, Hans-Peter Gerber, Frank Loganzo

    Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2+ metastatic breast cancer; however, its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2+ tumors, are not well understood. We used HER2+ cell lines to develop models of T-DM1 resistance using a cyclical dosing schema in which cells received T-DM1 in an “on-off” routine until a T-DM1–resistant population was generated. T-DM1–resistant N87 cells (N87-TM) were cross-resistant to a panel of trastuzumab-ADCs (T-ADCs) with non–cleavable-linked auristatins. N87-TM cells do not have a decrease in HER2 protein levels or an increase in drug transporter protein (e.g., MDR1) expression compared with parental N87 cells. Intriguingly, T-ADCs using auristatin payloads attached via an enzymatically cleavable linker overcome T-DM1 resistance in N87-TM cells. Importantly, N87-TM cells implanted into athymic mice formed T-DM1 refractory tumors that remain sensitive to T-ADCs with cleavable-linked auristatin payloads. Comparative proteomic profiling suggested enrichment in proteins that mediate caveolae formation and endocytosis in the N87-TM cells. Indeed, N87-TM cells internalize T-ADCs into intracellular caveolin-1 (CAV1)–positive puncta and alter their trafficking to the lysosome compared with N87 cells. T-DM1 colocalization into intracellular CAV1-positive puncta correlated with reduced response to T-DM1 in a panel of HER2+ cell lines. Together, these data suggest that caveolae-mediated endocytosis of T-DM1 may serve as a novel predictive biomarker for patient response to T-DM1. Mol Cancer Ther; 17(1); 243–53. ©2017 AACR .

    更新日期:2018-01-02
  • AKT1low Quiescent Cancer Cells Promote Solid Tumor Growth
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Cleidson P. Alves, Ipsita Dey-Guha, Sheheryar Kabraji, Albert C. Yeh, Nilesh P. Talele, Xavier Solé, Joeeta Chowdhury, Mari Mino-Kenudson, Massimo Loda, Dennis Sgroi, Anne-Lise Borresen-Dale, Hege G. Russnes, Kenneth N. Ross, Sridhar Ramaswamy

    Human tumor growth depends on rapidly dividing cancer cells driving population expansion. Even advanced tumors, however, contain slowly proliferating cancer cells for reasons that remain unclear. Here, we selectively disrupt the ability of rapidly proliferating cancer cells to spawn AKT1low daughter cells that are rare, slowly proliferating, tumor-initiating, and chemotherapy-resistant, using β1-integrin activation and the AKT1-E17K–mutant oncoprotein as experimental tools in vivo . Surprisingly, we find that selective depletion of AKT1low slow proliferators actually reduces the growth of a molecularly diverse panel of human cancer cell xenograft models without globally altering cell proliferation or survival in vivo . Moreover, we find that unusual cancer patients with AKT1-E17K–mutant solid tumors also fail to produce AKT1low quiescent cancer cells and that this correlates with significantly prolonged survival after adjuvant treatment compared with other patients. These findings support a model whereby human solid tumor growth depends on not only rapidly proliferating cancer cells but also on the continuous production of AKT1low slow proliferators. Mol Cancer Ther; 17(1); 254–63. ©2017 AACR .

    更新日期:2018-01-02
  • Metabolite Profiling Reveals the Glutathione Biosynthetic Pathway as a Therapeutic Target in Triple-Negative Breast Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Alexander Beatty, Lauren S. Fink, Tanu Singh, Alexander Strigun, Erik Peter, Christina M. Ferrer, Emmanuelle Nicolas, Kathy Q. Cai, Timothy P. Moran, Mauricio J. Reginato, Ulrike Rennefahrt, Jeffrey R. Peterson

    Cancer cells can exhibit altered dependency on specific metabolic pathways and targeting these dependencies is a promising therapeutic strategy. Triple-negative breast cancer (TNBC) is an aggressive and genomically heterogeneous subset of breast cancer that is resistant to existing targeted therapies. To identify metabolic pathway dependencies in TNBC, we first conducted mass spectrometry–based metabolomics of TNBC and control cells. Relative levels of intracellular metabolites distinguished TNBC from nontransformed breast epithelia and revealed two metabolic subtypes within TNBC that correlate with markers of basal-like versus non-basal–like status. Among the distinguishing metabolites, levels of the cellular redox buffer glutathione were lower in TNBC cell lines compared to controls and markedly lower in non-basal–like TNBC. Significantly, these cell lines showed enhanced sensitivity to pharmacologic inhibition of glutathione biosynthesis that was rescued by N-acetylcysteine, demonstrating a dependence on glutathione production to suppress ROS and support tumor cell survival. Consistent with this, patients whose tumors express elevated levels of γ-glutamylcysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, had significantly poorer survival. We find, further, that agents that limit the availability of glutathione precursors enhance both glutathione depletion and TNBC cell killing by γ-glutamylcysteine ligase inhibitors in vitro . Importantly, we demonstrate the ability to this approach to suppress glutathione levels and TNBC xenograft growth in vivo . Overall, these findings support the potential of targeting the glutathione biosynthetic pathway as a therapeutic strategy in TNBC and identify the non-basal-like subset as most likely to respond. Mol Cancer Ther; 17(1); 264–75. ©2017 AACR .

    更新日期:2018-01-02
  • CCL26 Participates in the PRL-3-Induced Promotion of Colorectal Cancer Invasion by Stimulating Tumor-Associated Macrophage Infiltration
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Qiusheng Lan, Wei Lai, Yujie Zeng, Lu Liu, Shoufeng Li, Shaowen Jin, Yang Zhang, Xingxi Luo, Heyang Xu, Xiangan Lin, Zhonghua Chu

    Both phosphatase of regenerating liver-3 (PRL-3) and tumor-associated macrophages (TAM) influence cancer progression. Whether PRL-3 plays a critical role in colorectal cancer invasion and metastasis by inducing TAM infiltration remains unclear. In the current study, we investigated the effects of chemokine ligand 26 (CCL26) on TAM infiltration and colorectal cancer invasion and the underlying mechanism in colorectal cancer cells by overexpressing or silencing PRL-3. We found that PRL-3 upregulated CCL26 expression correlatively and participated in cell migration, according to the results of gene ontology analysis. In addition, IHC analysis results indicated that the PRL-3 and CCL26 levels were positively correlated and elevated in stage III and IV colorectal cancer tissues and were associated with a worse prognosis in colorectal cancer patients. Furthermore, we demonstrated that CCL26 induced TAM infiltration by CCL26 binding to the CCR3 receptor. When LoVo-P and HT29-C cells were cocultured with TAMs, CCL26 binding to the CCR3 receptor enhanced the invasiveness of LoVo-P and HT29-C cells by mobilizing intracellular Ca2+of TAMs to increase the expression of IL6 and IL8. In addition, IHC results indicated that protein levels of CCR3 and TAMs counts were higher in stage III and IV colorectal cancer tissues and correlated with CCL26. Moreover, similar results were observed in vivo using mice injected with LoVo-P and HT29-C cells. These data indicate that PRL-3 may represent a potential prognostic marker that promotes colorectal cancer invasion and metastasis by upregulating CCL26 to induce TAM infiltration. Mol Cancer Ther; 17(1); 276–89. ©2017 AACR .

    更新日期:2018-01-02
  • Clinical Application of Circulating Tumor DNA in the Genetic Analysis of Patients with Advanced GIST
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Hao Xu, Liang Chen, Yang Shao, Dongqin Zhu, Xiaofei Zhi, Qiang Zhang, Fengyuan Li, Jianghao Xu, Xisheng Liu, Zekuan Xu

    Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. Although, circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance, but the concordance was strong for patients with tumor size > 10 cm or Ki-67 > 5%. Tumor size, mitotic figure, Ki-67, and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type, were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients. Mol Cancer Ther; 17(1); 290–6. ©2017 AACR .

    更新日期:2018-01-02
  • The Mutational Landscape of Gastrointestinal Malignancies as Reflected by Circulating Tumor DNA
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Paul Riviere, Paul T. Fanta, Sadakatsu Ikeda, Joel Baumgartner, Gregory M. Heestand, Razelle Kurzrock

    We aimed to assess the utility of a novel, noninvasive method of detecting genomic alterations in patients with gastrointestinal malignancies, i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma ( N = 55; 26%), appendiceal adenocarcinoma ( N = 46; 22%), hepatocellular carcinoma ( N = 31; 15%), and pancreatic ductal adenocarcinoma ( N = 25; 12%). The majority of patients (58%) had ≥1 characterized alteration (excluded variants of unknown significance). The median number of characterized alterations was 1 (range, 0–13). The number of detected alterations per patient varied between different cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had ≥1 characterized alteration(s) versus 24% of appendiceal adenocarcinoma patients (11/46). The median percent ctDNA among characterized alterations was 2.50% (interquartile range, 0.76%–8.96%). Overall, 95% of patients (117/123) had distinct molecular portfolios with 143 unique characterized alterations within 56 genes. Overall, concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy ( N = 105 patients) in the four most common alterations ( KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Of 123 patients with characterized alterations, >99% (122/123; 57% of entire population tested; 122/213) had one or more alterations potentially actionable by experimental or approved drugs. These observations suggest that many patients with gastrointestinal tumors, including difficult-to-biopsy malignancies like hepatocellular cancers, frequently have discernible and theoretically pharmacologically tractable ctDNA alterations that merit further studies in prospective trials. Mol Cancer Ther; 17(1); 297–305. ©2017 AACR .

    更新日期:2018-01-02
  • Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response-Targeted Therapies in Breast Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Kalnisha Naidoo, Patty T. Wai, Sarah L. Maguire, Frances Daley, Syed Haider, Divya Kriplani, James Campbell, Hasan Mirza, Anita Grigoriadis, Andrew Tutt, Paul M. Moseley, Tarek M.A. Abdel-Fatah, Stephen Y.T. Chan, Srinivasan Madhusudan, Emad A. Rhaka, Ian O. Ellis, Christopher J. Lord, Yinyin Yuan, Andrew R. Green, Rachael Natrajan

    Disruption of Cyclin-Dependent Kinase 12 ( CDK12 ) is known to lead to defects in DNA repair and sensitivity to platinum salts and PARP1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by IHC in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer–specific survival taking HER2 status into account; however, absent CDK12 protein expression significantly correlated with a triple-negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK, and γH2AX, suggesting a novel mechanism of CDK12-associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in breast cancer is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple-negative breast cancers. Mol Cancer Ther; 17(1); 306–15. ©2017 AACR .

    更新日期:2018-01-02
  • Comparative Oncology Evaluation of Intravenous Recombinant Oncolytic Vesicular Stomatitis Virus Therapy in Spontaneous Canine Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    Shruthi Naik, Gina D. Galyon, Nathan J. Jenks, Michael B. Steele, Amber C. Miller, Sara D. Allstadt, Lukkana Suksanpaisan, Kah Whye Peng, Mark J. Federspiel, Stephen J. Russell, Amy K. LeBlanc

    Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single-shot systemic therapy with a vesicular stomatitis virus (VSV)-IFNβ-NIS, a novel recombinant oncolytic VSV, can induce curative remission in tumor-bearing mice. Clinical translation of VSV-IFNβ-NIS therapy is dependent on comprehensive assessment of clinical toxicities, virus shedding, pharmacokinetics, and efficacy in clinically relevant models. Dogs spontaneously develop cancer with comparable etiology, clinical progression, and response to therapy as human malignancies. A comparative oncology study was carried out to investigate feasibility and tolerability of intravenous oncolytic VSV-IFNβ-NIS therapy in pet dogs with spontaneous cancer. Nine dogs with various malignancies were treated with a single intravenous dose of VSV-IFNβ-NIS. Two dogs with high-grade peripheral T-cell lymphoma had rapid but transient remission of disseminated disease and transient hepatotoxicity that resolved spontaneously. There was no shedding of infectious virus. Correlative pharmacokinetic studies revealed elevated levels of VSV RNA in blood in dogs with measurable disease remission. This is the first evaluation of intravenous oncolytic virus therapy for spontaneous canine cancer, demonstrating that VSV-IFNβ-NIS is well-tolerated and safe in dogs with advanced or metastatic disease. This approach has informed clinical translation, including dose and target indication selection, leading to a clinical investigation of intravenous VSV-IFNβ-NIS therapy, and provided preliminary evidence of clinical efficacy and potential biomarkers that correlate with therapeutic response. Mol Cancer Ther; 17(1); 316–26. ©2017 AACR .

    更新日期:2018-01-02
  • "Wnt/{beta}-Catenin in GIST"--Letter
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2018-01-01
    François Bertucci, Pascal Finetti, Alexandre De Nonneville, Daniel Birnbaum

    In an article published on September, 2017, in Molecular Cancer Therapeutics , Zeng and colleagues showed that the WNT/β-catenin oncogenic pathway was activated in a subset of human gastrointestinal stromal tumors (GIST) and that inhibiting its signaling alone or in combination with imatinib has antitumor efficacy in vitro and in vivo in imatinib-sensitive and resistant preclinical models. However, they concluded that “more investigation is needed to correlate β-catenin activation with clinicopathologic features in GIST clinical samples.” Here, we examined the activation score of the β-catenin pathway in 160 clinically annotated clinical samples of operated primary GISTs. We showed that the β-catenin activation score, assessed as continuous variable, was heterogeneous across samples. Higher score was associated with certain prognostic clinicopathologic characteristics, including mutational status, tumor size, and AFIP classification, and even more importantly, with more postoperative relapses in uni- and multivariate analyses. Such unfavorable independent prognostic value of β-catenin activation reinforces the potential therapeutic value of this new target in GIST and nicely complements Zeng's study. Mol Cancer Ther; 17(1); 327–8. ©2018 AACR .

    更新日期:2018-01-02
  • COX-2/sEH Dual Inhibitor PTUPB Potentiates the Anti-tumor Efficacy of Cisplatin
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Fuli Wang, Hongyong Zhang, Ai-Hong Ma, Weimin Yu, Maike Zimmermann, Jun Yang, Sung Hee Hwang, Daniel Zhu, Tzu-yin Lin, Michael Malfatti, Kenneth W. Turteltaub, Paul T. Henderson, Susan Airhart, Bruce D Hammock, Jianlin Yuan, Ralph W. de Vere White, Chong-Xian Pan

    Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in anti-tumor activity, and has organ protective effects. The goal of this study was to determine the anti-tumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single agent treatment as assessed by body weight, histochemical staining of major organs, blood counts and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared to controls. PTUPB treatment did not alter platinum-DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. In conclusion, PTUPB potentiated the anti-tumor activity of cisplatin-based treatment without increasing toxicity in vivo, and has potential for further development as a combination chemotherapy partner.

    更新日期:2017-12-31
  • Scavenger Receptor Type B1 and Lipoprotein Nanoparticle Inhibit Myeloid Derived Suppressor Cells
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Michael P Plebanek, Debayan Bhaumik, Paul J. Bryce, C. Shad Thaxton

    Myeloid derived suppressor cells (MDSCs) are innate immune cells that potently inhibit T cells. In cancer, novel therapies aimed to activate T cells can be rendered ineffective due to the activity of MDSCs. Thus, targeted inhibition of MDSCs may greatly enhance T cell-mediated anti-tumor immunity, but targeted mechanisms remain obscure. Here we show, for the first time, that scavenger receptor type B-1 (SCARB1), a high-affinity receptor for spherical high-density lipoprotein (HDL), is expressed by MDSCs. Furthermore, we demonstrate that SCARB1 is specifically targeted by synthetic high-density lipoprotein-like nanoparticles (HDL NP), which reduces MDSC activity. Using in vitro T cell proliferation assays, data show that HDL NPs specifically bind SCARB1 to inhibit MDSC activity. In murine cancer models, HDL NP treatment significantly reduces tumor growth, metastatic tumor burden, and increases survival due to enhanced adaptive immunity. Flow cytometry and immunohistochemistry demonstrate that HDL NP-mediated suppression of MDSCs increased CD8+ T cells and reduced Treg cells in the metastatic tumor microenvironment. Using transgenic mice lacking SCARB1, in vivo data clearly show that the HDL NPs specifically target this receptor for suppressing MDSCs. Ultimately, our data provide a new mechanism and targeted therapy, HDL NPs, to modulate a critical innate immune cell checkpoint to enhance the immune response to cancer.

    更新日期:2017-12-31
  • An anti-GDNF Family Receptor Alpha 1(GFRA1) Antibody-Drug Conjugate for the Treatment of Hormone Receptor-Positive Breast Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Sunil Bhakta, Lisa M. Crocker, Yvonne Chen, Meredith Hazen, Melissa M. Schutten, Dongwei Li, Coenraad Kuijl, Rachana Ohri, Fiona Zhong, Kirsten Achilles Poon, Mary Ann T. Go, Eric Cheng, Robert Piskol, Ron Firestein, Aimee Fourie-O'Donohue, Katherine R Kozak, Helga Raab, Jo-Anne Hongo, Deepak Sampath, Mark S. Dennis, Richard H. Scheller, Paul Polakis, Jagath R. Junutula

    Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line-Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody-drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and immunohistochemistry analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, while minimal or no expression was observed in most normal tissues. Anti-GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1 expressing cells both in vitro and in vivo. The ADCs employing humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker-payload based ADCs. Overall, these data suggest that anti-GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients.

    更新日期:2017-12-31
  • {beta}-catenin mRNA silencing and MEK inhibition display synergistic efficacy in preclinical tumor models
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Shanthi Ganesh, Xue Shui, Kevin Craig, Martin Koser, Girish R Chopda, Wendy A Cyr, Chengjung Lai, Henryk Dudek, Weimin Wang, Bob Brown, Marc Abrams

    Colorectal carcinomas (CRC) harbor well-defined genetic abnormalities including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. While the MAPK pathway can be targeted using potent small molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNA interference (RNAi) approaches have advanced to the stage of clinical viability, and are especially well-suited for transcriptional modulators such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacological agents. Using a recently-described tumor-selective nanoparticle containing a β-catenin-targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in in vivo models of CRC, melanoma and hepatocellular carcinoma. At dose levels which were insufficient to significantly impact tumor growth as monotherapies, combination regimens resulted in synergistic efficacy and complete tumor growth inhibition. Importantly, dual MEKi/RNAi therapy dramatically improved survival of mice bearing CRC liver metastases. In addition, pharmacological silencing of β-catenin mRNA was effective against tumors which are inherently resistant or which acquire drug-induced resistance to trametinib. These results provide a strong rationale for clinical evaluation of this dual-targeting approach for cancers harboring Wnt/β-catenin and MAPK pathway mutations.

    更新日期:2017-12-31
  • Inhibition of MDM2 by a rhein-derived compound AQ-101 suppresses cancer development in SCID mice
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Lubing Gu, Hailong Zhang, Tao Liu, Alexander Draganov, Sha Yi, Binghe Wang, Muxiang Zhou

    A novel small-molecule anthraquinone (AQ) analog, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a self-ubiquitination and proteasome-mediated mechanism. This AQ-101-induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild-type p53 phenotype and MDM2 expression in vitro and in vivo. When given for a period of 2 weeks (20mg/kg/day, 3x/week), AQ-101 inhibited development of ALL in nude or SCID mice with a human ALL xenograft and achieved cure by the end of the 5-month experiment. Importantly, AQ-101 showed minimal or no inhibitory effect on normal human hematopoiesis in vitro and was well tolerated in vivo in animal models. Given that MDM2-overexpressing cancers are commonly refractory to current treatment options, our study results suggest that further development of AQ-101 is warranted, as it represents a potentially new, safe anticancer drug with a novel strategy for targeting MDM2.

    更新日期:2017-12-31
  • An infrared dye-conjugated virus-like particle for the treatment of primary uveal melanoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Rhonda C Kines, Isabella Varsavsky, Sanghamitra Choudhary, Debaditya Bhattacharya, Sean Spring, Roger J. McLaughlin, Shin J Kang, Hans E Grossniklaus, Demitrios G Vavvas, Stephen Monks, John R MacDougall, Elisabet de los Pinos, John T Schiller

    The work outlined herein describes AU-011, a novel recombinant papillomavirus-like particle (VLP) drug conjugate and its initial evaluation as a potential treatment for primary uveal melanoma. The VLP is conjugated with a phthalocyanine photosensitizer, IRDye 700DX, that exerts its cytotoxic effect through photo-activation with a near-infrared laser. We assessed the anti-cancer properties of AU-011 in vitro utilizing a panel of human cancer cell lines and in vivo using murine subcutaneous and rabbit orthotopic xenograft models of uveal melanoma. The specificity of VLP binding (tumor targeting), mediated through cell surface heparan sulfate proteoglycans (HSPG), was assessed using HSPG deficient cells and by inclusion of heparin in in vitro studies. Our results provide evidence of potent and selective anti-cancer activity, both in vitro and in vivo. AU-011 activity was blocked by inhibiting its association with HSPG using heparin and using cells lacking surface HSPG, indicating that the tumor tropism of the VLP was not affected by dye conjugation and cell association is critical for AU-011 mediated cytotoxicity. Using the uveal melanoma xenograft models, we observed tumor uptake following intravenous (murine) and intravitreal (rabbit) administration and, after photoactivation, potent dose-dependent tumor responses. Further, in the rabbit orthotopic model, which closely models uveal melanoma as it presents in the clinic, tumor treatment spared the retina and adjacent ocular structures. Our results support further clinical development of this novel therapeutic modality that might transform visual outcomes and provide a targeted therapy for the early stage treatment of patients with this rare and life-threatening disease.

    更新日期:2017-12-15
  • Molecularly Targeted Cancer Combination Therapy with Near Infrared Photoimmunotherapy and Near Infrared Photo-release with Duocarmycin-antibody Conjugate.
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Tadanobu Nagaya, Alexander P Gorka, Roger R Nani, Shuhei Okuyama, Fusa Ogata, Yasuhiro Maruoka, Peter L. Choyke, Martin J Schnermann, Hisataka Kobayashi

    Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate (APC). However, the effect of NIR-PIT can be enhanced when combined with other therapies. NIR photocaging groups, based on the heptamethine cyanine scaffold, have been developed to release bioactive molecules near targets after exposure to light. Here, we investigated the combination of NIR-PIT employing panitumumab-IR700 (pan-IR700) and the NIR-releasing compound, CyEt-Panitumumab-Duocarmycin (CyEt-Pan-Duo). Both pan-IR700 and CyEt-Pan-Duo showed specific binding to the EGFR-expressing MDAMB468 cell line in vitro. In in vivo studies, additional injection of CyEt-Pan-Duo immediately after NIR light exposure resulted in high tumor accumulation and high tumor-background ratio. To evaluate the effects of combination therapy in vivo, tumor-bearing mice were separated into 4 groups: (1) control; (2) NIR-PIT; (3) NIR-release; (4) combination of NIR-PIT and NIR-release. Tumor growth was significantly inhibited in all treatment groups compared with the control group (p < 0.05), and significantly prolonged survival was achieved (p < 0.05 vs control). The greatest therapeutic effect was shown with NIR-PIT and NIR-release combination therapy. In conclusion, combination therapy of NIR-PIT and NIR-release enhanced the therapeutic effects compared with either NIR-PIT or NIR-release therapy alone.

    更新日期:2017-12-15
  • Phase 1 dose-escalation study of anti CTLA-4 antibody ipilimumab and lenalidomide in patients with advanced cancers
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Divya Sakamuri, Isabella C. Glitza, Sonia L. Betancourt Cuellar, Vivek Subbiah, Siqing Fu, Apostolia M. Tsimberidou, Jennifer J. Wheler, David S. Hong, Aung Naing, Gerald S. Falchook, Michelle A Fanale, Maria E Cabanillas, Filip Janku

    Preclinical data suggest that combining a check point inhibition with immunomodulatory derivative can increase anticancer response. We designed a dose escalation study using a 3+3 design to determine the safety, maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) and dose limiting toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3mg/kg intravenously every 28 days x 4) and lenalidomide (10-25mg orally daily for 21 of 28 days until disease progression or unacceptable toxicity) in advanced cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma, 4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior therapies) were enrolled. The MTD has not been reached and ipilimumab 3mg/kg and lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, rash, hypopituitarism, G3 pneumonitis, G3 transaminitis and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+ months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of the patients achieving a PR demonstrated intermediate mutation burden. In conclusion, combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers.

    更新日期:2017-12-15
  • Anti-Tumor Activity of Entrectinib, a Pan-TRK, ROS1 and ALK Inhibitor, in ETV6-NTRK3-Positive Acute Myeloid Leukemia
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Kristen M Smith, Patrick C Fagan, Elena Pomari, Giuseppe Germano, Chiara Frasson, Colin Walsh, Ian M Silverman, Paolo Bonvini, Gang Li

    Activation of tropomyosin receptor kinase (TRK) family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent and selective kinase inhibitor against TRKA/B/C, ROS1 and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion-driven hematologic malignancies. In acute myeloid leukemia (AML) cell lines with endogenous expression of the ETV6-NTRK3 fusion gene, entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with sub-nanomolar IC50 values. Phosphorylation of the ETV6-TRKC fusion protein and its downstream signaling effectors was inhibited by entrectinib treatment in a dose-dependent manner. In animal models, entrectinib treatment at clinically relevant doses resulted in tumor regression that was accompanied by elimination of residual cancer cells from the bone marrow. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with TRK fusion-driven AML and other hematologic malignancies.

    更新日期:2017-12-15
  • Preclinical evaluation of SCC244 (Glumetinib), a novel, potent and highly selective inhibitor of c-Met in MET-dependent cancer models
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Jing Ai, Yi Chen, Xia Peng, Yinchun Ji, Yong Xi, Yanyan Shen, Xinying Yang, Yi Su, Yi-Ming Sun, Yinglei Gao, Yuchi Ma, Bing Xiong, Jingkang Shen, Jian Ding, Meiyu Geng

    Because the receptor tyrosine kinase c-Met plays a critical role in tumor growth, metastasis, tumor angiogenesis and drug resistance, the c-Met axis represents an attractive therapeutic target. Herein, we report the first preclinical characterization of SCC244, a novel, potent and highly selective inhibitor of c-Met kinase. SCC244 showed subnanomolar potency against c-Met kinase activity and high selectivity versus 312 other tested protein kinases, making it one of the most selective c-Met inhibitors described to date. Moreover, this inhibitor profoundly and specifically inhibits c-Met signal transduction and thereby suppresses the c-Met-dependent neoplastic phenotype of tumor and endothelial cells. In xenografts of human tumor cell lines or non-small-cell lung cancer and hepatocellular carcinoma patient-derived tumor tissue driven by MET aberration, SCC244 administration exhibits robust antitumor activity at the well-tolerated doses. Additionally, the in vivo antitumor activity of SCC244 involves the inhibition of c-Met downstream signaling via a mechanism of combined anti-proliferation and antiangiogenic effects. The results of the current study provide a strong foundation for the clinical investigation of SCC244 in patients with tumors harboring c-Met pathway alterations.

    更新日期:2017-12-15
  • Afatinib is a new therapeutic approach in chordoma with a unique ability to target EGFR and Brachyury
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Paola Magnaghi, Barbara Salom, Liviana Cozzi, Nadia Amboldi, Dario Ballinari, Elena Tamborini, Fabio Gasparri, Alessia Montagnoli, Laura Raddrizzani, Alessio Somaschini, Roberta Bosotti, Christian Orrenius, Fabio Bozzi, Silvana Pilotti, Arturo Galvani, Josh Sommer, Silvia Stacchiotti, Antonella Isacchi

    Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in Phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRβ and EGFR tyrosine kinases, and assessed their anti-proliferative activity against a panel of chordoma cell lines. Chordoma cell lines were not responsive to MET and PDGFRβ inhibitors. U-CH1 and UM-Chor1 were sensitive to all EGFR inhibitors, while the remaining cell lines were generally insensitive to these drugs. Afatinib was the only EGFR inhibitor with activity across the chordoma panel. We then investigated the molecular mechanisms behind the responses observed and found that the anti-proliferative IC50s correlate with the unique ability of afatinib to promote degradation of EGFR and brachyury, an embryonic transcription factor considered a key driver of chordoma. Afatinib displayed potent antitumor efficacy in U-CH1, SF8894, CF322 and CF365 chordoma tumor models in vivo. In the panel analyzed, high EGFR phosphorylation and low AXL and STK33 expression correlated with higher sensitivity to afatinib and deserve further investigation as potential biomarkers of response. These data support the use of afatinib in clinical trials and provide the rationale for the upcoming European phase II study on afatinib in advanced chordoma.

    更新日期:2017-12-15
  • Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-01-01
    Yan Huang, Wei Hu, Jie Huang, Fanrong Shen, Yunjie Sun, Cristina Ivan, Sunila Pradeep, Robert Dood, Monika Haemmerle, Dahai Jiang, Lingegowda S. Mangala, Kyunghee Noh, Jean M. Hansen, Heather J Dalton, Rebecca Previs, Archana S. Nagaraja, Michael McGuire, Nicholas B Jennings, Russell R. Broaddus, Robert L. Coleman, Anil K. Sood

    While progesterone receptor (PR)-targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR-agonists (progestins) or PR-antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), while trametinib inhibited nuclear translocation of EGF induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior anti-tumor effects in uterine cancer models compared to either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib, significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation.

    更新日期:2017-12-15
  • Highlights of This Issue
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    American Association for Cancer Research

    ### [Venetsanakos et al. Page 2668][1] Many solid tumors demonstrate dysregulation of fibroblast growth factor receptors (FGFRs) but currently no selective inhibitors of FGFR are approved for cancer treatment. Here, Venetsanakos et al. describe the characterization of a pan-FGFR inhibitor PRN1371

    更新日期:2017-12-04
  • Precision Medicine: Progress, Pitfalls, and Promises
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Patrick G. Pilié, Patricia M. LoRusso, Timothy A. Yap

    See related article by Chae et al., [p. 2645][1] Cancer initiation and progression are driven by the accumulation of deleterious aberrations in key tumor suppressor genes and oncogenes. These are anomalies that give way to a network of interconnected, highly regulated pathways and biochemical

    更新日期:2017-12-04
  • Path toward Precision Oncology: Review of Targeted Therapy Studies and Tools to Aid in Defining "Actionability" of a Molecular Lesion and Patient Management Support
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Young Kwang Chae, Alan P. Pan, Andrew A. Davis, Sandip P. Patel, Benedito A. Carneiro, Razelle Kurzrock, Francis J. Giles

    Precision medicine trials and targeted therapies have shifted to the forefront of oncology. Although targeted therapies have shown initial promise, implementation across the broad landscape of oncology has many challenges. These limitations include an incomplete understanding of the functional significance of variant alleles as well as the need for clinical research and practice models that are more patient-centered and account for the complexity of individual patient tumors. Furthermore, successful implementation of targeted therapies will also be predicated on efforts to standardize the framework for patient management support. Here, we review current implementations of targeted therapies in precision oncology and discuss how “actionability” is defined for molecular targets in cancer therapeutics. We also comment on the growing need for bioinformatics tools and data platforms to complement advances in precision oncology. Finally, we discuss current frameworks for integrating precision oncology into patient management and propose an integrated model that combines features of molecular tumor boards and decision support systems. Mol Cancer Ther; 16(12); 2645–55. ©2017 AACR . See related article by Pilié et al., [p. 2641][1] [1]: /lookup/volpage/16/2641?iss=12

    更新日期:2017-12-04
  • Death by HDAC Inhibition in Synovial Sarcoma Cells
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Aimée N. Laporte, Neal M. Poulin, Jared J. Barrott, Xiu Qing Wang, Alireza Lorzadeh, Ryan Vander Werff, Kevin B. Jones, T. Michael Underhill, Torsten O. Nielsen

    Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell-cycle arrest, neuronal differentiation, and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb group targets were reactivated, including tumor suppressor CDKN2A , and proapoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and proapoptotic factors BIK, BIM, and BMF were important to apoptosis induction following HDAC inhibition in synovial sarcoma. HDAC inhibitor pathway activation results in apoptosis and decreased tumor burden following a 7-day quisinostat treatment in the Ptenfl/fl;hSS2 mouse model of synovial sarcoma. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of clinical treatment. Mol Cancer Ther; 16(12); 2656–67. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2639][1] [1]: /lookup/volpage/16/2639?iss=12

    更新日期:2017-12-04
  • The Irreversible Covalent Fibroblast Growth Factor Receptor Inhibitor PRN1371 Exhibits Sustained Inhibition of FGFR after Drug Clearance
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Eleni Venetsanakos, Ken A. Brameld, Vernon T. Phan, Erik Verner, Timothy D. Owens, Yan Xing, Danny Tam, Jacob LaStant, Kwan Leung, Dane E. Karr, Ronald J. Hill, Mary E. Gerritsen, David M. Goldstein, Jens Oliver Funk, J. Michael Bradshaw

    An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here, we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo , not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient-derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors. Mol Cancer Ther; 16(12); 2668–76. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2639][1] [1]: /lookup/volpage/16/2639?iss=12

    更新日期:2017-12-04
  • Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Coadministration
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Genshi Zhao, Colin F. Green, Yu-Hua Hui, Lourdes Prieto, Robert Shepard, Sucai Dong, Tao Wang, Bo Tan, Xueqian Gong, Lisa Kays, Robert L. Johnson, Wenjuan Wu, Shobha Bhattachar, Miriam Del Prado, James R. Gillig, Maria-Carmen Fernandez, Ken D. Roth, Sean Buchanan, Ming-Shang Kuo, Sandaruwan Geeganage, Timothy P. Burkholder

    NAMPT, an enzyme essential for NAD+ biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD+. LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. Mol Cancer Ther; 16(12); 2677–88. ©2017 AACR .

    更新日期:2017-12-04
  • The Combination of Metformin and Valproic Acid Induces Synergistic Apoptosis in the Presence of p53 and Androgen Signaling in Prostate Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Linh N.K. Tran, Ganessan Kichenadasse, Lisa M. Butler, Margaret M. Centenera, Katherine L. Morel, Rebecca J. Ormsby, Michael Z. Michael, Karen M. Lower, Pamela J. Sykes

    We investigated the potential of combining the hypoglycemic drug metformin (MET) and the antiepileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced antitumor responses in prostate cancer. Prostate cancer cell lines (LNCaP and PC-3), normal prostate epithelial cells (PrEC), and patient-derived prostate tumor explants were treated with MET and/or VPA. Proliferation and apoptosis were assessed. The role of p53 in response to MET + VPA was assessed in cell lines using RNAi in LNCaP (p53+) and ectopic expression of p53 in PC-3 (p53−). The role of the androgen receptor (AR) was investigated using the AR antagonist enzalutamide. The combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC-3, with no significant effect in PrEC. LNCaP, but not PC-3, demonstrated synergistic intrinsic apoptosis in response to MET + VPA. Knockdown of p53 in LNCaP (p53+, AR+) reduced the synergistic apoptotic response as did inhibition of AR. Ectopic expression of p53 in PC-3 (p53−, AR−) increased apoptosis in response to MET + VPA. In patient-derived prostate tumor explants, MET + VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells. In conclusion, we demonstrate that MET + VPA can synergistically kill more prostate cancer cells than either drug alone. The response is dependent on the presence of p53 and AR signaling, which have critical roles in prostate carcinogenesis. Further in vivo / ex vivo preclinical studies are required to determine the relative efficacy of MET + VPA as a potential treatment for prostate cancer. Mol Cancer Ther; 16(12); 2689–700. ©2017 AACR .

    更新日期:2017-12-04
  • HPMA-Copolymer Nanocarrier Targets Tumor-Associated Macrophages in Primary and Metastatic Breast Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Melissa N. Zimel, Chloe B. Horowitz, Vinagolu K. Rajasekhar, Alexander B. Christ, Xin Wei, Jianbo Wu, Paulina M. Wojnarowicz, Dong Wang, Steven R. Goldring, P. Edward Purdue, John H. Healey

    Polymeric nanocarriers such as N -(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Mol Cancer Ther; 16(12); 2701–10. ©2017 AACR .

    更新日期:2017-12-04
  • Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Haiyang Yu, Yuling Qiu, Xu Pang, Jian Li, Song Wu, Shuangshuang Yin, Lifeng Han, Yi Zhang, Chengyun Jin, Xiumei Gao, Wenwei Hu, Tao Wang

    Lycorine is a multifunctional bioactive compound, and it possesses potential anticancer activities. However, little is known about the underlying mechanism. In this research, we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells in vitro and in vivo . Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance–associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorine-induced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through the TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC. Mol Cancer Ther; 16(12); 2711–23. ©2017 AACR .

    更新日期:2017-12-04
  • ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus-Infected Cell Autophagic Death and Represses Tumor Growth
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Lu Dai, Aiping Bai, Charles D. Smith, Paulo C. Rodriguez, Fangyou Yu, Zhiqiang Qin

    Kaposi sarcoma–associated herpes virus (KSHV) is the etiologic agent of several malignancies, including Kaposi sarcoma and primary effusion lymphoma (PEL), which preferentially arise in HIV+ patients and lack effective treatment. Sphingosine kinase 2 (SphK2) is a key factor within sphingolipid metabolism, responsible for the conversion of proapoptotic ceramides to antiapoptotic sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to the accumulation of intracellular ceramides and induces apoptosis in KSHV-infected primary endothelial cells and PEL tumor cells but not in uninfected cells. In this study, we found that ABC294640 induces autophagic death instead of apoptosis in a KSHV long-term–infected immortalized endothelial cell-line, TIVE-LTC, but not in uninfected TIVE cells, through the upregulation of LC3B protein. Transcriptomic analysis indicates that many genes related to cellular stress responses, cell cycle/proliferation, and cellular metabolic process are altered in TIVE-LTC exposed to ABC294640. One of the candidates, Egr-1 , was found to directly regulate LC3B expression and was required for the ABC294640-induced autophagic death. By using a Kaposi sarcoma–like nude mice model with TIVE-LTC, we found that ABC294640 treatment significantly suppressed KSHV-induced tumor growth in vivo , which indicates that targeting sphingolipid metabolism, especially SphK2, may represent a promising therapeutic strategy against KSHV-related malignancies. Mol Cancer Ther; 16(12); 2724–34. ©2017 AACR .

    更新日期:2017-12-04
  • Restricted Delivery of Talazoparib Across the Blood-Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Sani H. Kizilbash, Shiv K. Gupta, Kenneth Chang, Ryo Kawashima, Karen E. Parrish, Brett L. Carlson, Katrina K. Bakken, Ann C. Mladek, Mark A. Schroeder, Paul A. Decker, Gaspar J. Kitange, Yuqiao Shen, Ying Feng, Andrew A. Protter, William F. Elmquist, Jann N. Sarkaria

    Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1–3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G2–M arrest in vitro . In vivo cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated. This talazoparib/temozolomide regimen prolonged tumor stasis more than temozolomide alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days versus 50 days temozolomide ( P = 0.005), 11 days placebo ( P < 0.001)]. However, talazoparib/temozolomide did not accentuate survival beyond that of temozolomide alone in corresponding orthotopic xenografts [median survival 37 vs. 30 days with temozolomide ( P = 0.93), 14 days with placebo, P < 0.001]. Average brain and plasma talazoparib concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49 ± 0.07 ng/g and 25.5±4.1 ng/mL, respectively. The brain/plasma distribution of talazoparib in Bcrp−/− versus wild-type (WT) mice did not differ, whereas the brain/plasma ratio in Mdr1a/b−/− mice was higher than WT mice (0.23 vs. 0.02, P < 0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased talazoparib accumulation in MDCKII cells. These results indicate that talazoparib has significant MDR1 efflux liability that may restrict delivery across the blood–brain barrier, and this may explain the loss of talazoparib-mediated temozolomide sensitization in orthotopic versus heterotopic GBM xenografts. Mol Cancer Ther; 16(12); 2735–46. ©2017 AACR .

    更新日期:2017-12-04
  • Pharmacological Dual Inhibition of Tumor and Tumor-Induced Functional Limitations in a Transgenic Model of Breast Cancer
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Ruizhong Wang, Poornima Bhat-Nakshatri, Maria B. Padua, Mayuri S Prasad, Manjushree Anjanappa, Max Jacobson, Courtney Finnearty, Victoria Sefcsik, Kyle McElyea, Rachael Redmond, George Sandusky, Narsimha Penthala, Peter A Crooks, Jianguo Liu, Teresa Zimmers, Harikrishna Nakshatri

    Breast cancer progression is associated with systemic effects, including functional limitations and sarcopenia without the appearance of overt cachexia. Autocrine/paracrine actions of cytokines/chemokines produced by cancer cells mediate cancer progression and functional limitations. The cytokine-inducible transcription factor NF-κB could be central to this process, as it displays oncogenic functions and is integral to the Pax7:MyoD:Pgc-1β:miR-486 myogenesis axis. We tested this possibility using the MMTV-PyMT transgenic mammary tumor model and the NF-κB inhibitor dimethylaminoparthenolide (DMAPT). We observed deteriorating physical and functional conditions in PyMT+ mice with disease progression. Compared with wild-type mice, tumor-bearing PyMT+ mice showed decreased fat mass, impaired rotarod performance, and reduced grip strength as well as increased extracellular matrix (ECM) deposition in muscle. Contrary to acute cachexia models described in the literature, mammary tumor progression was associated with reduction in skeletal muscle stem/satellite-specific transcription factor Pax7. Additionally, we observed tumor-induced reduction in Pgc-1β in muscle, which controls mitochondrial biogenesis. DMAPT treatment starting at 6 to 8 weeks age prior to mammary tumor occurrence delayed mammary tumor onset and tumor growth rates without affecting metastasis. DMAPT overcame cancer-induced functional limitations and improved survival, which was accompanied with restoration of Pax7, Pgc-1β, and mitochondria levels and reduced ECM levels in skeletal muscles. In addition, DMAPT restored circulating levels of 6 out of 13 cancer-associated cytokines/chemokines changes to levels seen in healthy animals. These results reveal a pharmacological approach for overcoming cancer-induced functional limitations, and the above-noted cancer/drug-induced changes in muscle gene expression could be utilized as biomarkers of functional limitations. Mol Cancer Ther; 16(12); 2747–58. ©2017 AACR .

    更新日期:2017-12-04
  • Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Katherine M. Morgan, Bruce S. Fischer, Francis Y. Lee, Jamie J. Shah, Joseph R. Bertino, Jeffrey Rosenfeld, Amartya Singh, Hossein Khiabanian, Sharon R. Pine

    Notch signaling is aberrantly activated in approximately one third of non–small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor, and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin [mean combination index (CI) value, 0.54 and 0.85, respectively, P = 0.01]. On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI, 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line– and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel and that wild-type KRAS and BRAF status may predict better patient response to the combination therapy. Mol Cancer Ther; 16(12); 2759–69. ©2017 AACR .

    更新日期:2017-12-04
  • Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Ramakumar Tummala, Wei Lou, Allen C. Gao, Nagalakshmi Nadiminty

    Prostate cancer remains dependent on androgen receptor signaling even after castration. Aberrant androgen receptor signaling in castration-resistant prostate cancer is mediated by mechanisms such as alterations in the androgen receptor and activation of interacting signaling pathways. Clinical evidence confirms that resistance to the next-generation antiandrogen, enzalutamide, may be mediated to a large extent by alternative splicing of the androgen receptor to generate constitutively active splice variants such as AR-V7. The splice variants AR-V7 and ARv567es have been implicated in the resistance to not only enzalutamide, but also to abiraterone and other conventional therapeutics such as taxanes. Numerous studies, including ours, suggest that splicing factors such as hnRNPA1 promote the generation of AR-V7, thus contributing to enzalutamide resistance in prostate cancer cells. In the present study, we discovered that quercetin, a naturally occurring polyphenolic compound, reduces the expression of hnRNPA1, and consequently, that of AR-V7. The suppression of AR-V7 by quercetin resensitizes enzalutamide-resistant prostate cancer cells to treatment with enzalutamide. Our results indicate that quercetin downregulates hnRNPA1 expression, downregulates the expression of AR-V7, antagonizes androgen receptor signaling, and resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vivo in mouse xenografts. These findings demonstrate that suppressing the alternative splicing of the androgen receptor may have important implications in overcoming the resistance to next-generation antiandrogen therapy. Mol Cancer Ther; 16(12); 2770–9. ©2017 AACR .

    更新日期:2017-12-04
  • Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Michael M. Grandal, Serhiy Havrylov, Thomas T. Poulsen, Klaus Koefoed, Anna Dahlman, Gunther R. Galler, Paolo Conrotto, Sara Collins, Karsten W. Eriksen, Dafna Kaufman, George F.Vande Woude, Helle J. Jacobsen, Ivan D. Horak, Michael Kragh, Johan Lantto, Thomas Bouquin, Morag Park, Mikkel W. Pedersen

    Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here, we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG1 antibodies against nonoverlapping epitopes of MET. Sym015 was selected by high-throughput screening searching for antibody mixtures with superior growth-inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified MET locus and was confirmed in vivo . Sym015 was found to exert its activity via multiple mechanisms. It disrupted interaction of MET with the HGF ligand and prompted activity-independent internalization and degradation of the receptor. In addition, Sym015 induced high levels of CDC and ADCC in vitro . The importance of these effector functions was confirmed in vivo using an Fc-effector function–attenuated version of Sym015. The enhanced effect of the two antibodies in Sym015 on both MET degradation and CDC and ADCC is predicted to render Sym015 superior to single antibodies targeting MET. Our results demonstrate strong potential for use of Sym015 as a therapeutic antibody mixture for treatment of MET-driven tumors. Sym015 is currently being tested in a phase I dose escalation clinical trial ([NCT02648724][1]). Mol Cancer Ther; 16(12); 2780–91. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2639][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02648724&atom=%2Fmolcanther%2F16%2F12%2F2780.atom [2]: /lookup/volpage/16/2639?iss=12

    更新日期:2017-12-04
  • Superior Properties of Fc-comprising scTRAIL Fusion Proteins
    Mol. Cancer Ther. (IF 5.764) Pub Date : 2017-12-01
    Meike Hutt, Lisa Marquardt, Oliver Seifert, Martin Siegemund, Ines Müller, Dagmar Kulms, Klaus Pfizenmaier, Roland E. Kontermann

    The TNF-related apoptosis-inducing ligand (TRAIL) has been considered as a promising molecule for cancer treatment. However, clinical studies with soluble TRAIL failed to show therapeutic activity, which resulted in subsequent development of more potent TRAIL-based therapeutics. In this study, we applied defined oligomerization and tumor targeting as strategies to further improve the activity of a single-chain version of TRAIL (scTRAIL). We compared three different formats of EGF receptor (EGFR)-targeting dimeric scTRAIL fusion proteins [Diabody (Db)-scTRAIL, scFv-IgE heavy chain domain 2 (EHD2)-scTRAIL, scFv-Fc-scTRAIL] as well as two nontargeted dimeric scTRAIL molecules (EHD2-scTRAIL, Fc-scTRAIL) to reveal the influence of targeting and protein format on antitumor activity. All EGFR-targeted dimeric scTRAIL molecules showed similar binding properties and comparable cell death induction in vitro , exceeding the activity of the respective nontargeted dimeric format and monomeric scTRAIL. Superior properties were observed for the Fc fusion proteins with respect to production and in vivo half-life. In vivo studies using a Colo205 xenograft model revealed potent antitumor activity of all EGFR-targeting formats and Fc-scTRAIL and furthermore highlighted the higher efficacy of fusion proteins comprising an Fc part. Despite enhanced in vitro cell death induction of targeted scTRAIL molecules, however, comparable antitumor activities were found for the EGFR-targeting scFv-Fc-scTRAIL and the nontargeting Fc-scTRAIL in vivo . Mol Cancer Ther; 16(12); 2792–802. ©2017 AACR . This article is featured in Highlights of This Issue, [p. 2639][1] [1]: /lookup/volpage/16/2639?iss=12

    更新日期:2017-12-04
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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