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  • RANKL-targeted combination therapy with osteoprotegerin variant devoid of TRAIL binding exerts biphasic effects on skeletal remodeling and antitumor immunity
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-23
    Hong Wang, Reading Ashton, Jonathan A Hensel, Joo Hyoung Lee, Vinayak Khattar, Yong Wang, Jessy S Deshane, Selvarangan Ponnazhagan

    Complexities in treating breast cancer with bone metastasis are enhanced by a vicious protumorigenic pathology, involving a shift in skeletal homeostasis towards aggressive osteoclast activity and polarization of immune cells supporting tumor growth and immune suppression. Recent studies signify the role of receptor activator of nuclear factor-κB ligand (RANKL) beyond skeletal pathology in breast cancer;

    更新日期:2020-11-25
  • A Combination of BRD4 and HDAC3 Inhibitors Synergistically Suppresses Glioma Stem Cell Growth by Blocking GLI1/IL6/STAT3 Signaling Axis
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-17
    Qian Wang, Shengnan Jia, Ding Wang, Xuyang Chen, Dhan V. Kalvakolanu, Hongwu Zheng, Xiaodong Wei, Naiyan Wen, Hang Liang, Baofeng Guo, Ling Zhang

    Glioma stem cells (GSC) are essential for tumor maintenance, invasiveness, and recurrence. Using a global epigenetic screening with an shRNA library, we identified HDAC3 as an essential factor for GSC stemness. Here, we demonstrated that GSCs poorly respond to an HDAC3 inhibitor, RGFP966 (HDAC3i), owing to the production of IL6 and STAT3 activation. To enhance GSC sensitivity to HDAC3i, we explored

    更新日期:2020-11-18
  • TriTACs, a novel class of T cell-engaging protein constructs designed for the treatment of solid tumors
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-17
    Richard J Austin, Bryan D Lemon, Wade H Aaron, Manasi Barath, Patricia A Culp, Robert B DuBridge, Luke B Evnin, Adrie Jones, Anand Panchal, Purbasa Patnaik, Vanitha Ramakrishnan, Sony S. Rocha, Pui Seto, Kenneth Sexton, Kathryn L Strobel, Russell Wall, Stephen Yu, Timothy Z. Yu, Che-Leung Law, Patrick A Baeuerle, Holger Wesche

    T cells have a unique capability to eliminate cancer cells and fight malignancies. Cancer cells have adopted multiple immune evasion mechanisms aimed at inhibiting T cells. Dramatically improved patient outcomes have been achieved with therapies genetically reprogramming T cells, blocking T cell inhibition by cancer cells, or transiently connecting T cells with cancer cells for redirected lysis. This

    更新日期:2020-11-18
  • IOX1 Suppresses Wnt Target Gene Transcription and Colorectal Cancer Tumorigenesis Through Inhibition of KDM3 Histone Demethylases
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-17
    Rosalie G. Hoyle, Huiqun Wang, Yana Cen, Yan Zhang, Jiong Li

    Epigenetic activation of Wnt/β-catenin signaling plays a critical role in Wnt-induced tumorigenesis, notably in colorectal cancers (CRCs). KDM3 and KDM4 histone demethylases have been reported to promote oncogenic Wnt signaling through demethylation of H3K9 on Wnt target gene promoters and are suggested to be potential therapeutic targets. However, potent inhibitors for these regulators are still not

    更新日期:2020-11-18
  • Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and Biopsy S100A4 as a Clinical Predictor
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-17
    Arsheed A. Ganaie, Adrian P. Mansini, Tabish Hussain, Arpit Rao, Hifzur R. Siddique, Ashraf Shabaneh, Marina G. Ferrari, Paari Murugan, Jörg Klingelhöfer, Jinhua Wang, Noona Ambartsumian, Christopher A. Warlick, Badrinath R. Konety, Mohammad Saleem

    S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy- S100A4 gene alteration independently predicts the outcome

    更新日期:2020-11-18
  • Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis addicted breast tumor growth.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-17
    Shauni Lien Geeraerts, Kim Rosalie Kampen, Gianmarco Rinaldi, Purvi Gupta, Melanie Planque, Nikolaos Louros, Elien Heylen, Kaat De Cremer, Katrijn De Brucker, Stijn Vereecke, Benno Verbelen, Pieter Vermeersch, Joost Schymkowitz, Frederic Rousseau, David Cassiman, Sarah-Maria Fendt, Arnout Voet, Bruno P.A. Cammue, Karin Thevissen, Kim De Keersmaecker

    Metabolic rewiring is a hallmark of cancer that supports tumor growth, survival and chemotherapy resistance. While normal cells often rely on extracellular serine and glycine supply, a significant subset of cancers becomes addicted to intracellular serine/glycine synthesis, offering an attractive drug target. Previously developed inhibitors of serine/glycine synthesis enzymes did not reach clinical

    更新日期:2020-11-18
  • Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-17
    Gabrielle McDonald, Victor Chubukov, John Coco, Kevin Truskowski, Rohini Narayanaswamy, Sung Choe, Mya Steadman, Erin Artin, Anil K. Padyana, Lei Jin, Sebastien Ronseaux, Charles Locuson, Zi-Peng Fan, Tabea Erdmann, Alan Mann, Sebastian Hayes, Mark Fletcher, Kavitha Nellore, Siva Sanjeeva Rao, Hosahalli Subramanya, K. Satish Reddy, Sunil K. Panigrahi, Thomas Antony, Sreevalsam Gopinath, Zhihua Sui

    Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic

    更新日期:2020-11-18
  • Targeting STAT3 with proteolysis targeting chimeras (PROTACs) and next generation antisense oligonucleotides
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-17
    Jamie V Shiah, Jennifer R. Grandis, Daniel E Johnson

    Signal transducer and activator of transcription 3 (STAT3) has been recognized for its key role in the progression of cancer, where it is frequently upregulated or constitutively hyperactivated, contributing to tumor cell proliferation, survival, and migration, as well as angiogenesis and suppression of anti-tumor immunity. Given the ubiquity of dysregulated STAT3 activity in cancer, it has long been

    更新日期:2020-11-18
  • Inhibition of EZH2 Enhances the Antitumor Efficacy of Metformin in Prostate Cancer
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-16
    Yifan Kong, Yanquan Zhang, Fengyi Mao, Zhuangzhuang Zhang, Zhiguo Li, Ruixin Wang, Jinghui Liu, Xiaoqi Liu

    Upregulation of EZH2 is associated with advanced stage and poor prognosis of prostate cancer; therefore, it is likely to be a promising therapeutic target. Metformin, a drug that has been used to treat type 2 diabetes, was found to have antineoplastic activity in different cancers. Herein, we report that the combination of metformin and the EZH2 inhibitor GSK126 exerts synergistic inhibition on prostate

    更新日期:2020-11-17
  • Repurposing of a Thromboxane Receptor Inhibitor Based on a Novel Role in Metastasis Identified by Phenome-Wide Association Study
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-16
    Thomas A. Werfel, Donna J. Hicks, Bushra Rahman, Wendy E. Bendeman, Matthew T. Duvernay, Jae G. Maeng, Heidi Hamm, Robert R. Lavieri, Meghan M. Joly, Jill M. Pulley, David L. Elion, Dana M. Brantley-Sieders, Rebecca S. Cook

    Although new drug discoveries are revolutionizing cancer treatments, repurposing existing drugs would accelerate the timeline and lower the cost for bringing treatments to cancer patients. Our goal was to repurpose CPI211, a potent and selective antagonist of the thromboxane A2-prostanoid receptor (TPr), a G-protein–coupled receptor that regulates coagulation, blood pressure, and cardiovascular homeostasis

    更新日期:2020-11-17
  • Molecular Characterization of Appendiceal Goblet Cell Carcinoid
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-16
    Hiroyuki Arai, Yasmine Baca, Francesca Battaglin, Natsuko Kawanishi, Jingyuan Wang, Shivani Soni, Wu Zhang, Joshua Millstein, Curtis Johnston, Richard M. Goldberg, Philip A. Philip, Andreas Seeber, Joanne Xiu, Jimmy J. Hwang, Anthony F. Shields, John L. Marshall, W. Michael Korn, Heinz-Josef Lenz

    Goblet cell carcinoid (GCC) is a distinct subtype of appendiceal neoplasm that exhibits unique clinical and pathologic features. We aimed to reveal the molecular profiles of GCC compared with other appendiceal tumors, such as adenocarcinomas and neuroendocrine tumors. A total of 495 appendiceal tumor samples (53 GCCs, 428 adenocarcinomas, and 14 neuroendocrine tumors) were tested with next-generation

    更新日期:2020-11-17
  • Circulating tumor cells and biomarker modulation with olaratumab monotherapy followed by olaratumab plus doxorubicin: phase 1b study in soft tissue sarcoma patients
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-11
    Javier Martín-Broto, Antonio Lopez Pousa, Andrew S Brohl, Brian A. Van Tine, Benjamin Powers, Silvia Stacchiotti, Jean-Yves Blay, James S. Hu, Gerard J. Oakley, Hong Wang, Anna M. Szpurka, Donna E Levy, Gary Mo, Matteo Ceccarelli, Robin L. Jones

    This phase 1b study enumerated whole blood circulating tumor cells (CTCs) and evaluated biomarkers in patients with potentially resectable soft tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for 1 cycle followed by up to 6 cycles of olaratumab (20 mg/kg, Cycles 1-2; 15 mg/kg Cycles 3-7) plus doxorubicin (75 mg/m2 on Day 1). CTCs, platelet-derived growth factor receptors (PDGFRs)

    更新日期:2020-11-12
  • Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody Drug Conjugates to Increase In Vivo Efficacy
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-11
    Jose F Ponte, Leanne Lanieri, Eshita Khera, Rassol Laleau, Olga Ab, Christopher Espelin, Neeraj Kohli, Bahar Matin, Yulius Setiady, Michael L Miller, Thomas A. Keating, Ravi Chari, Jan Pinkas, Richard Gregory, Greg M Thurber

    Several antibody-drug conjugates (ADCs) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRα). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react

    更新日期:2020-11-12
  • Rapid Induction of the Unfolded Protein Response and Apoptosis by Estrogen Mimic TTC-352 for the Treatment of Endocrine-Resistant Breast Cancer
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-11
    Balkees Abderrahman, Philipp Y. Maximov, Ramona F. Curpan, Sean W Fanning, Jay S Hanspal, Ping Fan, Charles E Foulds, Yue Chen, Anna Malovannaya, Antrix Jain, Rui Xiong, Geoffrey L Greene, Debra A. Tonetti, Gregory R.J. Thatcher, V. Craig Jordan

    Patients with long-term estrogen-deprived breast cancer (BC), after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen's anti-tumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecological and non-gynecological adverse events thus the development of safer estrogenic

    更新日期:2020-11-12
  • PLK1 and NOTCH Positively Correlate in Melanoma and their Combined Inhibition Results in Synergistic Modulations of Key Melanoma Pathways
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-11
    Shengqin Su, Gagan Chhabra, Mary A. Ndiaye, Chandra K. Singh, Ting Ye, Wei Huang, Colin N Dewey, Vijayasaradhi Setaluri, Nihal Ahmad

    Melanoma is one of the most serious forms of skin cancer, and its increasing incidence coupled with non-lasting therapeutic options for metastatic disease highlight the need for additional novel approaches for its management. In this study, we determined the potential interactions between polo-like kinase 1 (PLK1, a serine/threonine kinase involved in mitotic regulation) and NOTCH1 (a type I transmembrane

    更新日期:2020-11-12
  • Therapeutic vulnerabilities of transcription factors in AML
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-06
    Irum Khan, Elizabeth A. Eklund, Andrei L Gartel

    Acute myeloid leukemia (AML) is characterized by impaired myeloid lineage differentiation, uncontrolled proliferation and inhibition of pro-apoptotic pathways. In spite of a relatively homogenous clinical disease presentation, risk of long-term survival in AML varies from 20-80% depending on molecular disease characteristics. In recognition of the molecular heterogeneity of AML, the European Leukemia

    更新日期:2020-11-09
  • BRCA1/MAD2L1 deficiency disrupts the spindle assembly checkpoint to confer vinorelbine resistance in mesothelioma
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-06
    Sara Busacca, Laura O'Regan, Anita Singh, Annabel J Sharkey, Alan G Dawson, Joanna Dzialo, Aimee Parsons, Neelam Kumar, Laurel M Schunselaar, Naomi Guppy, Apostolos Nakas, Michael Sheaff, Aaron S Mansfield, Sam M. Janes, Paul Baas, Andrew M Fry, Dean A Fennell

    Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here we show that BRCA1 silencing abrogated vinorelbine-induced cell cycle arrest

    更新日期:2020-11-09
  • A Precision Medicine Drug Discovery Pipeline Identifies Combined CDK2 and 9 Inhibition as a Novel Therapeutic Strategy in Colorectal Cancer
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-06
    Jason A. Somarelli, Roham Salman Roghani, Ali Sanjari Moghaddam, Beatrice C Thomas, Gabrielle Rupprecht, Kathryn E Ware, Erdem Altunel, John B. Mantyh, So Young Kim, Shannon J McCall, Xiling Shen, Christopher R Mantyh, David S. Hsu

    Colorectal cancer is the 3rd most common cancer in the US and responsible for over 50,000 deaths each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new treatments for this deadly disease. To address this need, we developed a precision medicine pipeline that integrates high-throughput chemical screens with matched patient-derived

    更新日期:2020-11-09
  • Rigosertib induces mitotic arrest and apoptosis in RAS-driven rhabdomyosarcoma and neuroblastoma
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-06
    Joshua T. Kowalczyk, Xiaolin Wan, Edjay R. Hernandez, Ruibai Luo, Gaelyn C. Lyons, Kelli M Wilson, Devorah C. Gallardo, Kristine A. Isanogle, Christina M Robinson, Arnulfo Mendoza, Christine M Heske, Jinqiu-Qiu Chen, Xiaoling Luo, Alexander E. Kelly, Simone Difilippantonio, Robert W. Robey, Craig J. Thomas, Dan L. Sackett, Deborah K. Morrison, Paul A. Randazzo, Lisa M Miller Jenkins, Marielle E. Yohe

    Relapsed pediatric rhabdomyosarcomas (RMS) and neuroblastomas (NB) have a poor prognosis despite multi-modality therapy. In addition, the current standard of care for these cancers includes vinca alkaloids that have severe toxicity profiles, further underscoring the need for novel therapies for these malignancies. Here, we show that the small molecule rigosertib inhibits the growth of RMS and NB cell

    更新日期:2020-11-09
  • Enhanced immunotherapy with LHRH-R targeted lytic peptide in ovarian cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Mark Seungwook Kim,Shaolin Ma,Anca Chelariu-Raicu,Carola Leuschner,Hector W Alila,Sanghoon Lee,Robert L Coleman,Anil K Sood

    Here, we examined the role of EP-100 [luteinizing hormone-releasing hormone (LHRH) ligand joined to a lytic peptide], improving the efficacy of immune checkpoint blockade. LHRH-R–positive murine ovarian cancer cells (ID8, IG10, IF5, and 2C12) were sensitive to EP-100 and were specifically killed at low micromolar levels through LHRH-R. EP-100 increased PD-L1 levels on murine ovarian cancer cells. In

    更新日期:2020-11-03
  • Nf1 mutant tumors undergo transcriptome and kinome re-modeling after inhibition of either mTOR or MEK.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Daniela Pucciarelli,Steven P Angus,Benjamin Huang,Chi Zhang,Hiroki J Nakaoka,Ganesh Krishnamurthi,Sourav Bandyopadhyay,D Wade Clapp,Kevin Shannon,Gary L Johnson,Jean L Nakamura

    Loss of the tumor suppressor NF1 leads to activation of RAS effector pathways, which are therapeutically targeted by inhibition of mTOR (mTORi) or MEK (MEKi). However, therapeutic inhibition of RAS effectors leads to the development of drug resistance and ultimately disease progression. To investigate molecular signatures in the context of NF1 loss and subsequent acquired drug resistance, we analyzed

    更新日期:2020-11-03
  • Calcium channel blockers impair the antitumor activity of anti-CD20 monoclonal antibodies by blocking EGR-1 induction.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Ivana Spasevska,Eva Laure Matera,Kamel Chettab,Jade Ville,Marie Potier-Cartereau,Lars Petter Jordheim,Catherine Thieblemont,Denis Sahin,Christian Klein,Charles Dumontet

    Direct cell death induction, in addition to immune-effector cell-mediated mechanisms, is one of the key mechanisms of action of anti-CD20 antibodies, and yet the signaling pathways implicated remain poorly investigated. Here we show that the transcription factor EGR-1 is rapidly induced by anti-CD20 antibodies and is a key mediator for CD20-induced cell death. EGR-1 induction results from an increased

    更新日期:2020-11-03
  • Circulating Tumor Cells In Advanced Cervical Cancer: NRG Oncology - Gynecologic Oncology Group Study 240 (NCT 00803062).
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Krishnansu S Tewari,Michael W Sill,Bradley J Monk,Richard T Penson,David H Moore,Heather A Lankes,Lois M Ramondetta,Lisa M Landrum,Leslie M Randall,Ana Oaknin,Mario M Leitao,Eric L Eisenhauer,Paul DiSilvestro,Linda Van Le,Michael L Pearl,James J Burke,Ritu Salani,Debra L Richardson,Helen E Michael,David W Kindelberger,Michael J Birrer

    To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the

    更新日期:2020-11-03
  • Microparticle Encapsulation of a Prostate-Targeted Biologic for the Treatment of Liver Metastases in a Preclinical Model of Castration-Resistant Prostate Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Oliver C Rogers,Lizamma Antony,Oren Levy,Nitin Joshi,Brian W Simons,Susan Dalrymple,Marc Rosen,Andrew Pickering,Haoyue Lan,Heidi Kuang,Sudhir H Ranganath,Lei Zheng,Jeffrey M Karp,S Peter Howard,Samuel R Denmeade,John T Isaacs,W Nathaniel Brennen

    PRX302 is a highly potent, mutant bacterial pore-forming biologic protoxin engineered for selective activation by PSA, a serine protease expressed by benign and malignant prostate epithelial cells. Although being developed as a local therapy for benign prostatic hyperplasia and localized prostate cancer, PRX302 cannot be administered systemically as a treatment for metastatic disease due to binding

    更新日期:2020-11-03
  • Dual mechanisms of novel CD73-targeted antibody and antibody-drug conjugate in inhibiting lung tumor growth and promoting antitumor immune-effector function.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Rui Jin,Liang Liu,Yun Xing,Tao Meng,Lanping Ma,Jinpeng Pei,Ying Cong,Xuesai Zhang,Zhiqiang Ren,Xin Wang,Jingkang Shen,Ker Yu

    Although tyrosine kinase inhibitor therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non–small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched

    更新日期:2020-11-03
  • LILRB4-Targeting Antibody-Drug Conjugates for the Treatment of Acute Myeloid Leukemia.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Yasuaki Anami,Mi Deng,Xun Gui,Aiko Yamaguchi,Chisato M Yamazaki,Ningyan Zhang,Chengcheng Zhang,Zhiqiang An,Kyoji Tsuchikama

    Acute myeloid leukemia (AML) is the most common and aggressive blood cancer in adults. In particular, significant unmet medical needs exist for effective treatment strategies for acute myelomonocytic leukemia (M4) and acute monocytic leukemia (M5) AML subtypes. Antibody–drug conjugates (ADC) are a promising drug class for AML therapy, as demonstrated by the FDA-approved anti-CD33 ADC, gemtuzumab ozogamicin

    更新日期:2020-11-03
  • Menin-mediated repression of glycolysis in combination with autophagy protects colon cancer against small molecule EGFR inhibitors.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Bryson W Katona,Taylor Hojnacki,Rebecca A Glynn,Kayla E Paulosky,Katherine M Szigety,Yan Cao,Xuyao Zhang,Zijie Feng,Xin He,Jian Ma,Xianxin Hua

    Menin serves both tumor suppressor and promoter roles in a highly tumor-specific manner. In colorectal cancer, menin is overexpressed and plays a critical role in regulating transcription of SKP2, and combined treatment with a menin inhibitor and small-molecule EGFR inhibitor (EGFRi) leads to synergistic killing of colorectal cancer cells. However, the full spectrum of menin function in colorectal

    更新日期:2020-11-03
  • Efficacy, tolerability and pharmacokinetics of combined targeted MEK and dual mTORC1/2 inhibition in a preclinical model of mucosal melanoma.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Bih-Rong Wei,Shelley B Hoover,Cody J Peer,Jennifer E Dwyer,Hibret A Adissu,Priya Shankarappa,Howard Yang,Maxwell Lee,Tyler J Peat,William D Figg,R Mark Simpson

    Melanomas arising in the mucous membranes are a rare and aggressive subtype. New treatment approaches are needed, yet accumulating sufficient evidence to improve patient outcomes is difficult. Clinical and pathological correlates between human and canine mucosal melanomas are substantial, and the relatively greater incidence of spontaneous naturally occurring mucosal melanoma in dogs represents a promising

    更新日期:2020-11-03
  • Osimertinib, an EGFR tyrosine kinase inhibitor, exerts anti-tumor activity in preclinical NSCLC models harboring the uncommon EGFR mutations G719X or L861Q or S768I.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Nicolas Floc'h,Sangbin Lim,Sue Bickerton,Afshan Ahmed,Jonathan Orme,Jelena Urosevic,Matthew J Martin,Darren Ae Cross,Byoung Chul Cho,Paul D Smith

    Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M–resistance mutations with lower activity against wild-type EGFR and has demonstrated efficacy in non–small cell lung cancer (NSCLC) CNS metastases. The sensitizing mutations, the in-frame deletions in exon 19

    更新日期:2020-11-03
  • CH7233163 overcomes osimertinib resistant EGFR-Del19/T790M/C797S mutation.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Kenji Kashima,Hiroki Kawauchi,Hiromi Tanimura,Yukako Tachibana,Takashi Chiba,Takuya Torizawa,Hiroshi Sakamoto

    Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M–mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (e.g., EAI-045) that potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study

    更新日期:2020-11-03
  • Synthetic Lethal Metabolic Targeting of Androgen Deprived Prostate Cancer Cells with Metformin.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Bing Yang,Shivashankar Damodaran,Tariq A Khemees,Mikolaj J Filon,Adam Schultz,Joseph Gawdzik,Tyler Etheridge,Dmitry Malin,Kyle A Richards,Vincent L Cryns,David F Jarrard

    The initiation of androgen-deprivation therapy (ADT) induces susceptibilities in prostate cancer cells that make them vulnerable to synergistic treatment and enhanced cell death. Senescence results in cell-cycle arrest, but cells remain viable. In this study, we investigated the mechanisms by which prostate cancer cells undergo senescence in response to ADT, and determined whether an FDA-approved antidiabetic

    更新日期:2020-11-03
  • An RNA-binding protein, Hu-antigen R, in pancreatic cancer epithelial to mesenchymal transition, metastasis, and cancer stem cells.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Ruochen Dong,Ping Chen,Kishore Polireddy,Xiaoqing Wu,Tao Wang,Remya Ramesh,Dan A Dixon,Liang Xu,Jeffrey Aubé,Qi Chen

    Pancreatic cancer has poor prognosis and treatment outcomes due to its highly metastatic nature and resistance to current treatments. The RNA-binding protein (RBP) Hu-antigen R (HuR) is a central player in posttranscriptional regulation of cancer-related gene expression, and contributes to tumorigenesis, tumor growth, metastasis, and drug resistance. HuR has been suggested to regulate pancreatic cancer

    更新日期:2020-11-03
  • The dual androgen receptor and glucocorticoid receptor antagonist CB-03-10 as potential treatment for tumors that have acquired GR-mediated resistance to AR blockade.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Caridad Rosette,Frances J Agan,Niccolette Rosette,Alessandro Mazzetti,Luigi Moro,Mara Gerloni

    CB-03–10 (cortexolone 17α-valerate-21-propionate) is a synthetic steroidal compound derived from cortexolone (11-deoxycortisone), an intermediate in cortisol biosynthesis. Characterization of the activity of CB-03-10 and its main related compound CB-03–05 (cortexolone 17α-valerate) included in vitro binding to the androgen and glucocorticoid receptors (AR and GR), antagonism of AR and GR transcriptional

    更新日期:2020-11-03
  • Therapeutic Targeting of Mitochondrial One-Carbon Metabolism in Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Aamod S Dekhne,Zhanjun Hou,Aleem Gangjee,Larry H Matherly

    One-carbon (1C) metabolism encompasses folate-mediated 1C transfer reactions and related processes, including nucleotide and amino acid biosynthesis, antioxidant regeneration, and epigenetic regulation. 1C pathways are compartmentalized in the cytosol, mitochondria, and nucleus. 1C metabolism in the cytosol has been an important therapeutic target for cancer since the inception of modern chemotherapy

    更新日期:2020-11-03
  • Preclinical Development of MGC018, a Duocarmycin-based Antibody-drug Conjugate Targeting B7-H3 for Solid Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    Juniper A Scribner,Jennifer G Brown,Thomas Son,Michael Chiechi,Pam Li,Sharad Sharma,Hua Li,Anushka De Costa,Ying Li,Yan Chen,Ann Easton,Nicholas C Yee-Toy,Francine Z Chen,Sergey Gorlatov,Bhaswati Barat,Ling Huang,Christina R Wolff,Jeff Hooley,Tim E Hotaling,Timur Gaynutdinov,Valentina Ciccarone,James Tamura,Scott Koenig,Paul A Moore,Ezio Bonvini,Deryk Loo

    B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non–small cell lung cancer, and breast cancer. Overexpression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this

    更新日期:2020-11-03
  • Selected Articles from This Issue
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-11-01
    American Association for Cancer Research

    ### [Scribner et al. Page 2235][1] B7-H3, a member of the B7 family of immune regulators, is often overexpressed in cancers. In this manuscript, Scribner and colleagues disclose MGC018, an antibody-drug conjugate (ADC) targeting B7-H3. MGC018 carries a duocarmycin payload linked to the humanized

    更新日期:2020-11-03
  • HIV-protease inhibitors block HPV16-induced murine cervical carcinoma and promote vessel normalization in association with MMP-9 inhibition and TIMP-3 induction
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-20
    Yaqi Qiu, Federica Maione, Stefania Capano, Claudia Meda, Orietta Picconi, Serena Brundu, Alberto Pisacane, Anna Sapino, Clelia Palladino, Giovanni Barillari, Paolo Monini, Federico Bussolino, Barbara Ensoli, Cecilia Sgadari, Enrico Giraudo

    Antiretrovirals belonging to the HIV protease inhibitor (HIV-PI) class exert inhibitory effects across several cancer types by targeting tumor cells and its microenvironment. Cervical carcinoma (CC) represents a leading cause of morbidity and mortality, particularly in women doubly infected with high-risk human papillomaviruses (HR-HPV) and the human immunodeficiency virus (HIV); of note, combined

    更新日期:2020-10-26
  • Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90Y-DOTA
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-20
    Johnnie J Orozco, Aimee L. Kenoyer, Yukang Lin, Shyril O'Steen, Rosario Guel, Margaret E. Nartea, Alexandra H. Hernandez, Mark D. Hylarides, Darrell R Fisher, Ethan R. Balkin, Donald K Hamlin, D. Scott Wilbur, Kelly D Orcutt, K. Dane Wittrup, Damian J Green, Ajay K Gopal, Brian G. Till, Brenda Sandmaier, Oliver W Press, John M Pagel

    Pretargeted radioimmunotherapy (PRIT) has been investigated as a multi-step approach to decrease relapse and toxicity for high-risk acute myeloid leukemia (AML). Relevant factors including endogenous biotin and immunogenicity, however, have limited the use of PRIT with an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine

    更新日期:2020-10-26
  • HLA polymorphisms are associated with treatment-free remission following discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-20
    Hiroshi Ureshino, Takero Shindo, Hidenori Tanaka, Hiroh Saji, Shinya Kimura

    Treatment-free remission (TFR) is one of the therapeutic goals for patients with chronic phase chronic myeloid leukemia (CML-CP). Although previous reports indicated that anti-tumor immunity contributes to TFR, its determinants are still unclear. We previously reported that allelic polymorphisms of killer immunoglobulin-like receptors (KIRs) and human leukocyte antigens (HLAs) are associated with achievement

    更新日期:2020-10-26
  • ASR490, a Small Molecule, Overrides Aberrant Expression of Notch1 in colorectal cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-21
    Ashish Tyagi, Balaji Chandrasekaran, Venkatesh Kolluru, Becca v Baby, Cibi A Sripathi, Murali K Ankem, Srinivasa R. Ramisetti, Venkat R Chirasani, Nikolay V. Dokholyan, Arun K Sharma, Chendil Damodaran

    Aberrant activation of Notch1 triggers significant oncogenic signaling, which manifests as enhanced metastatic potential and tumorigenesis in colorectal cancer (CRC). Novel small molecule inhibitors, mainly plant-derived analogues, have gained attention because of their low toxicity profiles and higher bioavailability. In this study, we have developed a small molecule, ASR490 by modifying structure

    更新日期:2020-10-26
  • Survival implications of the relationship between tissue versus circulating tumor DNA TP53 mutations - a perspective from a real-world precision medicine cohort
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-21
    Shai Rosenberg, Ryosuke Okamura, Shumei Kato, Thierry Soussi, Razelle Kurzrock

    Interrogating the genomics of circulating tumor DNA (ctDNA) (the liquid biopsy) has advantages in patients in whom tissue biopsy is difficult. However, the reported concordance between genomic analysis of tissue DNA and ctDNA is variable among studies. Herein, we characterized the clinical implications of the relationship between mutations in TP53 genes in tissue DNA versus ctDNA. The molecular profiles

    更新日期:2020-10-26
  • Inhibition of Lysosomal Function Mitigates Protective Mitophagy and Augments Ceramide Nanoliposome-Induced Cell Death in Head and Neck Squamous Cell Carcinoma
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-21
    Jeremy JP Shaw, Timothy L Boyer, Emily Venner, Patrick J Beck, Tristen Slamowitz, Tara Caste, Alexandra Hickman, Michael H Raymond, Pedro Costa-Pinheiro, Mark J. Jameson, Todd E. Fox, Mark Kester

    Therapies for Head and Neck Squamous Cell Carcinoma (HNSCC) are, at best, moderately effective, underscoring the need for new therapeutic strategies. Ceramide treatment leads to cell death as a consequence of mitochondrial damage by generating oxidative stress and causing mitochondrial permeability. However, HNSCC cells are able to resist cell death through mitochondria repair via mitophagy. Through

    更新日期:2020-10-26
  • Reprogramming of nucleotide metabolism mediates synergy between epigenetic therapy and MAP Kinase inhibition
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-21
    Tatiana Shorstova, Jie Su, Tiejun Zhao, Michael Dahabieh, Matthew Leibovitch, Mariana De Sa Tavares Russo, Daina Avizonis, Shivshankari Rajkumar, Ian R. Watson, Sonia V. del Rincón, Wilson H. Miller, William D. Foulkes, Michael Witcher

    Small Cell Carcinoma of the Ovary, Hypercalcemic Type is a rare but often lethal cancer which is diagnosed at a median age of 24 years. Optimal management of patients is not well defined and current treatment remains challenging, necessitating the discovery of novel therapeutic approaches. The identification of SMARCA4-inactivating mutations invariably characterizing this type of cancer provided insights

    更新日期:2020-10-26
  • Glutaminase inhibitors induce thiol-mediated oxidative stress and radio-sensitization in treatment resistant cervical cancers
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-21
    Ramachandran Rashmi, Kay Jayachandran, Jin Zhang, Vishnu Menon, Naoshad Muhammad, Michael Zahner, Fiona Ruiz, Sisi Zhang, Kevin Cho, Yuting Wang, Xiaojing Huang, Yi Huang, Michael L McCormick, Buck E. Rogers, Douglas R Spitz, Gary J. Patti, Julie K Schwarz

    The purpose of the study was to determine if radiation resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radio-sensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN-/- cells engineered by CRISPR/Cas9

    更新日期:2020-10-26
  • TACIMA-218: A NOVEL PRO-OXIDANT AGENT EXHIBITING SELECTIVE ANTI-TUMORAL ACTIVITY
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-21
    Jamilah Abusarah, Yun Cui, Nehme El-Hachem, Abed El-Hakim El-Kadiry, Ian Hammond-Martel, Hugo Wurtele, Annie Beaudry, Noël J-M Raynal, Francis Robert, Jerry Pelletier, Maja Jankovic, Francois Mercier, Samaneh Kamyabiazar, Borhane Annabi, Moutih Rafei

    We report the discovery, via a unique high-throughput screening strategy, of a novel bioactive anticancer compound: Thiol Alkylating Compound Inducing Massive Apoptosis (TACIMA)-218. We demonstrate that this molecule engenders apoptotic cell death in genetically diverse murine and human cancer cell lines, irrespective of their p53 status, while sparing normal cells. TACIMA-218 causes oxidative stress

    更新日期:2020-10-26
  • Emerging CAR-T Cell Therapy for the Treatment of Triple Negative Breast Cancer
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-21
    Sundee Dees, Rajkumar Ganesan, Sanjaya Singh, Iqbal S. Grewal

    Triple negative breast cancer (TNBC), a highly aggressive cancer that lacks estrogen receptor, progesterone receptor, and HER2 2 expression, does not respond to traditional endocrine and anti-HER2 targeted therapies. Current treatment options for patients with TNBC only provide marginal clinical benefit. The immunogenic nature of TNBC has prompted researchers to harness the body's natural immune system

    更新日期:2020-10-26
  • The Landscape of Glycogen synthase kinase-3 beta (GSK-3b) Genomic Alterations in Cancer
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-21
    Brittany A Borden, Yasmine Baca, Joanne Xiu, Fabio Tavora, Ira Winer, Benjamin A. Weinberg, Ari M VanderWalde, Sourat Darabi, W. Michael Korn, Andrew P. Mazar, Francis J Giles, Lorin Crawford, Howard Safran, Wafik S. El-Deiry, Benedito A Carneiro

    Glycogen synthase kinase-3B (GSK-3B), a serine/threonine kinase, has been implicated in the pathogenesis of many cancers, with involvement in cell cycle regulation, apoptosis, and immune response. Small molecule GSK-3B inhibitors are currently undergoing clinical investigation. Tumor sequencing has revealed genomic alterations in GSK-3B, yet an assessment of the genomic landscape in malignancies is

    更新日期:2020-10-26
  • Heat shock protein-90 inhibition alters activation of pancreatic stellate cells and enhances the efficacy of PD-1 blockade in pancreatic cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-15
    Yuchen Zhang, Michael B. Ware, Mohammad Y Zaidi, Amanda N. Ruggieri, Brian M. Olson, Hannah Komar, Matthew R. Farren, Ganji Purnachandra Nagaraju, Chao Zhang, Zhengjia Chen, Juan M Sarmiento, Rafi Ahmed, Shishir K Maithel, Bassel F. El-Rayes, Gregory B. Lesinski

    Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC) or cancer associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90), is a chaperone protein and

    更新日期:2020-10-17
  • Development of tumor-targeting IRE-1 inhibitors for B cell cancer therapy
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-13
    Andong Shao, Qin Xu, Walker T. Spalek, Christopher F. Cain, Chang Won Kang, Chih-Hang Anthony Tang, Juan R. Del Valle, Chih-Chi Andrew Hu

    The IRE-1 kinase/RNase splices the mRNA of the XBP-1 gene, resulting in the spliced XBP-1 (XBP-1s) mRNA that encodes the functional XBP-1s transcription factor that is critically important for the growth and survival of B-cell leukemia, lymphoma and multiple myeloma (MM). Several inhibitors targeting the expression of XBP-1s have been reported; however, the cytotoxicity exerted by each inhibitor against

    更新日期:2020-10-14
  • MP-Pt(IV): A MAOB-sensitive mitochondrial-specific prodrug for treating glioblastoma
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-08
    Sudhir Raghavan, David S Baskin, Martyn A Sharpe

    We previously reported the in vitro and in vivo efficacy of N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propenamide, a prodrug that targeted the mitochondria of glioblastoma (GBM). The mitochondrial enzyme monoamine oxidase B (MAOB) is highly expressed in GBM and oxidizes an uncharged methyl-tetrahydropyridine (MP-) moiety into the mitochondrially-targeted cationic form, methyl-pyridinium

    更新日期:2020-10-11
  • Targeting oncogene mRNA translation in B cell malignancies with eFT226, a potent and selective inhibitor of eIF4A1
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-09
    Peggy A Thompson, Boreth Eam, Nathan P Young, Sarah Fish, Joan Chen, Maria Barrera, Haleigh Howard, Eric Sung, Ana Parra, Jocelyn Staunton, Gary G. Chiang, Adina Gerson-Gurwitz, Christopher J Wegerski, Andres Nevarez, Jeff Clarine, Samuel Sperry, Alan Xiang, Christian Nilewski, Garrick K Packard, Theodore Michels, Chinh Tran, Paul A Sprengeler, Justin T Ernst, Siegfried H Reich, Kevin R Webster

    The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226

    更新日期:2020-10-11
  • Targeting dormant ovarian cancer cells in vitro and in an in vivo mouse model of platinum resistance
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-09
    Zhiqing Huang, Eiji Kondoh, Zachary R Visco, Tsukasa Baba, Noriomi Matsumura, Emma Dolan, Regina S. Whitaker, Ikuo Konishi, Shingo Fujii, Andrew Berchuck, Susan K. Murphy

    Spheroids exhibit drug resistance and slow proliferation, suggesting involvement in cancer recurrence. The protein kinase C inhibitor, UCN-01 (7-hydroxystaurosporine) has shown higher efficacy against slow proliferating and/or quiescent ovarian cancer cells. In this study, tumorigenic potential was assessed using anchorage independent growth assays and spheroid forming capacity, which was determined

    更新日期:2020-10-11
  • Selective tumor cell apoptosis and tumor regression in CDH17-positive colorectal cancer models using BI 905711, a novel liver-sparing TRAILR2 agonist
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-09
    Juan Manuel Garcia-Martinez, Shirley Wang, Cordula Weishaeupl, Andreas Wernitznig, Paolo Chetta, Catarina Pinto, Jason Ho, Darrin Dutcher, Philip N Gorman, Rachel Kroe-Barrett, Joerg Rinnenthal, Craig Giragossian, Maria Antonietta Impagnatiello, Iñigo Tirapu, Frank Hilberg, Norbert Kraut, Mark Pearson, Klaus-Peter Kuenkele

    Activation of TRAILR2 has emerged as an important therapeutic concept in cancer treatment. TRAILR2 agonistic molecules have only had limited clinical success, to date, due either to lack of efficacy or hepatotoxicity. BI 905711 is a novel tetravalent bispecific antibody targeting both TRAILR2 and CDH17 and represents a novel liver-sparing TRAILR2 agonist specifically designed to overcome the disadvantages

    更新日期:2020-10-11
  • Hypomorphic mTOR downregulates CDK6 and delays thymic Pre-T LBL tumorigenesis.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-01
    Joy Gary,John K Simmons,Jinfei Xu,Shuling Zhang,Tyler J Peat,Nicholas Watson,Benjamin J Gamache,Ke Zhang,Alexander L Kovalchuk,Aleksandra M Michalowski,Jinqiu-Qiu Chen,Tuddow Thaiwong,Matti Kiupel,Snehal Gaikwad,Maudeline Etienne,R Mark Simpson,Wendy Dubois,Joseph R Testa,Beverly A Mock

    PI3K/AKT/mTOR pathway hyperactivation is frequent in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). To model inhibition of mTOR, pre–T-cell lymphoblastic leukemia/lymphoma (pre-T LBL) tumor development was monitored in mice with T lymphocyte–specific, constitutively active AKT (Lck-MyrAkt2) that were either crossed to mTOR knockdown (KD) mice or treated with the mTOR inhibitor everolimus

    更新日期:2020-10-02
  • Paternally Expressed Gene 10 (PEG10) Promotes Growth, Invasion and Survival of Bladder Cancer.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-01
    Martin E Gleave,Yoshihisa Kawai,Kenjiro Imada,Shusuke Akamatsu,Fan Zhang,Roland Seiler,Tetsutaro Hayashi,Jeffrey Leong,Eliana Beraldi,Neetu Saxena,Alexander Kretschmer,Htoo Zarni Oo,Alberto Contreras-Sanz,Hideyasu Matsuyama,Dong Lin,Ladan Fazli,Colin C Collins,Alexander W Wyatt,Peter C Black

    Paternally expressed gene 10 ( PEG10 ) has been associated with neuroendocrine muscle-invasive bladder cancer (MIBC), a subtype of the disease with the poorest survival. In this work, we further characterized the expression pattern of PEG10 in The Cancer Genome Atlas database of 412 patients with MIBC, and found that, compared with other subtypes, PEG10 mRNA level was enhanced in neuroendocrine-like

    更新日期:2020-10-02
  • Dysregulation of EAAT2 and VGLUT2 spinal glutamate transports via histone deacetylase 2 (HDAC2) contributes to paclitaxel-induced painful neuropathy.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-01
    Xiao-Min Wang,Pan Gu,Leorey Saligan,Michael Iadarola,Lian Kah Ti,Stanley Wong,Chi Wai Cheung

    Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain unavailable. Given the significance of spinal cord glutamate transporters in neuronal plasticity and central sensitization, this study investigated the role of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate transporter 2 (VGLUT2) in the development of paclitaxel-induced painful neuropathy. Paclitaxel

    更新日期:2020-10-02
  • The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-01
    Florencia Rago,GiNell Elliott,Ailing Li,Kathleen Sprouffske,Grainne Kerr,Aurore Desplat,Dorothee Abramowski,Julie T Chen,Ali Farsidjani,Kay X Xiang,Geoffrey Bushold,Yun Feng,Matthew D Shirley,Anka Bric,Anthony Vattay,Henrik Möbitz,Katsumasa Nakajima,Christopher D Adair,Simon Mathieu,Rukundo Ntaganda,Troy Smith,Julien P N Papillon,Audrey Kauffmann,David A Ruddy,Hyo-Eun C Bhang,Deborah Castelletti,Zainab

    Uveal melanoma is a rare and aggressive cancer that originates in the eye. Currently, there are no approved targeted therapies and very few effective treatments for this cancer. Although activating mutations in the G protein alpha subunits, GNAQ and GNA11 , are key genetic drivers of the disease, few additional drug targets have been identified. Recently, studies have identified context-specific roles

    更新日期:2020-10-02
  • Concurrent Targeting of Potential Cancer Stem Cells Regulating Pathways Sensitizes Lung Adenocarcinoma to Standard Chemotherapy.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-01
    Masahiro Shibata,Akira Ooki,Yoshikuni Inokawa,Pritam Sadhukhan,M Talha Ugurlu,Evgeny Izumchenko,Enrico Munari,Giuseppe Bogina,Charles M Rudin,Edward Gabrielson,Anju Singh,Mohammad O Hoque

    Cancer stem cells (CSC) are highly resistant to conventional chemotherapeutic drugs. YAP1 and STAT3 are the two transcription factors that facilitate the therapeutic resistance and expansion of CSCs. The objective of this study was to understand the cross-talk between YAP1 and STAT3 activities and to determine the therapeutic efficacy of targeting dual CSC-regulating pathways (YAP1 and STAT3) combined

    更新日期:2020-10-02
  • Expression of the of the androgen receptor governs radiation resistance in a subset of glioblastomas vulnerable to anti-androgen therapy.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-01
    Christian K Werner,Uchechi J Nna,Hanshi Sun,Kari Wilder-Romans,Joseph Dresser,Ayesha U Kothari,Weihua Zhou,Yangyang Yao,Arvind Rao,Stefanie Stallard,Carl Koschmann,Tarik Bor,Waldemar Debinski,Alexander M Hegedus,Meredith A Morgan,Sriram Venneti,Edwina Baskin-Bey,Daniel E Spratt,Howard Colman,Jann N Sarkaria,Arul M Chinnaiyan,Joel R Eisner,Corey Speers,Theodore S Lawrence,Roy E Strowd,Daniel R Wahl

    New approaches are needed to overcome intrinsic therapy resistance in glioblastoma (GBM). Because GBMs exhibit sexual dimorphism and are reported to express steroid hormone receptors, we reasoned that signaling through the androgen receptor (AR) could mediate therapy resistance in GBM, much as it does in AR-positive prostate and breast cancers. We found that nearly half of GBM cell lines, patient-derived

    更新日期:2020-10-02
  • Phase I, pharmacogenomic, drug-interaction study of sorafenib and bevacizumab in combination with paclitaxel in patients with advanced refractory solid tumors.
    Mol. Cancer Ther. (IF 5.615) Pub Date : 2020-10-01
    E Gabriela Chiorean,Susan M Perkins,Robert M Strother,Anne Younger,Jennifer M Funke,Safi G Shahda,Noah M Hahn,Kumaresan Sandrasegaran,David R Jones,Todd C Skaar,Bryan P Schneider,Christopher J Sweeney,Daniela E Matei

    VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 + 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks

    更新日期:2020-10-02
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