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Journal Mol Cancer Ther

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Combinatorial efficacy of olaparib with radiation and ATR inhibitor requires PARP1 protein in homologous recombination proficient pancreatic cancer.

Leslie A Parsels, Carl G Engelke, Joshua Parsels, Sheryl A Flanagan, Qiang Zhang, Daria Tanska, Daniel R Wahl, Christine E Canman, Theodore S Lawrence, Meredith A Morgan,

PARP inhibitor monotherapy (olaparib) was recently FDA-approved for the treatment of BRCA1/2 mutant, HR (homologous recombination repair)-deficient pancreatic cancer. Most pancreatic cancers, however, are HR-proficient and thus resistant to PARP inhibitor monotherapy. We tested the hypothesis that combined therapy with radiation and ATR inhibitor (AZD6738) would extend the therapeutic indication ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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A Pilot Study of Galunisertib Plus Stereotactic Body Radiotherapy in Patients with Advanced Hepatocellular Carcinoma.

Kim A Reiss, Max M Wattenberg, Nevena Damjanov, Elizabeth Prechtel Dunphy, Mona Jacobs-Small, M Judy Lubas, James Robinson, Lisa Dicicco, Luis Garcia-Marcano, Michael A Giannone, Thomas B Karasic, Emma E Furth, Erica L Carpenter, Andrzej P Wojcieszynski, Robert H Vonderheide, Gregory L Beatty, Edgar Ben-Josef,

TGF-β is a pleiotropic cytokine with immunosuppressive activity. In pre-clinical models blockade of TGF-β enhances the activity of radiation and invokes T cell anti-tumor immunity. Here, we combined galunisertib, an oral TGF-β inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy and ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Recombinant Orthopoxvirus Primes Colon Cancer for Checkpoint Inhibitor and Cross-Primes T Cells for Antitumor and Antiviral Immunity.

Sang-In Kim, Anthony K Park, Shyambabu Chaurasiya, Seonah Kang, Jianming Lu, Annie Yang, Venkatesh Sivanandam, Zhifang Zhang, Yanghee Woo, Saul J Priceman, Yuman Fong, Susanne G Warner,

Although it is known that oncolytic viruses can inflame and recruit immune cells to otherwise immunosuppressed tumor microenvironments, the influence of the antiviral immune response on antitumor immunity is less clear across viral platforms and tumor types. CF33 is a recombinant orthopoxvirus backbone effective against colon cancer. We tested derivatives ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Selected Articles from This Issue.

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, 19(12):2407]

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Disruption of SND1-MTDH interaction by a high affinity peptide results in SND1 degradation and cytotoxicity to breast cancer cells in vitro and in vivo.

Peng Li, Yunjiao He, Teng Chen, Kit-Ying Choy, Tsun Sing Chow, Iris L K Wong, Xinqing Yang, Wen-Qin Sun, Xiaochun Su, Tak-Hang Chan, Larry M C Chow,

SND1 is a multifunctional oncoprotein overexpressed in breast cancer. Binding of MTDH to SND1 results in the stabilization of SND1 and is important in the initiation and progression of breast cancer. Disruption of such interaction is a potential therapeutics for breast cancer. SN1/2 domain of SND1 was used as bait ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Repurposing the antidepressant sertraline as SHMT inhibitor to suppress serine/glycine synthesis addicted breast tumor growth.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Targeting STAT3 with proteolysis targeting chimeras (PROTACs) and next generation antisense oligonucleotides.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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TriTACs, a novel class of T cell-engaging protein constructs designed for the treatment of solid tumors.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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RANKL-Targeted Combination Therapy with Osteoprotegerin Variant Devoid of TRAIL Binding Exerts Biphasic Effects on Skeletal Remodeling and Antitumor Immunity.

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 toward aggressive osteoclast activity and polarization of immune cells supporting tumor growth and immunosuppression. Recent studies signify the role of receptor activator of NF-κB ligand (RANKL) beyond skeletal pathology ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, 19(12):2585-2597]

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Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody Drug Conjugates to Increase In Vivo Efficacy.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Circulating tumor cells and biomarker modulation with olaratumab monotherapy followed by olaratumab plus doxorubicin: phase 1b study in soft tissue sarcoma patients.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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IOX1 Suppresses Wnt Target Gene Transcription and Colorectal Cancer Tumorigenesis Through Inhibition of KDM3 Histone Demethylases.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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BRCA1/MAD2L1 deficiency disrupts the spindle assembly checkpoint to confer vinorelbine resistance in mesothelioma.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Therapeutic vulnerabilities of transcription factors in AML.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Rapid Induction of the Unfolded Protein Response and Apoptosis by Estrogen Mimic TTC-352 for the Treatment of Endocrine-Resistant Breast Cancer.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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PLK1 and NOTCH Positively Correlate in Melanoma and their Combined Inhibition Results in Synergistic Modulations of Key Melanoma Pathways.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Rigosertib induces mitotic arrest and apoptosis in RAS-driven rhabdomyosarcoma and neuroblastoma.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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A Precision Medicine Drug Discovery Pipeline Identifies Combined CDK2 and 9 Inhibition as a Novel Therapeutic Strategy in Colorectal Cancer.

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 third most common cancer in the United States 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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, 19(12):2516-2527]

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The Landscape of Glycogen synthase kinase-3 beta (GSK-3b) Genomic Alterations in Cancer.

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Glutaminase Inhibitors Induce Thiol-Mediated Oxidative Stress and Radiosensitization in Treatment-Resistant Cervical Cancers.

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 this study was to determine if radiation (RT)-resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radiosensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, 19(12):2465-2475]

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Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90Y-DOTA.

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 streptavidin conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, 19(12):2575-2584]

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TACIMA-218: A NOVEL PRO-OXIDANT AGENT EXHIBITING SELECTIVE ANTI-TUMORAL ACTIVITY.

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. ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, :]

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Emerging CAR-T Cell Therapy for the Treatment of Triple-Negative Breast Cancer.

Sundee Dees, Rajkumar Ganesan, Sanjaya Singh, Iqbal S Grewal,

Triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype that lacks estrogen receptor, progesterone receptor, and HER2 expression, does not respond to traditional endocrine and anti-HER2-targeted therapies. Current treatment options for patients with TNBC include a combination of surgery, radiotherapy, and/or systemic chemotherapy. FDA-approved therapies that target DNA damage ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, 19(12):2409-2421]

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HIV Protease Inhibitors Block HPV16-Induced Murine Cervical Carcinoma and Promote Vessel Normalization in Association with MMP-9 Inhibition and TIMP-3 Induction.

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

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, 19(12):2476-2489]

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Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase.

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, Nelamangala Nagaraja, Lenny Dang, Georg Lenz, Jonathan Hurov, Scott A Biller, Josh Murtie, Kevin M Marks, Danielle B Ulanet,

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 ... Read more >>

Mol Cancer Ther (Molecular cancer therapeutics)
[2020, 19(12):2502-2515]

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