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Molecular Cancer Therapeutics

Cindy R Timme, Barbara H Rath, John W O'Neill, Kevin Camphausen, Philip J Tofilon
Radiotherapy is a primary treatment modality for glioblastomas (GBMs). Because DNA-PKcs is a critical factor in the repair of radiation-induced double strand breaks (DSBs), this study evaluated the potential of VX-984, a new DNA-PKcs inhibitor, to enhance the radiosensitivity of GBM cells. Treatment of the established GBM cell line U251 and the GBM stem-like cell (GSC) line NSC11 with VX-984 under in vitro conditions resulted in a concentration-dependent inhibition of radiation-induced DNA-PKcs phosphorylation...
March 16, 2018: Molecular Cancer Therapeutics
Gauri Shishodia, Sweaty Koul, Qin Dong, Hari K Koul
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, but not in normal cells, as such is a promising therapeutic agent. However, therapeutic resistance limits its clinical use in many malignancies including prostate cancer (PCa). Strategies to sensitize cancer cells to TRAIL are urgently needed. We demonstrate here that small-molecule Tetrandrine (TET) potentially sensitizes previously resistant (LNCaP and C4-2B cells) and mildly sensitive (PC3 cells) PCa cells to TRAIL- induced apoptosis, and they do so by up-regulating mRNA expression and protein levels of death receptors Apo Trail R1 (DR4) and Apo Trail R2 (DR5)...
March 16, 2018: Molecular Cancer Therapeutics
Hetal Patel, Manikandan Periyasamy, Georgina P Sava, Alexander Bondke, Brian W Slafer, Sebastian H B Kroll, Marion Barbazanges, Richard Starkey, Silvia Ottaviani, Alison Harrod, Eric O Aboagye, Laki Buluwela, Matthew J Fuchter, Anthony G M Barrett, Charles Coombes, Simak Ali
Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including Estrogen receptor-α (ER). Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942...
March 15, 2018: Molecular Cancer Therapeutics
Akira Inoue, Tsunekazu Mizushima, Xin Wu, Daisuke Okuzaki, Nanami Kambara, Sho Ishikawa, Jiaqi Wang, Yamin Qian, Haruka Hirose, Yuhki Yokoyama, Ryo Ikeshima, Masayuki Hiraki, Norikatsu Miyoshi, Hidekazu Takahashi, Naotsugu Haraguchi, Taishi Hata, Chu Matsuda, Yuichiro Doki, Masaki Mori, Hirofumi Yamamoto
We previously demonstrated that miR-29b-3p is a hopeful microRNA (miRNA)-based therapies against colorectal cancer (CRC). In this study, we aimed to clarify a value of miR-29b-1-5p as a next generation treatment, especially for KRAS mutant CRC. RT-PCR assay showed that expression of miR-29b-3p was high and its partner strand, miR-29b-1-5p level was only negligible in clinical CRC samples. Mimic-miR-29b-1-5p significantly inhibited proliferation of KRAS mutant CRC cell lines DLD1 and SW480 and KRAS wild type HT29 cells...
March 15, 2018: Molecular Cancer Therapeutics
Sofie Ellebæk Pollmann, Valerie S Calvert, Shruti Rao, Simina M Boca, Subha Madhavan, Ivan D Horak, Andreas Kjaer, Emanuel F Petricoin, Michael Kragh, Thomas Tuxen Poulsen
Failure of clinical trials due to development of resistance to MET-targeting therapeutic agents is an emerging problem. Mechanisms of acquired resistance to MET tyrosine kinase inhibitors are well described, whereas characterization of mechanisms of resistance toward MET-targeting antibodies is limited. This study investigated mechanisms underlying in vivo resistance to two antibody therapeutics currently in clinical development: an analogue of the MET-targeting antibody emibetuzumab and Sym015, a mixture of two antibodies targeting non-overlapping epitopes of MET...
March 15, 2018: Molecular Cancer Therapeutics
Sen Xu, Zong-Yuan Yang, Ping Jin, Xin Yang, Xiaoting Li, Xiao Wei, Ya Wang, Sixiang Long, Taoran Zhang, Gang Chen, Chaoyang Sun, Ding Ma, Qinglei Gao
Ovarian cancer (OC) is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in OC. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the OC tumor cells...
March 15, 2018: Molecular Cancer Therapeutics
Michael D Oberst, Catherine Auge, Chad Morris, Stacy Kentner, Kathy Mulgrew, Kelly McGlinchey, James Hair, Shino Hanabuchi, Qun Du, Melissa Damschroder, Hui Feng, Steven Eck, Nicholas Buss, Lolke de Haan, Andrew J Pierce, Haesun Park, Andrew Sylwester, Michael K Axthelm, Louis Picker, Nicholas P Morris, Andrew Weinberg, Scott A Hammond
Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells...
March 15, 2018: Molecular Cancer Therapeutics
Omer M Toor, Zaheer Ahmed, Waled Bahaj, Urooge Boda, Lee S Cummings, Megan E McNally, Kevin F Kennedy, Timothy J Pluard, Arif Hussain, Janakiraman Subramanian, Ashiq Masood
Next Generation Sequencing (NGS) of cancer tissues is increasingly being carried out to identify somatic genomic alterations that may guide physicians to make therapeutic decisions. However, a single tissue biopsy may not reflect complete genomic architecture due to the heterogeneous nature of tumors. Circulating tumor DNA (ctDNA) analysis is a robust noninvasive method to detect and monitor genomic alterations in blood in real time. We analyzed 28 matched tissue NGS and ctDNA from gastrointestinal and lung cancers for concordance of somatic genomic alterations, driver and actionable alterations...
March 2, 2018: Molecular Cancer Therapeutics
Sharon M Sagnella, Jennifer Trieu, Himanshu Brahmbhatt, Jennifer A MacDiarmid, Alex MacMillan, Renee M Whan, Christopher M Fife, Joshua A McCarroll, Andrew J M Gifford, David S Ziegler, Maria Kavallaris
Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC delivery vehicle (EDVTM) is a nanocell which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase 1 trials in adults with refractory tumors have shown an acceptable safety profile...
February 28, 2018: Molecular Cancer Therapeutics
Mariana Malvicini, Ana Gutierrez-Moraga, Marcelo M Rodriguez, Sofia Gomez-Bustillo, Lorena Salazar, Carlos Sunkel, Leonor Nozal, Antonio Salgado, Manuel Hidalgo, Pedro P Lopez-Casas, Jose Luis Novella, Juan Jose Vaquero, Julio Alvarez-Builla, Adda Mora, Manuel Gidekel, Guillermo Mazzolini
In colorectal carcinoma (CRC) patients, distant metastatic disease is present at initial diagnosis in nearly 25% of them. The majority of patients with metastatic CRC have incurable disease; therefore, new therapies are needed. Agents derived from medicinal plants have already demonstrated therapeutic activities in human cancer cells. Antartina™ is an antitumor agent isolated from Deschampsia antarctica Desv. This study aimed to evaluate the antitumor properties of Antartina™ in CRC models. We used human and murine CRC cell lines for investigating proliferation, apoptosis and cell cycle effects of Antartina™ therapy in vitro...
February 26, 2018: Molecular Cancer Therapeutics
Jiyu Guan, Dan Huang, Konstantin Yakimchuk, Sam Okret
Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here we demonstrate that stromal cells protect MCL cells from ibrutinib-induced apoptosis and support MCL cell regrowth after drug removal by impairing ibrutinib-mediated down-regulation of phosphoinositide-3-kinase (PI3K)/AKT signaling...
February 26, 2018: Molecular Cancer Therapeutics
Tatyana Zykova, Feng Zhu, Lei Wang, Haitao Li, Do Young Lim, Ke Yao, Eunmiri Roh, Sang-Pil Yoon, Hong-Gyum Kim, Ki Beom Bae, Weihong Wen, Seung Ho Shin, Janos Nadas, Yan Li, Weiya Ma, Ann M Bode, Zigang Dong
The biological functions of the p53 related protein kinase (PRPK) remain unclear. We have previously demonstrated that PRPK is phosphorylated by the T-LAK cell-originated protein kinase (TOPK) and that phosphorylated PRPK (p-PRPK) promotes colon cancer metastasis. Here, we analyzed colon adenocarcinomas from 87 patients, and found that higher expression levels of p-PRPK were associated with later stages of metastatic dissemination (stages III or IV), as compared to earlier stages (stages I and II). Indeed, levels of p-PRPK were higher in metastatic versus malignant human colon adenocarcinomas...
February 26, 2018: Molecular Cancer Therapeutics
Ke Liu, Lijing Fang, Haiyan Sun, Zhengyin Pan, Jianchao Zhang, Juntao Chen, Ximing Shao, Wei Wang, Yuanyan Tan, Zhihao Ding, Lijiao Ao, Chunlei Wu, Xiaoqi Liu, Huashun Li, Rui Wang, Wu Su, Hongchang Li
The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the Plk1 promoter...
February 26, 2018: Molecular Cancer Therapeutics
Nicholas Forsythe, Alaa Refaat, Arman Javadi, Hajrah Khawaja, Jessica-Anne Weir, Heba Emam, Wendy L Allen, Frank Burkamp, Vlad Popovici, Puthen V Jithesh, Claudio Isella, Melissa J LaBonte, Ian G Mills, Patrick G Johnston, Sandra Van Schaeybroeck
BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome...
February 26, 2018: Molecular Cancer Therapeutics
Fei Liu, Wei Li, Shangbo Hua, Ye Han, Zhihua Xu, Daiwei Wan, Yilin Wang, Weichang Chen, Yuting Kuang, Jianming Shi, Qiaoming Zhi
Nigericin, an antibiotic derived from Streptomyces hygroscopicus that works by acting as an H+, K+ and Pb2+ ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/β-catenin signaling pathway in colorectal cancer (CRC) cells and clarify the underlying mechanism. We exposed two CRC lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC50) values were evaluated...
February 26, 2018: Molecular Cancer Therapeutics
Hee Kyung Kim, InKyoung Lee, Heejin Bang, Hee Cheol Kim, Woo Yong Lee, Seong Hyeon Yun, Jeeyun Lee, Su Jin Lee, Young Suk Park, Kyoung-Mee Kim, Won Ki Kang
Monocarboxylate transporters (MCTs) are transmembrane proteins which control the lactate metabolism and associated with poor prognosis in solid tumors including colorectal cancer (CRC). Here we aimed to investigate the biological and clinical role of MCTs in CRC and to assess the potential of therapeutic application. A total of 16 human CRC cell lines, 11 patient-derived cells from malignant ascites (PDC), and 39 matched pairs of primary CRC and normal colorectal tissues were used to assess the role of MCT in vitro and in vivo...
February 26, 2018: Molecular Cancer Therapeutics
Neil O'Brien, Dylan Conklin, Richard Beckmann, Tong Luo, Kevin Chau, Josh Thomas, Ann Mc Nulty, Christophe Marchal, Ondrej Kalous, Erika von Euw, Sara Hurvitz, Colleen Mockbee, Dennis J Slamon
The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2- and ER+/HER2+ subtypes. However, a subset of triple negative breast cancer (TNBC) cell lines with intact Rb-signaling were also found to be responsive...
February 26, 2018: Molecular Cancer Therapeutics
Jing-Hung Wang, Alexis V Forterre, Jingjing Zhao, Daniel O Frimannsson, Alain Delcayre, Travis J Antes, Bradley Efron, Stefanie S Jeffrey, Mark D Pegram, A C Matin
This paper deals with specific targeting of the prodrug/enzyme regimen, CNOB/HChrR6, to treat a serious disease namely HER2+ve human breast cancer with minimal off-target toxicity. HChrR6 is an improved bacterial enzyme that converts CNOB into the cytotoxic drug MCHB. Extracellular vesicles (EVs) were used for mRNA-based HchrR6 gene delivery: EVs may cause minimal immune rejection, and mRNA may be superior to DNA for gene delivery. To confine HChrR6 generation and CNOB activation to the cancer, the EVHB chimeric protein was constructed...
February 26, 2018: Molecular Cancer Therapeutics
Barbara H Rath, Isabella Waung, Kevin Camphausen, Philip J Tofilon
The processes mediating the repair of DNA double strand breaks (DSBs) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines...
February 26, 2018: Molecular Cancer Therapeutics
Nicolas Floc'h, Matthew J Martin, Jonathan W Riess, Jonathan P Orme, Anna D Staniszewska, Ludovic Menard, Maria Emanuela Cuomo, Daniel J O'Neill, Richard A Ward, M Raymond V Finlay, Darren McKerrecher, Mingshan Cheng, Daniel P Vang, Rebekah A Tsai, James G Keck, David R Gandara, Philip C Mack, Darren Ae Cross
EGFR exon 20 insertions (Ex20Ins) account for 4-10% of EGFR activating mutations in non-small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to 1st and 2nd generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed...
February 26, 2018: Molecular Cancer Therapeutics
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