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Molecular Cancer Therapeutics

Hung-Chih Hsu, Nina Lapke, Chuang-Wei Wang, Pei-Yi Lin, Jeng-Fu You, Chien-Yuh Yeh, Wen-Sy Tsai, Hsin-Yuan Hung, Sum-Fu Chang, Hua-Chien Chen, Shu-Jen Chen, An Hsu, Tsai-Sheng Yang
Substantial improvements have been made in the management of metastatic colorectal cancer (mCRC) in the last two decades, but disease monitoring remains underdeveloped. Circulating tumor DNA (ctDNA) is a promising prognostic and predictive biomarker, however, ctDNA as a marker for mCRC patients is not well-established, and there is still no consensus about how to utilize it most cost-effectively. In this study, we aim to investigate plasma ctDNA levels as a biomarker for therapeutic response of mCRC patients...
July 11, 2018: Molecular Cancer Therapeutics
Kathleen I Pishas, Christina D Drenberg, Cenny Taslim, Emily R Theisen, Kirsten M Johnson, Ranajeet S Saund, Ioana L Pop, Brian D Crompton, Elizabeth R Lawlor, Franck Tirode, Jaume Mora, Olivier Delattre, Mary C Beckerle, David F Callen, Sunil Sharma, Stephen L Lessnick
Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/LSD1 (Lysine Specific Demethylase 1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P=0...
July 11, 2018: Molecular Cancer Therapeutics
Yingmiao Liu, Mark D Starr, John C Brady, Christel Rushing, Herbert Pang, Bonne Adams, Delia Alvarez, Charles P Theuer, Herbert I Hurwitz, Andrew B Nixon
TRC105 is an anti-endoglin antibody currently being tested in combination with VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both TRC105 and bevacizumab (BEV) and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-VEGF therapy. Plasma samples were tested for angiogenic and inflammatory biomarkers at baseline and on-treatment. To provide broader context of this combination biomarker study, direct cross-study comparisons were made to biomarker studies previously conducted in patients treated with either BEV or TRC105 monotherapy...
July 11, 2018: Molecular Cancer Therapeutics
Tatiana Lepikhova, Piia-Riitta Karhemo, Riku Louhimo, Bhagwan Yadav, Astrid Murumägi, Evgeny Kulesskiy, Mikko Kivento, Harri Sihto, Reidar Grénman, Stina M Syrjänen, Olli Kallioniemi, Tero Aittokallio, Krister Wennerberg, Heikki Joensuu, Outi Monni
There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers and point mutations in 45 human papillomavirus negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK and EGFR inhibitors...
July 3, 2018: Molecular Cancer Therapeutics
Hisatsugu Maekawa, Hiroyuki Miyoshi, Tadayoshi Yamaura, Yoshiro Itatani, Kenji Kawada, Yoshiharu Sakai, M Mark Taketo
Current genomic and gene expression analyses provide versatile tools to improve cancer chemotherapy. However, it is still difficult to predict whether each patient responds to a particular regimen or not. To predict chemosensitivity in each colorectal cancer patient, we developed an evaluation method using the primary tumor initiating cells (TIC, aka cancer stem cells) xenografted in nude mice subcutaneously (patient-derived spheroid xenografts; PDSXs). Simultaneously, we also prepared the conventional patient-derived xenografts (PDXs) from the same patients' tumors, and compared the dosing results with those of PDSXs...
July 3, 2018: Molecular Cancer Therapeutics
Shilpa Bhatia, Anastacia Griego, Shelby Lennon, Ayman Oweida, Jaspreet Sharma, Christina Rohmer, Nomin Uyanga, Sanjana Bukkapatnam, Benjamin Van Court, David Raben, Christian Young, Lynn Heasley, Sana D Karam
Eph proteins have emerged as critical drivers affecting tumor growth and progression in human malignancies. Our TCGA data analysis showed that EphB3, a receptor tyrosine kinase, is frequently co-amplified with PIK3CA in head and neck squamous cell carcinoma (HNSCC). We therefore hypothesized that EphB3 amplification plays a pro-tumorigenic role in HNSCC and that EphB3 and PIK3CA are co-operating oncogenes that contribute toward its pathogenesis. This hypothesis was not experimentally supported since EphB3 knockdown failed to alter HNSCC tumor cell growth in vitro or in vivo with an orthotopic model...
July 3, 2018: Molecular Cancer Therapeutics
Aashish Soni, Fanghua Li, You Wang, Martha Grabos, Lisa Marie Krieger, Shipra Chaudhary, Mohammad Sharif Mortoga Hasan, Mansoor M Ahmed, C Norman Coleman, Beverly A Teicher, Richard L Piekarz, Dian Wang, George E Iliakis
Parp inhibitors (Parpi) are commonly used as single agents for the management of tumors with homologous recombination repair (HRR) deficiencies, but combination with radiotherapy is not widely considered due to the modest radiosensitization typically observed. BMN673 is one of the most recently developed Parpi and has been shown to mediate strong cell sensitization to methylating agents. Here we explore the mechanisms of BMN673 radiosensitization to killing, aiming to combine it with radiotherapy (RT). We demonstrate markedly stronger radiosensitization by BMN673 at concentrations substantially lower (50nM) than Olaparib (3µM) or AG14361 (0...
July 3, 2018: Molecular Cancer Therapeutics
Minjee Kim, Daniel J Ma, David Calligaris, Shuangling Zhang, Ryan W Feathers, Rachael A Vaubel, Isabelle Meaux, Ann C Mladek, Karen E Parrish, Fang Jin, Cedric Barriere, Laurent Debussche, James Watters, Shulan Tian, Paul A Decker, Jeanette E Eckel-Passow, Gaspar J Kitange, Aaron J Johnson, Ian F Parney, Panos Z Anastasiadis, Nathalie Y R Agar, William F Elmquist, Jann N Sarkaria
Controversy exists surrounding whether heterogeneous disruption of the blood-brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. In vitro efficacy of SAR405838 was evaluated in PDX models with varying MDM2-expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy...
July 3, 2018: Molecular Cancer Therapeutics
Dong Hoon Shin, Jeong Yeon Jo, Ji-Youn Han
We characterized the SLC3A2-NRG1 fusion gene in non-small cell lung cancer (NSCLC) and established an effective therapy for patients with SLC3A2-NRG1 fusion-positive cancer. The SLC3A2-NRG1 fusion product was composed of the SLC3A2 transmembrane domain and the epidermal growth factor (EGF)-like domain of the neuregulin 1 (NRG1) protein. The NRG1 family is classified as a ligand of the ERBB family. We identified ERBB3 and ERBB4 in the ERBB family as binding partners of the SLC3A2-NRG1 fusion protein via ligand and receptor binding assays...
June 29, 2018: Molecular Cancer Therapeutics
Maria Cristina Manara, Sergio Valente, Camilla Cristalli, Giordano Nicoletti, Lorena Landuzzi, Clemens Zwergel, Roberta Mazzone, Giulia Stazi, Paola B Arimondo, Michela Pasello, Clara Guerzoni, Piero Picci, Patrizia Nanni, Pier-Luigi Lollini, Antonello Mai, Katia Scotlandi
The identification of new therapeutic strategies against osteosarcoma (OS), the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. OS originates from the transformation of mesenchymal stem cells (MSCs) and/or osteoblast progenitors, and the loss of differentiation is a common biological OS feature which strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits...
June 29, 2018: Molecular Cancer Therapeutics
Rui Wang, Ying Li, Ping Gong, Janice Gabrilove, Samuel Waxman, Yongkui Jing
Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity, produces an impressive but short-lived remission in FLT3-ITD AML patients. The second, arsenic trioxide (ATO), at therapeutically achievable concentrations, reduces the level of FLT3-ITD and Mcl-1 proteins, and induces apoptosis in leukemic cell lines and in primary cells expressing FLT3-ITD...
June 29, 2018: Molecular Cancer Therapeutics
Xin Xin Quan, Nga Voong Hawk, Weiping Chen, Jamie Coupar, Steven Lee, David W Petersen, Paul S Meltzer, Andrew Montemarano, Martin Braun, Zhong Chen, Carter Van Waes
Cancer stem-like cells are hypothesized to be the major tumor initiating cell population of human cutaneous squamous cell carcinoma (cSCC), but the landscape of molecular alterations underpinning their signaling and cellular phenotypes as drug targets remain undefined. In this study, we developed an experimental pipeline to isolate a highly enriched CD133+CD31-CD45-CD61-CD24- (CD133+) cell population from primary cSCC specimens by flow cytometry. The CD133+ cells show enhanced stem-like phenotypes, which were verified by spheroid and colony formation in vitro and tumor generation in vivo...
June 29, 2018: Molecular Cancer Therapeutics
Francis P Roche, Ilkka Pietilä, Hiroshi Kaito, Elisabet O Sjöström, Nadine Sobotzki, Oriol Noguer, Tor Persson Skare, Magnus Essand, Bernd Wollscheid, Michael Welsh, Lena Claesson-Welsh
The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and anti-tumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T cell accumulation in the tumor...
June 26, 2018: Molecular Cancer Therapeutics
Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Luni Emdad, Swadesh K Das, Devanand Sarkar, Paul B Fisher
Prostate cancer (PC) is a principal cause of cancer-associated morbidity in men. Although 5-year survival of patients with localized PC approaches 100 percent, survival decreases precipitously after metastasis. Bone is the preferred site for disseminated PC cell colonization, altering the equilibrium of bone homeostasis resulting in weak and fragile bones. Currently, no curative options are available for PC bone metastasis. MDA-7/IL-24 is a well-studied cytokine established as a therapeutic in a wide-array of cancers upon delivery as a gene therapy...
June 22, 2018: Molecular Cancer Therapeutics
Paul L Feingold, Deborah R Surman, Kate Brown, Yuan Xu, Lucas A McDuffie, Vivek Shukla, Emily S Reardon, Daniel R Crooks, Jane B Trepel, Sunmin Lee, Min-Jung Lee, Shaojian Gao, Sichuan Xi, Kaitlin C McLoughlin, Laurence P Diggs, David G Beer, Derek J Nancarrow, Leonard M Neckers, Jeremy L Davis, Chuong D Hoang, Jonathan M Hernandez, David S Schrump, R Taylor Ripley
In 2017, an estimated 17,000 individuals were diagnosed with esophageal adenocarcinoma (EAC) and less than 20% will survive 5 years. PET-avidity is indicative of high glucose utilization and is nearly universal in EAC. TXNIP blocks glucose uptake and exhibits pro-apoptotic functions. Higher expression in EAC has been associated with improved disease-specific survival, lack of lymph node involvement, reduced perineural invasion, and increased tumor differentiation. We hypothesized that TXNIP may act as a tumor suppressor that sensitizes EAC cells to standard chemotherapeutics...
June 22, 2018: Molecular Cancer Therapeutics
Wenyu Wang, Keng Gat Lim, Min Feng, Yi Bao, Puay Leng Lee, Cai Yu, Yufeng Chen, Hao Zhang, Diego Marzese, Dave Sb Hoon, Qiang Yu
Despite showing promise against PIK3CA-mutant breast cancers in preclinical studies, phosphatidylinositol-3-kinase (PI3K)/AKT pathway inhibitors demonstrate limited clinical efficacy as monotherapy. Here, we found that histone H3K27me3 demethylase KDM6B-targeted IGFBP5 expression provides a protective mechanism for PI3K/AKT inhibitor-induced apoptosis in breast cancer cells. We found that overexpression of KDM6B and IGFBP5 in luminal breast cancer are positively associated with poorer disease outcomes. Mechanistically, KDM6B promotes IGFBP5 expression by antagonizing EZH2-mediated repression, and pharmacologic inhibition of KDM6B augments apoptotic response to PI3K/AKT inhibitor treatment...
June 20, 2018: Molecular Cancer Therapeutics
Andrew M Donson, Vladimir Amani, Elliot A Warner, Andrea M Griesinger, Davis A Witt, Jean M Mulcahy Levy, Lindsey M Hoffman, Todd C Hankinson, Michael H Handler, Rajeev Vibhakar, Kathleen Dorris, Nicholas K Foreman
Children with ependymoma are cured in less than 50% of cases, with little improvement in outcome over the last several decades. Chemotherapy has not impacted survival in ependymoma, due in part to a lack of preclinical models that has precluded comprehensive drug testing. We recently developed two human ependymoma cell lines harboring high-risk phenotypes which provided us with an opportunity to execute translational studies. ependymoma and other pediatric brain tumor cell lines were subject to a large-scale comparative drug screen of ependymoma -approved oncology drugs for rapid clinical application...
June 20, 2018: Molecular Cancer Therapeutics
Yang Yang, Kenza Mamouni, Xin Li, Yanhua Chen, Sravan Kavuri, Yuhong Du, Haian Fu, Omer Kucuk, Daqing Wu
Docetaxel resistance remains a major obstacle in the treatment of prostate cancer (PCa) bone metastasis. In this study, we demonstrate that the dopamine D2 receptor (DRD2) agonist bromocriptine effectively enhances docetaxel efficacy and suppresses skeletal growth of PCa in preclinical models. DRD2 is ubiquitously expressed in PCa cell lines, and DRD2 is significantly reduced in PCa tissues with high Gleason score. Bromocriptine has weak to moderate cytotoxicity in PCa cells, but effectively induces cell cycle arrest...
June 15, 2018: Molecular Cancer Therapeutics
Benjamin L Woolbright, Dharamainder Choudhary, Andrew Mikhalyuk, Cassandra Trammel, Sambantham Shanmugam, Erika Abbott, Carol C Pilbeam, John A Taylor
Advanced bladder cancer (BCa) remains a major source of mortality, with poor treatment options. Cisplatin based chemotherapy is the standard treatment, however many patients are or become resistant. One potential cause of chemoresistance is the Warburg Effect, a metabolic switch to aerobic glycolysis that occurs in many cancers. Upregulation of the pyruvate dehydrogenase kinase family (PDK1-4) is associated with aerobic glycolysis and chemoresistance through inhibition of the pyruvate dehydrogenase complex (PDH)...
June 15, 2018: Molecular Cancer Therapeutics
Ananda Mukherjee, Amanda L Patterson, Jitu W George, Tyler J Carpenter, Zachary B Madaj, Galen Hostetter, John I Risinger, Jose M Teixeira
Endometrial adenocarcinoma (EndoCA) is the most common gynecological cancer type in the US, and its incidence is increasing. The majority of patients are disease-free after surgical resection of stage I tumors, which is often followed by radiation therapy, but most patients with advanced disease recur and have a poor prognosis, largely because the tumors become refractory to cytotoxic chemotherapies. PTEN, a commonly mutated tumor suppressor in EndoCAs, is well known for its ability to inhibit the AKT/mTOR signaling pathway...
June 13, 2018: Molecular Cancer Therapeutics
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