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Molecular Cancer Therapeutics

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https://www.readbyqxmd.com/read/29167315/a-novel-yap1-inhibitor-targets-cscs-enriched-radiation-resistant-cells-and-exerts-strong-antitumor-activity-in-esophageal-adenocarcinoma
#1
Shumei Song, Min Xie, Ailing W Scott, Jiankang Jin, Lang Ma, Xiaochuan Dong, Heath D Skinner, Randy L Johnson, Sheng Ding, Jaffer A Ajani
Mounting evidence suggests that the Hippo co-activator Yes-associated protein 1 (YAP1) is a major mediator of cancer stem cell (CSC) properties, tumor progression, and therapy resistance as well as often a terminal node of many oncogenic pathways. Thus, targeting YAP1 may be a novel therapeutic strategy for many types of tumors with high YAP1 expression, including esophageal adenocarcinoma (EAC). However, effective YAP1 inhibitors are currently lacking. Here, we identify a small molecule (CA3) that not only has remarkable inhibitory activity on YAP1/Tead transcriptional activity but also demonstrates strong inhibitory effects on EAC cell growth especially on YAP1 high expressing EAC cells both in vitro and in vivo...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29167314/wnt-%C3%AE-catenin-pathway-activation-mediates-adaptive-resistance-to-braf-inhibition-in-colorectal-cancer
#2
Guangming Chen, Chenxi Gao, Xuan Gao, Dennis Han Zhang, Shih-Fan Kuan, Timothy F Burns, Jing Hu
One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma. However, in contrast to its striking efficacy in BRAF-mutant melanomas, BRAF inhibitor monotherapy is ineffective in BRAF-mutant colorectal cancer (CRC). While many studies on BRAF inhibitor resistance in CRC have focused on mechanisms underlying the reactivation of the EGFR/RAS/RAF/MEK/ERK pathway, the current study focuses on identifying novel adaptive signaling mechanisms, a fresh angle on CRC resistance to BRAF inhibition...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29167313/mechanism-informed-repurposing-of-minocycline-overcomes-resistance-to-topoisomerase-inhibition-for-peritoneal-carcinomatosis
#3
Huang-Chiao Huang, Joyce Liu, Yan Baglo, Imran Rizvi, Sriram Anbil, Michael Pigula, Tayyaba Hasan
Mechanism-inspired drug repurposing that augments standard treatments offers a cost-effective and a rapid route toward addressing the burgeoning problem of plateauing of effective therapeutics for drug-resistant micrometastases. We show that the antibiotic minocycline, by its ability to minimize DNA repair via reduced expression of tyrosyl-DNA phosphodiesterase-1 (Tdp1), removes a key process attenuating the efficacy of irinotecan, a frequently used chemotherapeutic against metastatic disease. Moreover, minocycline and irinotecan cooperatively mitigate each other's undesired cytokine inductions of VEGF and IL-8 respectively, thereby reinforcing the benefits of each modality...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29167312/inhibition-of-o-glcnacase-sensitizes-apoptosis-and-reverses-bortezomib-resistance-in-mantle-cell-lymphoma-through-modification-of-truncated-bid
#4
Sudjit Luanpitpong, Nawin Chanthra, Montira Janan, Jirarat Poohadsuan, Parinya Samart, Yaowalak U-Pratya, Yon Rojanasakul, Surapol Issaragrisil
Aberrant energy metabolism represents a hallmark of cancer and contributes to numerous aggressive behaviors of cancer cells, including cell death and survival. Despite the poor prognosis of mantle cell lymphoma (MCL), due to the inevitable development of drug resistance, metabolic reprograming of MCL cells remains an unexplored area. Post-translational modification of proteins via O-GlcNAcylation is an ideal sensor for nutritional changes mediated by O-GlcNAc transferase (OGT) and is removed by O-GlcNAcase (OGA)...
November 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29158470/comparative-oncology-evaluation-of-intravenous-recombinant-oncolytic-vesicular-stomatitis-virus-therapy-in-spontaneous-canine-cancer
#5
Shruthi Naik, Gina D Galyon, Nathan J Jenks, Michael B Steele, Amber C Miller, Sara D Allstadt, Lukkana Suksanpaisan, Kah Whye Peng, Mark J Federspiel, Stephen J Russell, Amy K LeBlanc
Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single shot systemic therapy with a VSV-IFNβ-NIS, a novel recombinant oncolytic Vesicular stomatitis virus (VSV), can induce curative remission in tumor bearing mice. Clinical translation of VSV-IFNβ-NIS therapy is dependent on comprehensive assessment of clinical toxicities, virus shedding, pharmacokinetics, and efficacy in clinically relevant models...
November 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29158469/molecular-basis-for-necitumumab-inhibition-of-egfr-variants-associated-with-acquired-cetuximab-resistance
#6
Atrish Bagchi, Jaafar N Haidar, Scott W Eastman, Michal Vieth, Michael Topper, Michelle D Iacolina, Jason M Walker, Amelie Forest, Yang Shen, Ruslan D Novosiadly, Kathryn M Ferguson
Acquired resistance to cetuximab, an antibody that targets the epidermal growth factor receptor (EGFR), impacts clinical benefit in head and neck, and colorectal cancers (CRC). One of the mechanisms of resistance to cetuximab is the acquisition of mutations that map to the cetuximab epitope on EGFR and prevent drug binding. We find that necitumumab, another FDA approved EGFR antibody, can bind to EGFR that harbors the most common cetuximab resistance substitution, S468R (or S492R, depending on the amino acid numbering system)...
November 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29158468/evaluating-the-mechanism-and-therapeutic-potential-of-ptc-028-a-novel-inhibitor-of-bmi-1-function-in-ovarian-cancer
#7
Anindya Dey, Xunhao Xiong, Aleia Crim, Shailendra Kumar Dhar Dwivedi, Soumyajit Banerjee Mustafi, Priyabrata Mukherjee, Liangxian Cao, Nadiya Sydorenko, Ramil Baiazitov, Young-Choon Moon, Melissa Dumble, Thomas Davis, Resham Bhattacharya
BMI-1, also known as a stem cell factor, is frequently upregulated in several malignancies. Elevated expression of BMI-1 correlates with poor prognosis and is therefore considered a viable therapeutic target in a number of malignancies including ovarian cancer. Realizing the immense pathological significance of BMI-1, small molecule inhibitors against BMI1 are recently being developed. In the current study, we functionally characterize PTC-028, an orally bioavailable compound that decreases BMI-1 levels by post-translational modification We report that PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays whereas normal cells remain unaffected...
November 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29146630/a-role-for-cxcr4-in-peritoneal-and-hematogenous-ovarian-cancer-dissemination
#8
Agnes Figueras, Elisenda Alsina-Sanchís, Alvaro Lahiguera, Manuel Abreu, Laura Muinelo-Romay, Gema Moreno-Bueno, Oriol Casanovas, Mariona Graupera, Xavier Matias-Guiu, August Vidal, Alberto Villanueva, Francesc Viñals
Epithelial ovarian cancer is characterized by a low recovery rate because the disease is typically diagnosed at an advanced stage, by which time, most patients (80%) already exhibit disseminated neoplasia. The cytokine receptor CXCR4 has been implicated in the development of metastasis in various tumor types. Using a patient-derived tissue macroarray and mRNA expression analysis we observed high CXCR4 levels in high-grade serous epithelial ovarian carcinomas, the most metastatic tumor, compared with those in endometrioid carcinomas...
November 16, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29142069/cat-02-106-a-site-specifically-conjugated-anti-cd22-antibody-bearing-an-mdr1-resistant-maytansine-payload-yields-excellent-efficacy-and-safety-in-preclinical-models
#9
Penelope M Drake, Adam Carlson, Jesse M McFarland, Stefanie Banas, Robyn M Barfield, Wesley Zmolek, Yun Cheol Kim, Betty C B Huang, Romas Kudirka, David Rabuka
Hematologically-derived tumors make up ~10% of all newly-diagnosed cancer cases in the U.S. Of these, the non-Hodgkin lymphoma (NHL) designation describes a diverse group of cancers that collectively rank among the top 10 most commonly diagnosed cancers worldwide. Although long-term survival trends are improving, there remains a significant unmet clinical need for treatments to help patients with relapsed or refractory disease, one cause of which is drug efflux through upregulation of xenobiotic pumps, such as MDR1...
November 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29142068/pharmacologic-inhibition-of-the-menin-mll-interaction-leads-to-transcriptional-repression-of-peg10-and-blocks-hepatocellular-carcinoma
#10
Katarzyna Kempinska, Bhavna Malik, Dmitry Borkin, Szymon Klossowski, Shirish Shukla, Hongzhi Miao, Jingya Wang, Tomasz Cierpicki, Jolanta Grembecka
Hepatocellular carcinoma (HCC) accounts for ~85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein-protein interaction between menin and histone methyltransferase Mixed Lineage Leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients...
November 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29142067/jq1-induces-dna-damage-and-apoptosis-and-inhibits-tumor-growth-in-a-patient-derived-xenograft-model-of-cholangiocarcinoma
#11
Patrick L Garcia, Aubrey L Miller, Tracy L Gamblin, Leona N Council, John D Christein, J Pablo Arnoletti, Marty J Heslin, Sushanth Reddy, Joseph H Richardson, Xiangqin Cui, Robert C A M van Waardenburg, James E Bradner, Eddy S Yang, Karina J Yoon
Cholangiocarcinoma (CCA) is a fatal disease with a five-year survival of <30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA...
November 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29142066/characterization-of-sgn-cd123a-a-potent-cd123-directed-antibody-drug-conjugate-for-acute-myeloid-leukemia
#12
Fu Li, May Kung Sutherland, Changpu Yu, Roland B Walter, Lori Westendorf, John Valliere-Douglass, Lucy Pan, Ashley Cronkite, Django Sussman, Kerry Klussman, Michelle Ulrich, Martha E Anderson, Ivan J Stone, Weiping Zeng, Mechthild Jonas, Timothy S Lewis, Maitrayee Goswami, Sa A Wang, Peter D Senter, Che-Leung Law, Eric J Feldman, Dennis R Benjamin
Treatment choices for acute myeloid leukemia (AML) patients resistant to conventional chemotherapies are limited and novel therapeutic agents are needed. Interleukin-3 receptor alpha (IL-3Rα, or CD123) is expressed on the majority of AML blasts and there is evidence that its expression is increased on leukemic relative to normal hematopoietic stem cells, which makes it an attractive target for antibody-based therapy. Here we report the generation and preclinical characterization of SGN-CD123A, an antibody-drug conjugate utilizing the pyrrolobenzodiazepine dimer (PBD) linker and a humanized CD123 antibody with engineered cysteines for site-specific conjugation...
November 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29138265/targeted-delivery-of-stat-3-modulator-to-breast-cancer-stem-like-cells-down-regulates-a-series-of-stem-ness-genes
#13
Santosh K Misra, Arun De, Dipanjan Pan
Cancer stem cells are known to be controlled by pathways that are dormant in normal adult cells, e.g. PTEN, which is a negative regulator of transcription factor STAT3. STAT3 regulates genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of enormous clinical significance. Studies on breast cancer stem cells (BCSCs) have been also significantly correlated with STATs. We describe here for the first time a novel strategy to selectively target CSCs and to induce downregulation of STAT3 downstream target genes reducing expression of series of 'stem-ness genes' in treated tumors...
November 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133623/immu-140-a-novel-sn-38-antibody-drug-conjugate-targeting-hla-dr-mediates-dual-cytotoxic-effects-in-hematological-cancers-and-malignant-melanoma
#14
Thomas M Cardillo, Serengulam V Govindan, Maria B Zalath, Diane L Rossi, Yang Wang, Chien-Hsing Chang, David M Goldenberg
HLA-DR is a member of the MHC class II antigen family expressed on hematological and solid tumors.  Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development.  IMMU-140 is an anti-HLA-DR antibody-drug conjugate comprised of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133622/ceritinib-enhances-the-efficacy-of-trametinib-in-braf-nras-wild-type-melanoma-cell-lines
#15
Daniel Verduzco, Brent M Kuenzi, Fumi Kinose, Vernon K Sondak, Zeynep Eroglu, Uwe Rix, Keiran S M Smalley
Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both 3D spheroid culture and long-term colony formation experiments...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133621/the-mutational-landscape-of-gastrointestinal-malignancies-as-reflected-by-circulating-tumor-dna
#16
Paul Riviere, Paul T Fanta, Sadakatsu Ikeda, Joel Baumgartner, Gregory M Heestand, Razelle Kurzrock
We aimed to assess the utility of a novel, non-invasive method of detecting genomic alterations in patients with gastrointestinal malignancies i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N=55 (26%)), appendiceal adenocarcinoma (N=46 (22%)), hepatocellular carcinoma (N=31 (15%)), and pancreatic ductal adenocarcinoma (N=25 (12%))...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133620/evaluation-of-cdk12-protein-expression-as-a-potential-novel-biomarker-for-dna-damage-response-targeted-therapies-in-breast-cancer
#17
Kalnisha Naidoo, Patty T Wai, Sarah L Maguire, Frances Daley, Syed Haider, Divya Kriplani, James Campbell, Hasan Mirza, Anita Grigoriadis, Andrew Tutt, Paul M Moseley, Tarek M A Abdel-Fatah, Stephen Yt Chan, Srinivasan Madhusudan, Emad A Rakha, Ian O Ellis, Christopher J Lord, Yinyin Yuan, Andrew R Green, Rachael Natrajan
Disruption of Cyclin Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and poly(ADP-ribose) polymerase 1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by immunohistochemistry (IHC) in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133619/clinical-application-of-circulating-tumor-dna-in-the-genetic-analysis-of-patients-with-advanced-gist
#18
Hao Xu, Liang Chen, Yang Shao, Dongqin Zhu, Xiaofei Zhi, Qiang Zhang, Fengyuan Li, Jianghao Xu, Xisheng Liu, Zekuan Xu
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. While circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133618/therapeutic-impact-of-nanoparticle-therapy-targeting-tumor-associate-macrophages
#19
Courtney Penn, Kun Yang, Hong Zong, Jae-Young Lim, Alex Cole, Dongli Yang, James Baker, Sascha N Goonewardena, Ronald J Buckanovich
Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest anti-angiogenic therapy induced hypoxia can induce tumor "stemness' as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor associated macrophages (TAMs). As such TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin...
November 13, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29133617/response-and-resistance-to-paradox-breaking-braf-inhibitor-in-melanomas-in-vivo-and-ex-vivo
#20
Edward J Hartsough, Curtis H Kugel, Michael J Vido, Adam C Berger, Timothy J Purwin, Allison Goldberg, Michael A Davies, Matthew J Schiewer, Karen E Knudsen, Gideon Bollag, Andrew E Aplin
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox breaking RAF inhibitor (PLX8394) has been designed. Here we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib...
November 13, 2017: Molecular Cancer Therapeutics
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