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Molecular Cancer Therapeutics

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https://read.qxmd.com/read/30755456/a-simple-three-dimensional-hydrogel-platform-enables-ex-vivo-cell-culture-of-patient-and-pdx-tumors-for-assaying-their-response-to-clinically-relevant-therapies
#1
Kolin C Hribar, Christopher J Wheeler, Alexey Bazarov, Kunal Varshneya, Ryosuke Yamada, Padraig Buckley, Chirag G Patil
A cell culture platform that enables ex vivo tissue growth from patients or patient-derived xenograft (PDX) models and assesses sensitivity to approved therapies (e.g. Temozolomide, TMZ) in a clinically relevant timeframe would be very useful in translational research and personalized medicine. Here, we present a novel three-dimensional (3D) ECM hydrogel system, VersaGel, for assaying ex vivo growth and therapeutic response with standard image microscopy. Specifically, multicellular spheroids deriving from either five glioblastoma (GBM) patients or a renal cell carcinoma (RCC) PDX model were incorporated into VersaGel and treated with TMZ and several other therapies, guided by the most recent advances in GBM treatment...
February 12, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30683810/tgf%C3%AE-blockade-enhances-radiotherapy-abscopal-efficacy-effects-in-combination-with-anti-pd1-and-anti-cd137-immunostimulatory-monoclonal-antibodies
#2
Maria E Rodriguez-Ruiz, Inmaculada Rodriguez, Lina Mayorga, Tania Labiano, Benigno Barbes, Inaki Etxeberria, Mariano Ponz-Sarvise, Arantza Azpilikueta, Elixabet Bolaños, Miguel F Sanmamed, Pedro Berraondo, Felipe A Calvo, Mary Helen Barcellos-Hoff, Jose Luis Perez-Gracia, Ignacio Melero
Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effects against syngeneic transplanted murine tumors up to a certain tumor size. Knowing that TGF-beta expression or activation increases in irradiated tissues, we tested whether TGF-beta blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination...
January 25, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30679390/combined-mek-and-bcl-2-xl-inhibition-is-effective-in-high-grade-serous-ovarian-cancer-patient-derived-xenograft-models-and-bim-levels-are-predictive-of-responsiveness
#3
Claudia Iavarone, Ioannis K Zervantonakis, Laura M Selfors, Sangeetha Palakurthi, Joyce F Liu, Ronny Drapkin, Ursula A Matulonis, Dorothy Hallberg, Victor E Velculescu, Joel D Leverson, Deepak Sampath, Gordon B Mills, Joan S Brugge
Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft (PDX) models...
January 24, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30679389/the-antitumor-drug-lb-100-is-a-catalytic-inhibitor-of-protein-phosphatase-2a-ppp2ca-and-5-ppp5c-coordinating-with-the-catalytic-metals-in-the-active-site-of-pp5c
#4
Brandon M D'Arcy, Mark R Swingle, Cinta Maria Papke, Kevin A Abney, Erin S Bouska, Aishwarya Prakash, Richard E Honkanen
LB-100 is an experimental cancer-therapeutic with cytotoxic activity against cancer cells in culture and antitumor activity in animals. The first Phase I trial (NCT01837667) evaluating LB-100 recently concluded that safety and efficacy parameters are favorable for further clinical testing. Although LB-100 is widely reported as a specific inhibitor of serine/threonine phosphatase 2A (PP2AC/PPP2CA:PPP2CB), we could find no experimental evidence in the published literature demonstrating the specific engagement of LB-100 with PP2A in vitro, in cultured cells, or in animals...
January 24, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30679388/first-in-human-phase-i-study-of-an-oral-hsp90-inhibitor-tas-116-in-patients-with-advanced-solid-tumors
#5
Akihiko Shimomura, Noboru Yamamoto, Shunsuke Kondo, Yutaka Fujiwara, Shigenobu Suzuki, Noriko Yanagitani, Atsushi Horiike, Satoru Kitazono, Fumiyoshi Ohyanagi, Toshihiko Doi, Yasutoshi Kuboki, Akihito Kawazoe, Kohei Shitara, Izumi Ohno, Udai Banerji, Raghav Sundar, Shuichi Ohkubo, Elizabeth M Calleja, Makoto Nishio
HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1), or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD...
January 24, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30679387/nanoparticle-delivery-of-mir-708-mimetic-impairs-breast-cancer-metastasis
#6
Divya Ramchandani, Seung Koo Lee, Shira Yomtoubian, Myung Shin Han, Ching-Hsuan Tung, Vivek Mittal
Triple-negative breast cancer (TNBC) patients exhibit the worst clinical outcome due to its aggressive clinical course, higher rate of recurrence, and a conspicuous lack of FDA approved targeted therapies. Here, we show that multilayered nanoparticles (NPs) carrying the metastasis suppressor microRNA miR-708 (miR708-NP) localize to orthotopic primary TNBC, and efficiently deliver the miR-708 cargo to reduce lung metastasis. Using a SOX2/OCT4 promoter reporter, we identified a population of miR-708low cancer cells with tumor-initiating properties, enhanced metastatic potential and marked sensitivity to miR-708 treatment...
January 24, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30679386/a-kinase-inhibitor-with-anti-pim-kinase-activity-is-a-potent-and-selective-cytotoxic-agent-towards-acute-myeloid-leukemia
#7
Ronja Bjørnstad, Reidun Aesoy, Øystein Bruserud, Annette K Brenner, Francis Giraud, Tara Helen Dowling, Gro Gausdal, Pascale Moreau, Stein Ove Døskeland, Fabrice Anizon, Lars Herfindal
More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo[2,3-a]carbazole-3-carbaldehyde, pyrazolo[3,4-c]carbazole, pyrazolo[4,3-a]phenanthridine or pyrrolo[2,3-g] indazole...
January 24, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30674566/maternal-embryonic-leucine-zipper-kinase-melk-a-potential-therapeutic-target-for-neuroblastoma
#8
Alexandre Chlenski, Chanyoung Park, Marija Dobratic, Helen R Salwen, Brian Budke, Jae-Hyun Park, Ryan Miller, Mark A Applebaum, Emma Wilkinson, Yusuke Nakamura, Philip P Connell, Susan L Cohn
Maternal Embryonic Leucine Zipper Kinase (MELK) activates pathways that mediate aggressive tumor growth and therapy resistance in many types of adult cancers. Pharmacologic and genomic inhibition of MELK impairs tumor growth and increases sensitivity to radiation and chemotherapy. Based on these promising preclinical studies, early phase adult clinical trials testing the MELK inhibitor OTS167 are ongoing. To investigate if MELK is also a therapeutic target in neuroblastoma, we analyzed MELK expression in primary tumors and cell lines, and examined the effects of OTS167 on neuroblastoma growth...
January 23, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30647122/chemically-modified-antisense-oligonucleotide-against-arl4c-inhibits-primary-and-metastatic-liver-tumor-growth
#9
Takeshi Harada, Shinji Matsumoto, Suguru Hirota, Hirokazu Kimura, Shinsuke Fujii, Yuuya Kasahara, Hidetoshi Gon, Toshihiko Yoshida, Tomoo Itoh, Naotsugu Haraguchi, Tsunekazu Mizushima, Takehiro Noda, Hidetoshi Eguchi, Satoshi Nojima, Eiichi Morii, Takumi Fukumoto, Satoshi Obika, Akira Kikuchi
ADP-ribosylation factor-like 4c (ARL4C) is identified as a small GTP-binding protein that is expressed by Wnt and EGF signaling and plays an important role in tubulogenesis of cultured cells and the ureters. ARL4C is little expressed in adult tissues, but it is highly expressed in lung cancer and colorectal cancer (CRC) and shown to represent a molecular target for cancer therapy based on siRNA experiments. This study revealed that ARL4C is highly expressed in primary hepatocellular carcinoma (HCC) tumors and CRC liver metastases and that ARL4C expression is associated with poor prognosis for these cancers...
January 15, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30647121/the-rolipram-perillyl-alcohol-conjugate-neo214-is-a-mediator-of-cell-death-through-the-death-receptor-pathway
#10
Hee-Yeon Cho, Thu Zan Thein, Weijun Wang, Stephen D Swenson, Rochelle A Fayngor, Mengting Ou, Nagore I Marín-Ramos, Axel H Schönthal, Florence M Hofman, Thomas C Chen
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Treatment with temozolomide (TMZ), standard of care for gliomas, usually results in drug resistance and tumor recurrence. Therefore, there is a great need for drugs that target GBM. NEO214 was generated by covalently linking rolipram to perillyl alcohol (POH) via a carbamate bond to form the rolipram-perillyl alcohol conjugate. We show here that NEO214 is effective against both TMZ-sensitive and TMZ-resistant glioma cells. Furthermore, NEO214 is effective for different mechanisms of TMZ-resistance: overexpression of MGMT (O6-methylguanine methyl-transferase); deficiency in specific mismatch repair (MMR) proteins; and overexpression of base excision repair (BER) proteins...
January 15, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30642883/antimalarial-drug-pyrimethamine-plays-a-dual-role-in-anti-tumor-proliferation-and-metastasis-through-targeting-dhfr-and-tp
#11
Huijuan Liu, Yuan Qin, Denghui Zhai, Qiang Zhang, Ju Gu, Yuanhao Tang, Jiahuan Yang, Kun Li, Lan Yang, Shuang Chen, Weilong Zhong, Jing Meng, Yanrong Liu, Tao Sun, Cheng Yang
Pyrimethamine (Pyr), an antimalarial drug that targeting plasmodium dihydrofolate reductase (pDHFR), has been proved to have antitumor activity. However, its direct target on cancer cells remains unclear. Methotrexate (MTX) is a widely used anticancer drug that blocks human dihydrofolate reductase (hDHFR). In this work, we examined the anticancer effects of Pyr in vitro and in vivo. Our results showed that hDHFR and pDHFR have similar secondary and three-dimensional structures and that Pyr can inhibit the activity of hDHFR in lung cancer cells...
January 14, 2019: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30587558/blood-interactions-pharmacokinetics-and-depth-dependent-ablation-of-rat-mammary-tumors-with-photoactivatable-liposomal-doxorubicin
#12
Kevin A Carter, Dandan Luo, Jumin Geng, Stephan T Stern, Jonathan F Lovell
Photosensitizers can be integrated with drug delivery vehicles to develop chemophototherapy agents with anti-tumor synergy between chemo- and photo- components. Long-circulating doxorubicin (Dox) in porphyrin-phospholipid (PoP) liposomes (LC-Dox-PoP) incorporates a phospholipid-like photosensitizer (2 mole %) in the bilayer of Dox-loaded stealth liposomes. Hematological effects of endotoxin-minimized LC-Dox-PoP were characterized via standardized assays. In vitro interaction with erythrocytes, platelets, and plasma coagulation cascade were generally unremarkable while complement activation was found to be similar to that of commercial Doxil...
December 26, 2018: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30587557/tsr-033-a-novel-therapeutic-antibody-targeting-lag-3-enhances-t-cell-function-and-the-activity-of-pd-1-blockade-in-vitro-and-in-vivo
#13
Srimoyee Ghosh, Geeta Sharma, Jon Travers, Sujatha Kumar, Justin Choi, H Toni Jun, Marilyn Kehry, Sridhar Ramaswamy, David Jenkins
Progressive upregulation of checkpoints on tumor infiltrating lymphocytes promotes an immunosuppressive tumor microenvironment, severely compromising tumor immunity. Lymphocyte activation gene-3 (LAG-3) is a co-inhibitory receptor associated with impaired T cell function and is frequently co-expressed with programmed cell death protein-1 (PD-1) in the context of human cancers. Targeting LAG-3 in conjunction with PD-1 thus represents a strategy to amplify and broaden the therapeutic impact of PD-1 blockade alone...
December 26, 2018: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30587556/tgf%C3%AE-blockade-augments-pd-1-inhibition-to-promote-t-cell-mediated-regression-of-pancreatic-cancer
#14
Daniel R Principe, Alex Park, Matthew J Dorman, Sandeep Kumar, Navin Viswakarma, Jonathan Rubin, Carolina Torres, Ronald McKinney, Hidayatullah G Munshi, Paul J Grippo, Ajay Rana
Pancreatic ductal adenocarcinoma (PDAC) remains remarkably lethal with a 5-year survival rate of 8%. This is mainly attributed to the late stage of presentation, as well as widespread resistance to conventional therapy. Additionally, PDAC tumors are largely non-immunogenic, and most patients have displayed incomplete responses to cancer immunotherapies. Our group has previously identified Transforming Growth Factor Beta (TGFβ) as a crucial repressor of anti-tumor immune function in PDAC, particularly with respect to cytotoxic T lymphocytes...
December 26, 2018: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30587555/enhancing-chemosensitivity-of-breast-cancer-stem-cells-by-down-regulating-sox2-and-abcg2-using-wedelolactone-encapsulated-nanoparticles
#15
Sreemanti Das, Pritha Mukherjee, Ranodeep Chatterjee, Zarqua Jamal, Urmi Chatterji
A major caveat in the treatment of breast cancer is disease recurrence after therapeutic regime at both local and distal sites. Tumor relapse is attributed to the persistence of chemoresistant cancer stem cells (CSCs), which need to be obliterated along with conventional chemotherapy. Wedelolactone (Wdl), a naturally occurring coumestan, demonstrates anticancer effects in different cancer cells, though with several limitations, and is mostly ineffective against CSCs. In order to enhance its biological activity in cancer cells and additionally target the CSCs, Wdl-encapsulated PLGA nanoparticles (nWdl) were formulated...
December 26, 2018: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30587554/germline-variant-in-slco2b1-and-response-to-abiraterone-acetate-plus-prednisone-aa-in-new-onset-metastatic-castration-resistant-prostate-cancer-mcrpc
#16
Andrew W Hahn, David M Gill, Austin Poole, Roberto H Nussenzveig, Sara Wilson, James M Farnham, Robert A Stephenson, Lisa A Cannon-Albright, Benjamin L Maughan, Neeraj Agarwal
There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently available. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate (AA) for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line AA in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah...
December 26, 2018: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30530769/combined-pparg-activation-and-xiap-inhibition-as-a-potential-therapeutic-strategy-for-ovarian-granulosa-cell-tumors
#17
Dilys T H Leung, Trang Nguyen, Edwina May Oliver, Juliana Matti, Maria Alexiadis, John Silke, Thomas W Jobling, Peter J Fuller, Simon Chu
Ovarian granulosa cell tumors (GCT) are characterized by indolent growth and late relapse. No therapeutic modalities aside from surgery have proven effective. We previously reported overexpression of the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPARg) and constitutive activity of the NFkB and AP1 signaling pathways in GCT. PPARg presents as a potential therapeutic target as it impedes proliferation and promotes terminal differentiation of granulosa cells. However, resistance to the actions of PPARg is caused by NFkB transrepression in GCT-derived cell lines, KGN and COV434...
December 7, 2018: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30523050/the-secretome-engages-stat3-to-favor-a-cytokine-rich-microenvironment-in-mediating-acquired-resistance-to-fgfr-inhibitors
#18
Xinyi Wang, Jing Ai, Hongyan Liu, Xia Peng, Hui Chen, Yi Chen, Yi Su, Aijun Shen, Xun Huang, Jian Ding, Meiyu Geng
Acquired resistance severely hinders the application of small molecule inhibitors. Our understanding of acquired resistance related to fibroblast growth factor receptors (FGFRs) is limited. Here, to explore the underlying mechanism of acquired resistance in FGFR-aberrant cancer cells, we generated cells resistant to multiple FGFR inhibitors and investigated the potential mechanisms underlying acquired resistance. We discovered that reprogramming of the secretome is closely associated with acquired resistance to FGFR inhibitors...
December 6, 2018: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30523049/genome-wide-sequencing-of-cell-free-dna-identifies-copy-number-alterations-that-can-be-used-for-monitoring-response-to-immunotherapy-in-cancer-patients
#19
Taylor J Jensen, Aaron M Goodman, Shumei Kato, Christopher K Ellison, Gregory A Daniels, Lisa Kim, Prachi Nakashe, Erin McCarthy, Amin R Mazloom, Graham McLennan, Daniel S Grosu, Mathias Ehrich, Razelle Kurzrock
Inhibitors of the PD-1/PD-L1/CTLA4 immune checkpoint pathway have revolutionized cancer treatment. Indeed, some patients with advanced, refractory malignancies achieve durable responses; however, only a subset of patients benefit, necessitating new biomarkers to predict outcome. Interrogating cell-free DNA (cfDNA) isolated from plasma (liquid biopsy) provides a promising method for monitoring response. We describe the use of low-coverage, genome-wide sequencing of cfDNA, validated extensively for non-invasive prenatal testing (NIPT), to detect tumor-specific copy number alterations, and the development of a new metric--the genome instability number (GIN)--to monitor response to these drugs...
December 6, 2018: Molecular Cancer Therapeutics
https://read.qxmd.com/read/30523048/kdm5b-promotes-drug-resistance-by-regulating-melanoma-propagating-cell-subpopulations
#20
Xiaoni Liu, Shang-Min Zhang, Meaghan K McGeary, Irina Krykbaeva, Ling Lai, Daniel J Jansen, Stephen C Kales, Anton Simeonov, Matthew D Hall, Daniel P Kelly, Marcus W Bosenberg, Qin Yan
Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75- (CD34+) and CD34-p75- (CD34-) tumor subpopulations were characterized as melanoma-propagating cells (MPCs) that exhibit some of those key features. However, these two subpopulations differ from each other in tumorigenic potential, ability to recapitulate heterogeneity, and chemo-resistance. In this study, we demonstrate that CD34+ and CD34- subpopulations carrying the BRAFV600E mutation confer differential sensitivity to targeted BRAF inhibition...
December 6, 2018: Molecular Cancer Therapeutics
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