المؤلفون: F. Manig, Michael Baumann, Oleg Chen, Oleh V. Stasyk, Zhanru Yu, Leoni A. Kunz-Schughart, Benedikt M. Kessler, Anna Dubrovska, Loreen Lehmann, Nagwa Sorour, Steffen Löck

المصدر: Cellular and Molecular Life Sciences 78(2021), 3021-3044
Cellular and Molecular Life Sciences

مصطلحات موضوعية: 0301 basic medicine, Arginine, Eukaryotic Initiation Factor-2, Cell Culture Techniques, Apoptosis, Radiation Tolerance, Arginine-deprivation therapy, chemistry.chemical_compound, 0302 clinical medicine, RNA, Small Interfering, Chemistry, Endoplasmic Reticulum Stress, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Molecular Medicine, Original Article, RNA Interference, ER stress, Canavanine, Signal Transduction, Head and neck squamous carcinoma, Metabolic targeting, Protein Serine-Threonine Kinases, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cell Line, Tumor, 3-D culture, Endoribonucleases, medicine, Humans, Radiosensitivity, Molecular Biology, Cell Proliferation, Radiosensitization, Pharmacology, Squamous Cell Carcinoma of Head and Neck, X-Rays, Head and neck cancer, Cell Biology, medicine.disease, Activating Transcription Factor 4, Head and neck squamous-cell carcinoma, Culture Media, 030104 developmental biology, Cancer cell, Unfolded protein response, Cancer research, Transcription Factor CHOP

الوصف: Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms determining the sensitivity of intrinsically non-auxotrophic cancers to arginine deficiency are still poorly understood. We here show for the first time that arginine deficiency is accompanied by global metabolic changes and protein/membrane breakdown, and results in the induction of specific, more or less pronounced (severe vs. mild) ER stress responses in head and neck squamous cell carcinoma (HNSCC) cells that differ in their intrinsic ADT sensitivity. Combination of ADT with canavanine triggered catastrophic ER stress via the eIF2α-ATF4(GADD34)-CHOP pathway, thereby inducing apoptosis; the same signaling arm was irrelevant in ADT-related radiosensitization. The particular strong supra-additive effect of ADT, canavanine and irradiation in both intrinsically more and less sensitive cancer cells supports the rational of ER stress pathways as novel target for improving multi-modal metabolic anti-cancer therapy. Electronic supplementary material The online version of this article (10.1007/s00018-020-03704-7) contains supplementary material, which is available to authorized users.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::df213edef1933636ae00b4bbabbdef14Test
https://www.hzdr.de/publications/Publ-33956-1Test

المؤلفون: Holly Brunton, Giuseppina Caligiuri, Richard Cunningham, Rosie Upstill-Goddard, Ulla-Maja Bailey, Ian M. Garner, Craig Nourse, Stephan Dreyer, Marc Jones, Kim Moran-Jones, Derek W. Wright, Viola Paulus-Hock, Colin Nixon, Gemma Thomson, Nigel B. Jamieson, Grant A. McGregor, Lisa Evers, Colin J. McKay, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephen J. Pettitt, Michele L. Dziubinski, Simon T. Barry, Robert Grützmann, Robert Brown, Edward Curry, Marina Pajic, Elizabeth A. Musgrove, Gloria M. Petersen, Emma Shanks, Alan Ashworth, Howard C. Crawford, Diane M. Simeone, Fieke E.M. Froeling, Christopher J. Lord, Debabrata Mukhopadhyay, Christian Pilarsky, Sean E. Grimmond, Jennifer P. Morton, Owen J. Sansom, David K. Chang, Peter J. Bailey, Andrew V. Biankin, Sarah Allison, Susanna L. Cooke, Paul Grimwood, Shane Kelly, John Marshall, Brian McDade, Daniel McElroy, Donna Ramsay, Selma Rebus, Jane Hair, Paul Westwood, Nicola Williams, Fraser Duthie, Amber L. Johns, Amanda Mawson, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, R. Scott Mead, Adnan M. Nagrial, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connnor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero, Janet S. Graham

المساهمون: Basic (bio-) Medical Sciences

مصطلحات موضوعية: 0301 basic medicine, Biology, Adenocarcinoma, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, GATA6, GSK-3, Pancreatic cancer, Cell Line, Tumor, GATA6 Transcription Factor, medicine, Biomarkers, Tumor, Humans, GSK3B, chromatin landscapes, metabolic targeting, intronic and distal promoters, medicine.disease, Phenotype, HNF4A, Chromatin, 030104 developmental biology, Hepatocyte nuclear factor 4, Hepatocyte Nuclear Factor 4, PDAC subtypes, oncology, Cancer research, therapeutic tolerance, 030217 neurology & neurosurgery, Carcinoma, Pancreatic Ductal

الوصف: Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3b5ec52000a29e72c3d00ca316985478Test
http://hdl.handle.net/11562/1031969Test

المؤلفون: Weihua Zhou, Daniel R. Wahl

المصدر: Cancers, Vol 11, Iss 9, p 1231 (2019)
Cancers

مصطلحات موضوعية: 0301 basic medicine, Cancer Research, medicine.medical_treatment, Metabolic reprogramming, Brain tumor, Review, urologic and male genital diseases, lcsh:RC254-282, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, metabolic remodeling, Glioma, glioma, Medicine, metabolic targeting, Treatment resistance, Chemotherapy, business.industry, urogenital system, glioblastoma, Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, nervous system diseases, radiation, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, business, metabolism, Glioblastoma

الوصف: Glioblastoma (GBM) is the most common and aggressive primary brain tumor and is nearly universally fatal. Targeted therapy and immunotherapy have had limited success in GBM, leaving surgery, alkylating chemotherapy and ionizing radiation as the standards of care. Like most cancers, GBMs rewire metabolism to fuel survival, proliferation, and invasion. Emerging evidence suggests that this metabolic reprogramming also mediates resistance to the standard-of-care therapies used to treat GBM. In this review, we discuss the noteworthy metabolic features of GBM, the key pathways that reshape tumor metabolism, and how inhibiting abnormal metabolism may be able to overcome the inherent resistance of GBM to radiation and chemotherapy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::02eb638e67eb793240f03ce97dcc608dTest
https://www.mdpi.com/2072-6694/11/9/1231Test

المؤلفون: Fritz C. Eilber, Sarah M. Dry, Qinghong Han, Takashi Murakami, Kentaro Miyake, Scott D. Nelson, Michiaki Unno, Shukuan Li, Robert M. Hoffman, Yunfeng Li, Bartosz Chmielowski, Kentaro Igarashi, Kei Kawaguchi, Tara A. Russell, Yuying Tan, Tasuku Kiyuna

المصدر: Oncotarget, vol 8, iss 49
Oncotarget

مصطلحات موضوعية: 0301 basic medicine, Oncology, medicine.medical_specialty, Combination therapy, Oncology and Carcinogenesis, temozolomide, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Nude mouse, Surgical oncology, law, Internal medicine, melanoma, medicine, metabolic targeting, methionine dependence, Temozolomide, Methionine, biology, business.industry, Melanoma, Cancer, recombinant methioninase, biology.organism_classification, medicine.disease, 3. Good health, Surgery, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Recombinant DNA, business, Research Paper, medicine.drug

الوصف: // Kei Kawaguchi 1, 2, 3 , Kentaro Igarashi 1, 2 , Shukuan Li 1 , Qinghong Han 1 , Yuying Tan 1 , Tasuku Kiyuna 1, 2 , Kentaro Miyake 1 , 2 , Takashi Murakami 1, 2 , Bartosz Chmielowski 4 , Scott D. Nelson 5 , Tara A. Russell 6 , Sarah M. Dry 5 , Yunfeng Li 5 , Michiaki Unno 3 , Fritz C. Eilber 6 and Robert M. Hoffman 1, 2 1 AntiCancer, Inc., San Diego, CA, USA 2 Department of Surgery, University of California, San Diego, CA, USA 3 Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan 4 Division of Hematology-Oncology, University of California, Los Angeles, CA, USA 5 Department of Pathology, University of California, Los Angeles, CA, USA 6 Division of Surgical Oncology, University of California, Los Angeles, CA, USA Correspondence to: Robert M. Hoffman, email: all@anticancer.com Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: recombinant methioninase, methionine dependence, metabolic targeting, temozolomide, melanoma Received: June 06, 2017 Accepted: July 06, 2017 Published: August 12, 2017 ABSTRACT An excessive requirement for methionine termed methionine dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by methionine deprivation such as with recombinant methioninase (rMETase). The present study used a previously-established patient-derived orthotopic xenograft (PDOX) nude mouse model of BRAF V600E-mutant melanoma to determine the efficacy of rMETase in combination with a first-line melanoma drug, temozolomide (TEM). In the present study 40 melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n=10); TEM (25 mg/kg, oral 14 consecutive days, n=10); rMETase (100 units, intraperitoneal 14 consecutive days, n=10); combination TEM + rMETase (TEM: 25 mg/kg, oral rMETase: 100 units, intraperitoneal 14 consecutive days, n=10). All treatments inhibited tumor growth compared to untreated control (TEM: p =0.0081, rMETase: p =0.0037, TEM-rMETase: p =0.0024) on day 14 after initiation. However, the combination therapy of TEM and rMETase was significantly more efficacious than either mono-therapy (TEM: p =0.0051, rMETase: p =0.0051). The present study is the first demonstrating the efficacy of rMETase combination therapy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as melanoma, where rMETase may enhance first-line therapy.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a5657a1113de9ec7018a5035eba1757bTest
https://doi.org/10.18632/oncotarget.20231Test

المؤلفون: Padman Vamadevan, Shanna Wilson, Sarah Edwards, Ndaba Mazibuko, Robin Bannister, Samir G. Agrawal, Raphael Swery

المصدر: Frontiers in Pharmacology, Vol 10 (2019)
Frontiers in Pharmacology

مصطلحات موضوعية: 0301 basic medicine, Drug, Oncology, medicine.medical_specialty, media_common.quotation_subject, Context (language use), Off-label use, mebendazole, law.invention, 03 medical and health sciences, off-label, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Medicine, Pharmacology (medical), metabolic targeting, media_common, Protocol (science), Pharmacology, doxycycline, business.industry, lcsh:RM1-950, glioblastoma, atorvastatin, medicine.disease, Clinical trial, 030104 developmental biology, lcsh:Therapeutics. Pharmacology, Tolerability, 030220 oncology & carcinogenesis, Perspective, pluralistic evidence, business, metformin, Glioblastoma

الوصف: In oncology, preclinical and early clinical data increasingly support the use of a number of candidate "non-cancer" drugs in an off-label setting against multiple tumor types. In particular, metabolically targeted drugs show promise as adjuvant chemo and radiosensitizers, improving or restoring sensitivity to standard therapies. The time has come for large scale clinical studies of off-label drugs in this context. However, it is well recognized that high-cost randomized controlled trials may not be an economically viable option for studying patent-expired off-label drugs. In some cases, randomized trials could also be considered as ethically controversial. This perspective article presents a novel approach to generating additional clinical data of sufficient quality to support changes in clinical practice and relabeling of such drugs for use in oncology. Here, we suggest that a pluralistic evidence base and triangulation of evidence can support clinical trial data for off-label drug use in oncology. An example of an off-label drug protocol brought to the clinic for glioblastoma patients is presented, along with preliminary retrospective data from the METRICS study (NCT02201381). METRICS is a novel participant-funded, open-label, non-randomized, single-arm real-world study designed to gather high-quality evidence on the safety, tolerability, and effectiveness of four off-label metabolically targeted medicines as an adjunctive cancer treatment for glioblastoma patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6b0114ddedb715e2ba464b763bc97a64Test
https://www.frontiersin.org/article/10.3389/fphar.2019.00681/fullTest