Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity
Douglas W. McMillin,Jake Delmore,Jake Delmore,Ellen Weisberg,Ellen Weisberg,Joseph Negri,Joseph Negri,D. Corey Geer,D. Corey Geer,Steffen Klippel,Steffen Klippel,Nicholas Mitsiades,Robert L. Schlossman,Robert L. Schlossman,Nikhil C. Munshi,Andrew L. Kung,James D. Griffin,James D. Griffin,Paul G. Richardson,Paul G. Richardson,Kenneth C. Anderson,Kenneth C. Anderson,Constantine S. Mitsiades,Constantine S. Mitsiades +23 more
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TLDR
In this paper, a tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay was developed to identify stroma-induced chemoresistance in diverse malignancies, including imatinib resistance in leukemic cells.Abstract:
Conventional anticancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter antitumor drug activity. To address this limitation, we developed the tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay. Tumor cells (for example, myeloma, leukemia and solid tumors) stably expressing luciferase are cultured with nonmalignant accessory cells (for example, stromal cells) for selective quantification of tumor cell viability, in presence versus absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse malignancies, including imatinib resistance in leukemic cells. A stroma-induced signature in tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras, NF-kappaB, HIF-1alpha, myc, hTERT and IRF4; for biological aggressiveness; and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against tumor cells interacting with stroma. One such compound, reversine, shows more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate anticancer agents to enrich preclinical pipelines with potential therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of tumor-stroma interactions.read more
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BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc
Jake Delmore,Ghayas C Issa,Madeleine E. Lemieux,Peter B. Rahl,Junwei Shi,Hannah M. Jacobs,Efstathios Kastritis,Timothy Gilpatrick,Ronald M. Paranal,Jun Qi,Marta Chesi,Anna C. Schinzel,Michael R. McKeown,Timothy P. Heffernan,Christopher R. Vakoc,P. Leif Bergsagel,Irene M. Ghobrial,Paul G. Richardson,Richard A. Young,William C. Hahn,William C. Hahn,Kenneth C. Anderson,Andrew L. Kung,James E. Bradner,Constantine S. Mitsiades +24 more
TL;DR: In this paper, a small-molecule bromodomain inhibitor, JQ1, was used to identify BET proteins as regulatory factors for c-Myc oncoprotein.
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Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
Ravid Straussman,Teppei Morikawa,Kevin Shee,Michal Barzily-Rokni,Zhi Rong Qian,Jinyan Du,Ashli Davis,Margaret M. Mongare,Joshua Gould,Dennie T. Frederick,Zachary A. Cooper,Paul B. Chapman,David B. Solit,Antoni Ribas,Roger S. Lo,Keith T. Flaherty,Shuji Ogino,Jennifer A. Wargo,Todd R. Golub +18 more
TL;DR: It is found that stroma-mediated resistance is common, particularly to targeted agents, and the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.
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Mina J. Bissell,William C. Hines +1 more
TL;DR: How normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state are reviewed.
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Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy.
TL;DR: The suitability of spheroids as an in vitro platform for testing drug delivery systems is examined and the assay techniques required for the characterization of drug delivery and efficacy in sp Heroids are discussed.
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BM mesenchymal stromal cell–derived exosomes facilitate multiple myeloma progression
Aldo M. Roccaro,Antonio Sacco,Patricia Maiso,Abdel Kareem Azab,Yu-Tzu Tai,Michaela R. Reagan,Feda Azab,Ludmila Flores,Federico Campigotto,Edie Weller,Kenneth C. Anderson,David T. Scadden,Irene M. Ghobrial +12 more
TL;DR: In vitro and in vivo studies demonstrated that exosome transfer from BM-MSCs to clonal plasma cells represents a previously undescribed and unique mechanism that highlights the contribution of BM- MSCs to MM disease progression.
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