Cooperative Drug Combinations Target Oncogenes and Tumor Suppressors in Cancer
Abstract
Multiple myeloma (MM)is a neoplasm involving plasma cells in the bone marrow. Drug resistance and progression are common, underscoring the need for new drug combinations. We utilized a high-throughput screen of tool compounds to limit growth of 47 human MM cell lines. In silicorobust regression analysis of drug responses revealed 43 potential synergistic combinations. We hypothesized that effective combinations would reduce oncogene expression and/or enhance tumor suppressor gene activity based on earlier genetic and drug studies that identified p16, Myc and mTOR as appropriate targets in myeloma. Thus, candidate combinations were evaluated for cooperative reductions in MYC protein expression in MM cells. Ten combinations cooperatively reduced MYC expression, which is frequently over-expressed in MM. Cooperative reductions in viability were observed with top combinations in proteasome inhibitor-resistant and sensitive MM cell lines but did not limit normal fibroblast viability. The combinations cooperatively increased p16 activity, while also enhancing cleaved caspase 3, leading to increased apoptosis. Combinationassociated survival was evaluated in a transplantable Ras-driven allograft model of advanced MM that closely recapitulates myeloma in humans. Three combinations significantly prolonged survival in sublethally-irradiated C57BL/6 mice injected intracardiac with donor MM cells compared to control mice. Furthermore, the top three combinations reduced viability of ex vivo treated patient cells. Common genetic pathways similarly affected by the top drug combinations were those implicated in promoting cell cycle transition and pathways most upregulated by all combinations were involved in TGFB and SMAD3 signaling. These data identify potentially useful drug combinations for preclinical evaluation in drug-resistant MM and may ultimately reveal novel mechanisms of combined drug sensitivity.
Degree
Ph.D.
Advisors
Mock, Purdue University.
Subject Area
Oncology|Cellular biology|Pharmaceutical sciences|Pharmacology
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