<p>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. Utilizing a high-throughput
screen of tool compounds to limit growth of human MM cell lines and <i>i</i><i>n silico</i> robust regression analysis of
drug responses, potential synergistic combinations were identified. Further
selection of effective combinations that reduce oncogenic MYC expression and enhance
tumor suppressor p16 activity was based on earlier genetic and drug studies that
identified MYC and p16 as appropriate targets in MM. Furthermore, the top three
combinations synergistically reduced drug sensitive and resistant cell
viability <i>in vitro</i> and the were effective in <i>ex vivo</i> treated patient cells Combination-associated survival was also
prolonged in a transplantable Ras-driven allograft model of advanced MM that closely
recapitulates MM in humans. One top drug combination was selected for further
preclinical development. Targets, mechanism of action, and efficacy of the
combination were evaluated through several <i>in vitro</i> and <i>in vivo </i>models,
as well as <i>ex vivo</i> in myeloma patient cells. Effective targeting of the
combination resulted in synergistic inhibition of proteasome inhibitor (PI) sensitive
MM cells, as well as cell with induced PI resistance. Additionally, the
combination was effective at delaying L363 MM xenograft growth in NSG mice and
prolonging survival compared to single agent therapy. Finally, a cooperative
signature of combined targeting was elucidated via RNA sequencing. These data
identify potentially useful drug combinations for preclinical evaluation in
drug-resistant MM and may ultimately reveal novel mechanisms of combined drug
sensitivity.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/17122760 |
| Date | 19 December 2021 |
| Creators | Tyler John Peat (11790659) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY-ND 4.0 |
| Relation | https://figshare.com/articles/thesis/Cooperative_Drug_Combinations_Target_Oncogenes_and_Tumor_Suppressors_in_Cancer/17122760 |
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