期刊
MOLECULAR CANCER THERAPEUTICS
卷 20, 期 12, 页码 2352-2361出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-21-0370
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资金
- Gulf Coast Consortia, on the Computational Cancer Biology Training Program (CPRIT Grant) [RP170593]
- NIH through the Ovarian SPORE Career Enhancement Program
- NCI grant [P50CA217685]
- Foundation for Women's Cancer research grant [FP00009883]
- Ovarian Cancer Research Alliance (OCRA) [FP00006137]
- Department of Defense Ovarian Cancer Research Program [W81XWH-20-1-0335]
- NIH Uterine Cancer SPORE [P50CA098258]
- National Comprehensive Cancer Network
- GOG Foundation Scholar Investigator Award
- American Cancer Society Research Professor Award
- LeBert Suess Family Endowment for Ovarian Cancer Research
- Frank McGraw Memorial Chair in Cancer Research
- NIH/NCI [P30CA016672]
- CPRIT Core Facilities Support Award [RP150578]
- Gulf Coast Consortia High Throughput Screening Program Core grant
- The Com-binatorial Drug Discovery Program [RP150578]
- [P50 CA217685]
CRM1 inhibitors have shown antitumor effects in ovarian cancer, and a high-throughput drug library screen identified olaparib as synergistic with selinexor. In vitro and in vivo studies confirmed the synergy, with RPPA analysis revealing changes in DNA damage repair and tumor suppressor protein expression. This preclinical study suggests potential for combining selinexor with PARP inhibitors in ovarian cancer treatment.
CRM1 inhibitors have demonstrated antitumor effects in ovarian and other cancers; however, rational combinations are largely unexplored. We performed a high-throughput drug library screen to identify drugs that might combine well with selinexor in ovarian cancer. Next, we tested the combination of selinexor with the top hit from the drug screen in vitro and in vivo. Finally, we assessed for mechanisms underlying the identified synergy using reverse phase protein arrays (RPPA). The drug library screen assessing 688 drugs identified olaparib (a PARP inhibitor) as the most synergistic combination with selinexor. Synergy was further demonstrated by MTT assays. In the A2780luc ip1 mouse model, the combination of selinexor and olaparib yielded significantly lower tumor weight and fewer tumor nodules compared with the control group (P < 0.04 and P < 0.03). In the OVCAR5 mouse model, the combination yielded significantly fewer nodules (P = 0.006) and markedly lower tumor weight compared with the control group (P = 0.059). RPPA analysis indicated decreased expression of DNA damage repair proteins and increased expression of tumor suppressor proteins in the combination treatment group. Collectively, our preclinical findings indicate that combination with selinexor to expand the utility and efficacy of PARP inhibitors in ovarian cancer warrants further exploration.
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