Abstract
Abstract Sarcomas are heterogeneous mesenchymal neoplasms which have very limited treatment options. Chemotherapies for advanced sarcoma include DNA damaging agents such as doxorubicin, dacarbazine and gemcitabine with very low response rates. We elected to study the effects of olaparib (AZD2281), a novel, potent orally active PARP inhibitor in combination with standard chemotherapy Temozolomide (TMZ) in various sarcoma subtypes. We examined the effects of olaparib and TMZ in a panel of 7 sarcoma cell lines including leiomyosarcoma (SK-LMS, SK-UT1, SK-UT1b), liposarcoma (LS141, DDLS) and malignant peripheral nerve sheath tumors (MPNST, ST8814). In vitro results have shown inhibition of cell viability with combination treatment in all cell lines at concentrations of 300uM TMZ and 1 uM olaparib. After 48 hrs of drug treatment, we also examined biochemical effects showing PAR inhibition, p53 induction and γH2AX increase, indicative of DNA damage. Flow cytometric analysis of each cell line indicated G2/M cell cycle arrest with combination treatment. These observations correlated with enhanced apoptosis as measured by biochemical PARP cleavage and DNA content (sub-G1 population). Taking these observations and results, there is strong evidence to support combining standard chemotherapy TMZ with the PARP inhibitor olaparib in various sarcoma subtypes. Citation Format: Elgilda Musi, Grazia Ambrosini, Gary K. Schwartz. The parp inhibitor olaparib (AZD2281) greatly enances the effect of temozolomide in soft tissue sarcoma cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2073. doi:10.1158/1538-7445.AM2013-2073
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