(P 191) SYNERGISTIC ACTIVITY OF PARP INHIBITORS IN COMBINATION WITH STANDARD CHEMOTHERAPY IN LEIOMYOSARCOMA

Objective: Leiomyosarcomas (LMS) are genetically heterogeneous tumors that arise from smooth muscle. Currently, the mainstay of systemic treatment for patients with advanced/metastatic disease is doxorubicin (Dox) based chemotherapy ( CTx) . Several genomic analyses of LMS reveal defects in the homologous recombination (HR) DNA repair pathway in about 50% of patients, consistent with a druggable “BRCAness” phenotype. Thus, we sought to determine which combinations of standard CTx and PARPi might be promising synergistic therapeutic strategies for LMS, and to understand the mechanisms whereby drug response occurs.Methods: Dox, Docetaxel (Doc), and Temozolomide (Tmz) were evaluated in combination with several PARPi (Olaparib [Ola], Niraparib [Nira] and Talazoparib [Tala]) at 12 different drug concentrations. Patient derived LMS cell lines of different origins (gynecological - GY, abdominal - A and extremity - E) were tested in a high throughput manner. All drug concentrations for combination experiments were chosen according to EC50 concentrations. Cells were incubated with each combination for 7 days, allowing for at least two cell cycles of action. Viability was assessed using ATPlite Luminescence Assay System. Evaluation of drug combination effect was calculated using a Bliss synergy score. This system quantifies the degree of synergy as multiplicative effect of single drugs as if they acted independently. Specifically, the interaction between two drugs is considered synergistic if the score is >5%, and therefore a promising combination; additive with a score of -5 to 5%, and antagonistic with a score of Results: Anticancer activity, ranging from additive to synergistic, was seen with all combinations. Results were consistent among all cell lines, independent of site of origin (Table 1). The most synergistic combination in the majority of LMS cell lines were Dox or Tmz with Tala, reaching up to 15 % and 27% above Bliss, respectively. In contrast, Doc showed only additive effect with all analyzed PARPi. Cell cycle analysis revealed that CTx combined with PARPi induces cell cycle arrest at the G2/M phase. Investigation of apoptosis levels with drug combinations is currently underway. The most commonly identified genetic alterations by WGS were TP53 and ATRX mutations. Finally, we present data to correlate HRD with transcriptomic profiles post therapy.Conclusion: Our functional LMS studies suggests that the combination of Dox or Tmz with PARPi may be promising treatment options for LMS patients. In addition, the analyzed drug combinations will be correlated to molecular data including WGS and RNAseq. The latter will provide insight into the mechanism of action and assist with predicting efficacy of future drug combinations. Recent clinical studies support the combination of CTx with PARPi in uterine LMS. Importantly, our data suggest that such approach may be extended to all sites of LMS. Pre-clinical studies are underway to identify the most promising combinations for future clinical trial design.Table.docx