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Raushan Kurmasheva

Raushan Kurmasheva

University of Texas Health Science Center, USA

Title: PARP1 inhibition sensitizes Ewing sarcoma cells to DNA damage

Biography

Raushan Kurmasheva has completed her PhD at the age of 29 years at Kazakh State National University, and her postdoctoral studies at University of Arkansas for Medical Sciences and St. Jude Children’s Research Hospital. She is an Assistant Professor at the Greehey Children’s Cancer Research Institute, UTHSC San Antonio. To date, she has published 46 peer-reviewed papers in reputed journals and has been serving as an AdHoc reviewer on MCT journal.

Abstract

Eighty-five percent of all Ewing sarcomas, the fourth most common highly malignant childhood cancer, is defined by a tumor-specific chromosomal translocation t(11;22)(q24;q12) between the EWSR1 and FLI1 genes. DNA damage induced by expression of EWSR1-FLI1 fusion gene is potentiated by PARP1 inhibition in Ewing cells, where EWSR1-FLI1 genes act in a positive feedback loop to maintain the expression of PARP1. As single agents, PARP1 inhibitors have shown promising activity in-vitro, but only modest activity in in-vivo models. In our previous work (in PPTP), we showed that low level DNA damage by temozolomide (TMZ) can be potentiated up-to 40-fold through inhibition of PARP1 by talazoparib, leading to dramatic tumor regressions in half of the Ewing sarcoma xenograft models. We are currently investigating the biochemical differences between Ewing cell lines where there is synergy in xenograft models in mice, and those where the combination is inactive; we hypothesize that resistance of Ewing sarcoma xenografts to the synergy of the drug combination is a consequence of intrinsic resistance to either or both talazoparib or TMZ. The combination talazoparib-TMZ in Ewing sarcoma xenografts is the most dramatic synergy between two drugs to be reported. Determining the mechanism(s) of resistance to combination therapy will allow potentially identify biomarkers that will allow identification of patients likely to benefit from such treatment, and spare toxicity for those unlikely to respond.