DRES-07. SIGNIFICANT SEX DIFFERENCES IN TEMOZOLOMIDE EFFICACY IN GLIOBLASTOMA (GBM) ARE DETECTABLE IN CELL AND PATIENT BASED EVALUATIONS

Abstract

A considerable amount of research is currently focused on the biology of sex differences under normal and pathological conditions. The work has highlighted the multiple mechanisms by which sexual differentiation affects disease phenotype. An important aspect of this for brain tumor patients is potential sex differences in therapeutic responses. While a focus on sex differences in immune function, drug metabolism, and blood-brain barrier function are important considerations, the potential for tumor cell-intrinsic mechanisms is often overlooked. We undertook a staged evaluation of cell intrinsic differences in the response of male and female glioblastoma cells to standard and experimental therapeutics. In the first stage, we screened the 5,500 FDA Bioactives Library with male and female murine GBM cells. This screen identified approximately 30 compounds with significant sex differences in activity, including temozolomide and other alkylators, PI3 kinase- AKT-mTOR pathway inhibitors, as well as EGFR antagonists. Next, we determined that temozolomide had significantly greater cytotoxic effects in a panel of female compared to a panel of male primary human GBM specimens. Finally, we assessed the therapeutic response, by way of radial tumor growth rate, on clinical T1 Gadolinium MRIs for 22 female and 38 male patients treated with radiation and temozolomide and found that adjuvant temozolomide exhibited significant sex differences in therapeutic effects in patients. Specifically, female patients exhibited better tumor control as the number of cycles of temozolomide increased. Together, these data indicate that temozolomide treatment may be further optimized by tailoring it to its sex-specific activity and that sex differences for all therapeutics should be further evaluated in lab and clinic based studies. Finally, our murine cell based sex-specific drug screening is a valuable platform for detecting sex differences in therapeutic effects.