UC Irvine

To this day, most preclinical research and clinical use of chemo and radiation cancer therapies do not take sex-differences into consideration, despite women having higher risk of adverse treatment toxicities and making up a larger survivor population than men. Additionally, evolving advances in cancer treatments continue to increase clinical success and there remains a growing unmet need to characterize the long-term toxic effects of frontline therapies, used in both women and men, on cancer survivors’ quality of life. To address these needs, a series of experiments examined the sex-specific effects of paclitaxel, a commonly used taxane family chemotherapeutic, and thoracic radiotherapy treatments on rodents’ cognitive and/or cardiac function. Female and male Wild Type (WT) mice were treated with paclitaxel (150 and 300 mg/kg) administered weekly over 6 weeks or exposed to 19 Gy cardiac irradiation. Systemic, behavioral, and cardiovascular endpoints were examined to assess paclitaxel-induced toxicity and cardiac function and histology were used to assess thoracic radiotherapy-induced toxicity. Interestingly, female WT mice exhibited enhanced tolerance compared to male WT mice in both treatment regimens. To gain more understanding of the observed female-specific protection, RhoB-deficient and aged female WT mice (22 months) were used. RhoB GTPase deficiency was interrogated for the possible impact of sex-hormones in cancer therapy toxicity (RhoB proteins being associated with estrogen receptors in females and cardiac fibrosis in males). In female mice, RhoB deficiency and advanced age had no impact on paclitaxel-induced neurocognitive impairment, but RhoB deficiency did compromise survival after radiotherapy. Conversely, RhoB deficiency reduced paclitaxel-induced neurotoxicity in males and extended male survival after radiation. In summary, this study revealed novel sexually dimorphic toxicities for commonly used taxane and radiation treatments, mediated in-part through age and/or RhoB-dependent pathways, which are associated with estrogen function in females and immune function in both sexes. This study provides additional data to the growing preclinical and clinical body of literature revealing sex-differences in disease progression and the critical roles of sex-hormones in immune response mechanisms. Therefore, further research is justified to elucidate estrogen and androgen-dependent mechanisms involved in the sex- and organ-specific toxicities observed after taxane and radiation therapies in preclinical and clinical research.