Modulation of sex and obesity hormone signalling to improve anti-cancer response.

Many cancers display differences in incidence, prognosis, and treatment response between males and females. In most cases, it is not well understood at a biological level why these differences exist. Sex hormone signalling has long been thought to play a role, even in cancer types that are not classically sex-specific (e.g. prostate cancer in males, ovarian cancer in females), but evidence is lacking. In melanoma, females experience lower incidence rates and better survival outcomes than males, and this extends to better responses to both molecular targeted therapy (BRAF and MEK inhibitors) and immunotherapy. In a phase II clinical trial of targeted therapy in melanoma patients with resectable disease [1], we observed clearly superior response rates and survival outcomes in female patients, suggesting a previously unrecognised interaction between sex and MAPK pathway blockade. Correlative analyses implicated androgen signalling in males as the driver of their inferior responses [2]. Clinical data suggests a further interaction between sex and obesity, with a suggestion that this may be mediated by hormonal interactions. Although there appears to be a mechanistic interaction between androgen signalling, adiposity and cancer therapy response, the molecular details of this interaction are not known. This project aims to explore this interaction further, using a combination of in vitro, ex vivo and in vivo pre-clinical models to evaluate the cellular responses to androgen and/or adipokine modulation in combination with anti-cancer therapy, using a step-wise approach to determine the relative contribution of cancer cell intrinsic, local microenvironmental, and systemic factors. The goal of these studies is to identify whether androgen or adipokine modulation are applicable to other cancer types and other treatment modalities (i.e. immunotherapy) as a therapeutic strategy. 1. Lancet Oncol. 2018 Feb;19(2):181-193. doi: 10.1016/S1470-2045(18)30015-9. 2. Nature. 2022 Jun;606(7915):797-803. doi: 10.1038/s41586-022-04833-8.