Investigating the Impact of Obesity and Androgen Receptor Signaling on BRAF/MEKi Resistance in Melanoma - PROJECT SUMMARY As a surgical oncologist at the University of Virginia, I strive not only to deliver excellent surgical care but also to understand the mechanisms underlying treatment resistance in melanoma. My research focuses on the phenomenon known as the “obesity paradox,” where obese individuals with melanoma exhibit improved overall survival and progression-free survival while treated with BRAF/MEK inhibitors (BRAF/MEKi) compared to lean counterparts. Clinical data demonstrate that the obesity paradox is primarily observed in men, and our preliminary data show that obesity delays delayed resistance to BRAF/MEK inhibitors. The central hypothesis of this study is that in obese males, improved survival and delayed BRAF/MEKi resistance are due to obesity reducing metabolic plasticity within melanoma cells and diminishing androgen receptor signaling. To address this, I have designed a comprehensive research plan with two specific aims: (1) to define the effect of obesity on melanoma metabolism, AR signaling, and BRAF/MEKi resistance by examining the systemic effects of obesity, diet, and the microbiome, and (2) to elucidate the mechanisms of AR-mediated BRAF/MEKi resistance by examining how AR signaling alters the ER stress response and cellular metabolism under BRAF/MEKi-induced metabolic stress. This project will leverage advanced in vivo modeling, metabolomics, and human samples to achieve these goals. Specifically, we will utilize diet-induced obesity mouse models and pharmacological manipulation of key pathways to elucidate the intricate relationships between obesity, androgen receptor signaling, and melanoma treatment resistance. This K08 award will provide a structured career development plan that includes mentorship from Dr. Craig Slingluff and a distinguished advisory committee comprising Drs. Jianjie Ma, Shengyi Iris Sun, Thurl Harris, Daniel Gioeli, David Kashatus, Chengli Shen, and Allan Tsung. The mentorship team will offer diverse expertise in melanoma research, ER stress, obesity, androgen signaling, and cancer metabolism, ensuring my success. The career development plan includes targeted coursework in advanced topics in cancer biology, statistics, and scientific communication. My short-term career goals include learning lab techniques, understanding biostatistics, improving grantsmanship, and advancing my clinical expertise in treating melanoma. In the long term, I aim to become an independent NIH-funded surgeon-scientist focused on determining how obesity and sexual dimorphisms impact cancer treatment responses. By elucidating the cellular mechanisms underlying the obesity paradox in melanoma, this project aims to develop novel therapeutic strategies that improve patient outcomes and contribute significantly to public health advancements. Overall, this K08 award will be pivotal in equipping me with the skills, knowledge, and mentorship necessary to achieve my goal of becoming an independent researcher and making substantial contributions to the field of melanoma treatment.
