PROJECT SUMMARY: Despite the intensive effort and huge progress in cancer research, survival rate of many cancers remains low and one of the biggest challenges is resistance to anti-cancer targeted therapies. Recently, a novel mechanism of resistance has been recognized: by switching lineages from a cell type that is dependent on the drug target to a different cell type that is not. My previous and ongoing work revealed that advanced prostate cancer might escape antiandrogen therapy by increasing cellular lineage plasticity and transdifferentiate into a progenitor-like transition state which no longer responds to treatment. I have further demonstrated that this lineage plasticity is enabled by reactivation of SOX2, and can be reversed by inhibiting SOX2 expression. Although direct therapeutic inhibition of SOX2 is currently infeasible, clinical interruption of SOX2 upregulation and its downstream signaling is very promising, upon a clear elucidation of the mechanism of SOX2-driven plasticity. Furthermore, my preliminary observation shows that epigenetic modification may contribute to this SOX2-driven plasticity and resistance, which suggests novel therapeutic approaches targeting the epigenetic modifying machinery. Building on these findings, the proposed studies in Aim 1 and 2 focus on elucidating the exact mechanism of increasing plasticity and resistance driven by SOX2 in prostate cancer, possibly through epigenetic modification, and developing novel strategies to prevent it. In an effort to identify additional genomic alterations responsible for resistance, I successfully identified a novel tumor suppressor gene, SYNCRIP, that confer resistance to antiandrogen therapy via in vivo library screening. Because of the known interaction between SYNCRIP and deaminase Apobec-1, I will also test the hypothesis that loss of SYNCRIP in prostate cancer may confer resistance by releasing the inhibition of Apobec-1-driven methylation/demethylation, thus leading to increased epigenetic reprogramming and cell plasticity in Aim 3. The potential outcome of proposed studies will provide novel insight into the connection between epigenetic modification and resistance to targeted therapy in advanced prostate cancer, as well as novel approaches for clinical intervention of resistance. The support of the K99/R00 award for these proposed studies will provide me the protected time and required training in the fields of cancer epigenetics, chromatin biology and bioinformatics, as well as serve as a platform for me to obtain career development trainings such as grant writing, job application, manuscript writing and lab management. I believe all these supports and trainings are critical for achieving my career goal to become an independent investigator studying targeted therapy resistance.