PROJECT SUMMARY: Novel treatment strategies for cancer The urgent need to develop effective treatments for non-clear cell renal cell carcinomas (NCCRCC) is underscored by consistently poor overall survival, despite decades of clinical trials. This is because there are no biologically rational treatments for NCCRCC, compared to conventional clear cell renal cell carcinomas. Accordingly, the lack of therapies for NCCRCC is a critical clinical unmet need. We addressed this need by developing a novel JAK and AKT inhibitor combination treatment that blocked the growth of NCCRCC cancer cells invitro and in mouse models. Importantly, we discovered a non-genomic early adaptive survival signal following JAK-AKT inhibition therapy characterized by a “lipid reprogrammed” transcriptional state. This non-genomic metabolic adaptation resulted in phospholipid hydrolysis to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Our objective is to definitely establish the mechanistic and functional basis for this observed effect. This leads us to hypothesize that the induction of metabolic catastrophe is essential to inducing cytotoxicity. We will test this hypothesis as follows: In Aim 1, we will explore how mitochondrial biogenesis and dynamics converge to increase respiration in the setting of metabolic stress. Next, in Aim 2, we will elucidate how lysophospholipids and fatty acids are marshalled to maintain cancer cell survival despite nutrient depletion. Importantly, in both aims we will seek to discover molecular targets that can potentially lead to even more potent therapeutic combinations. The extension of this research to the broader scientific and clinical community will be significant because this work will establish the framework for co-targeting of signaling and metabolic pathways to improve and extend the lives of patients with NCCRCC.