Developing novel polytherapies for Non-Clear Cell Renal Cell Carcinoma

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PROJECT SUMMARY: Developing novel polytherapies for Non-Clear Cell Renal Carcinoma Non-clear cell renal cell carcinoma (NCCRCC) is the therapeutic outlier in kidney cancer because there are no approved treatments for these patients. Consequently, diverse treatments that are currently given to NCCRCC patients result in variable, incomplete and short-lived responses, contributing to a dismal 5-year survival rate of just 8%. Accordingly, the lack of mechanistically-guided therapies to treat NCCRCC is a critical unmet need in cancer treatment. We recently reported that a therapeutic approach combining JAK and AKT inhibitors (JAK-AKT) potently extinguished both signaling pathways to restrain NCCRCC tumor growth, with good tolerability1. However, despite effective inhibition of critical growth, survival and bypass signals, we did not achieve deep tumor regressions. Consequently, metabolic and transcriptomic profiling of JAK-AKT treated NCCRCC cells and patient tumors revealed that while the co-treatment inhibited glycolysis with decreases in glucose consumption and lactate production, it also paradoxically induced phospholipid hydrolysis with release of free fatty acids within 24 hours to meet their bioenergetic needs, therefore enabling their survival. We have termed this rapidly emergent non-mutational metabolic survival adaptation: treatment-induced metabolic reprogramming (TIMR). Here, we now show that TIMR is associated with increased mitochondrial mass and respiration. Importantly, inhibition of mitochondrial respiration synergizes with JAK-AKT inhibitors to cause tumor regressions in vivo. Further, JAK-AKT induced TIMR in cells and patient tumors promotes phospholipid hydrolysis, with subsequent release of polyunsaturated fatty acids (PUFA) such as arachidonic acid and linoleic acid in NCCRCC cells and treated patient tumors, establishing the clinical relevance of our findings. We observed that the increase in PUFAs enhanced lipid peroxidation, causing increased sensitivity to glutathione peroxidase (GPX4) inhibition and ferroptosis, a non-apoptotic regulated cell death program. Taken together, co-targeting TIMR and JAK- AKT was synthetically lethal in NCCRCC tumors in cells and mouse models. Therefore, the long-term goal of this new research proposal is to improve the outcomes for patients with NCCRCC by leveraging the momentum of our findings into mechanistically guided new combination treatment strategies. Accordingly, our objective now is to identify the mechanisms regulating TIMR, and to provide proof- of-concept that targeting TIMR is a valuable therapeutic strategy in NCCRCC. Our central hypothesis is that TIMR enables cancer cells to adapt and survive anti-cancer therapies by hijacking metabolic processes, and that these vulnerabilities can be therapeutically exploited. We will test this hypothesis in the following specific aims: Aim 1: Determining the extent to which inhibition of mitochondrial respiration enhances the effect of JAK-AKT inhibitors in NCCRCC. Aim 2: Establish the therapeutic effect of inducing ferroptosis in the setting of JAK-AKT inhibition.