Reversing metabolic reprogramming in obesity-associated hepatocellular carcinoma by inhibiting receptor protein tyrosine phosphatases

ongoing

REPRO-PTP is addressing the critical need for effective treatments in obesity-associated hepatocellular carcinoma (HCC). HCC, which accounts for 90% of primary liver cancers, is refractory to conventional chemotherapy with very low survival rate. As obesity is a major risk factor for HCC, it is imperative to develop new therapeutic approaches. My laboratory has identified receptor protein tyrosine phosphatases (PTPs) as key regulators of glycolysis and lipogenesis, with PTPRK emerging as a particularly promising target. Mechanistically, PTPRK is selectively increased in tumorigenic hepatocytes, inactivating fructose-1,6-bisphosphatase 1 (FBP1) and promoting glycolysis. PTPRK-mediated glycolysis increases peroxisome proliferator-activated receptor (PPAR)γ-dependent lipogenic signalling and HCC progression in obesity. REPRO-PTP aims to optimize and validate new PTPRK inhibitors that exhibit high selectivity, potency, and in vivo activity. By targeting both hepatic glycolysis and lipogenesis, these inhibitors have the unique potential to improve treatment outcomes for HCC in obese patients by reducing cancer progression and relapse risk. We will provide a robust pipeline for the broader development of PTPRK and additional PTP inhibitors for translational applicability, devise an intellectual property strategy, and perform a commercial feasibility analysis. The project represents a collaborative effort involving experts in oncology, biochemistry, and pharmacology, and is expected to yield novel insights into PTPs as drug targets in cancer and metabolic diseases. REPRO-PTP aims to pave the way for the development of innovative therapies that can improve the quality of life and survival rates for patients suffering from HCC and potentially other obesity-related hepatic complications.