Small molecule inhibitors of the proton-sensing receptor GPR68 for pancreatic cancer therapy - ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) accounts for ~90% of pancreatic cancers and is the 3rd leading cause of cancer-related death in the US. Most patients are diagnosed at an advanced stage due to a lack of symptoms and effective screening, and only ~15% are eligible for surgery. Standard chemotherapies offer limited survival benefits and cause substantial toxicity. The 5-year survival rate remains only ~8%. While KRAS inhibitors may offer improvement, tumors quickly develop resistance, highlighting the urgent need for new treatment approaches. A hallmark of PDAC is its desmoplastic, hypoxic tumor microenvironment (TME) generated via extracellular matrix deposition by cancer-associated fibroblasts (CAFs). Desmoplasia impairs drug delivery and suppresses antitumor immunity due to acidosis and poor vascularization. Extracellular acidification, from the “Warburg effect” and increased lactate production by cancer cells, shapes the desmoplastic TME cell interplay and drives PDAC malignant phenotypes, but is not targeted by current PDAC therapies. One of the two principal acidity-sensing G protein coupled receptors in humans, GPR68 (OGR1), is expressed in cancer cells, CAFs, and immune cells in PDAC. Its pH-induced cAMP signaling can drive cancer proliferation and immunoevasion, fibrotic and immunosuppressive phenotypes in CAFs, and terminal exhaustion of immune cells. These associations provide a compelling motivation for the development of GPR68-targeting pharmacological agents and for mechanistic studies of their effects in PDAC models: an endeavor we undertake in this proposal. We hypothesize that by simultaneously blocking GPR68 effects in cancer cells, CAFs, and T cells, pharmacological inhibitors of GPR68 can normalize the PDAC TME, slow tumor progression, and ultimately enhance the efficacy of concurrent chemo- and immunotherapies. In Aim 1, we will use GPR68 structures, artificial intelligence (AI) -powered molecular design, medicinal chemistry, and pharmacological assays to optimize the low-potency GPR68 inhibitors we identified in preliminary work. In Aim 2, we will map the effects of GPR68 inhibition on cell phenotypes and paracrine signaling in human patient-derived in vitro and ex vivo models of PDAC. This exploratory project will validate GPR68 as a therapeutic target in PDAC and yield small molecules that suppress tumor growth by blocking its acidity-induced signaling in cancer, immune, and stromal cells. This innovative approach could improve patient outcomes in this highly lethal cancer and set the stage for preclinical and clinical development. Composed of experts in GPCR pharmacology, medicinal chemistry, drug discovery, tumor biology, and clinical oncology, our multidisciplinary team is ideally positioned to succeed.
