TLR7 as a therapeutic target for pancreatic ductal adenocarcinoma and cancer-associated cachexia Public Deposited
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of malignancies, with a dismal survival rate and limited treatment options. Advances in therapeutic modalities are urgently needed not only to successfully restrain tumor growth, but to address the underlying physiological aberrations that drive significant morbidity and mortality in PDAC. Specifically, no therapies exist to treat cachexia, a complex metabolic and behavioral syndrome that is present in up to 85% of patients with PDAC. To address this therapeutic gap, I performed three main studies detailed over the course of this dissertation. First, we established a novel model of pancreatic cancer cachexia using transplantation mouse models. Using epithelial cells transplanted from KRASLSL.G12D/+ TP53LSL.R172H/+ Pdx-Cre (KPC) mice into the pancreas of immunocompetent syngeneic recipient mice, we demonstrated key behavioral, physiological, and molecular manifestations of cachexia were reliably induced in conjunction with PDAC lesion development. Next, I used mouse models to determine whether the immune-enhancing agent R848, an agonist of Toll-like receptor 7 (TLR7), could be delivered in a manner to overcome sickness responses and allow safe therapeutic use during cancer. This study revealed that sickness responses to TLR7 stimulation undergo tachyphylaxis using a daily systemic dosing schedule, likely via induction of immune tolerance. Finally, I applied the optimized R848 dosing strategy to our model of PDAC and cancer-associated cachexia to determine effects on tumor response and cachexia status. This revealed that for a majority of epithelial clones, R848 results in stromal TLR7-dependent anti-tumor responses, reduced cachexia manifestations, and extended survival. Overall, these studies show that when delivered appropriately, immune enhancing agents such as R848 could provide demonstrable benefit in the context of PDAC and cancer-associated cachexia.