ProAgio, a Novel Integrin αvβ3 Targeted Cytotoxin, Suppresses Tumor Growth and Reprograms the PDAC Microenvironment

BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, hypoxic and immune-suppressive tumor microenvironment (TME). Integrin v{beta}3-expressing cells, including endothelial and cancer-associated fibroblasts (CAFs), contribute to the development of this TME. ProAgio is a novel cytotoxin that targets integrin v{beta}3-expressing cells. ProAgio is currently in clinical trials. We have previously shown that the combination of GPH (gemcitabine, paricalcitol, and hydroxychloroquine) influences PDAC TME. Based on the overlapping mechanisms of action, we hypothesized that ProAgio could potentiate effects of GPH and enhance its anti-tumor immunity. MethodsPatient-derived xenograft (PDX) and orthotopic models of PDAC were used to assess the therapeutic activity and mechanism of action of ProAgio in combination with GPH. Immunohistochemistry was used to evaluate hypoxia, EMT and angiogenesis. Changes in the immune cells were measured with multi-parameter flow cytometry. Dynamic contrast-enhanced MRI (DCE-MRI) was used to study tumor perfusion in mice and patients (NCT06182072). FindingsProAgio potentiated the growth inhibitory effects of GPH in PDX and orthotopic models by depleting integrin {beta}3 expressing cells, leading to ECM remodeling, reduced vascular leakage, improved hypoxia, and reversed EMT. DCE-MRI showed a significant increase in tumor perfusion following ProAgio treatment in mice and patients (NCT06182072). Immune profiling revealed that the combination treatment significantly increased the infiltration of {gamma}{delta} T cells, natural killer T (NKT) cells, CD4+ effector T cells, and M1-like macrophages. Furthermore, the combination treatment reduced the expression of myofibroblastic CAFs (myCAFs), further supporting the immunomodulatory and stromal normalizing effects of GPH and ProAgio. ConclusionTargeting integrin v{beta}3 using ProAgio modulates the PDAC TME by improving perfusion, reducing hypoxia, reversing EMT, and alleviating immune suppression. ProAgio potentiates the effects of GPH therapy, which should be evaluated in future trials.