Abstract Pancreatic ductal adenocarcinoma is a highly aggressive malignancy that is characterized by an expansive desmoplastic stroma that establishes an unusual local microenvironment. In contrast to many other cancers, angiogenesis in PDAC is tempered by the effects of the stroma, through a process called angiosuppression. Consequently, tissue perfusion is reduced in tumor tissues, leading to extreme hypoxia that alters the tumor metabolism and can promote local immunosuppression. Angiosuppression also reduces drug delivery to tumors, which can limit the effectiveness of some chemotherapeutic agents. In prior work, we learned that the hedgehog pathway, which forms a paracrine signal from malignant epithelial cells to nearby myofibroblasts, initiates of cascade of signals that ultimately repress angiogenesis. Recently, the development of multiple pharmacological agents designed to inhibit the RAS pathway has built enthusiasm for the ongoing clinical development of this new class of anti-cancer agents since KRAS is mutationally activated in ∼94% of human PDAC cases. We previously showed that RMC-7977, a preclinical RAS (ON) -multi inhibitor related to the investigational agent daraxonrasib, shows strong preclinical efficacy at clinically-relevant, tolerable doses. Noting that the SHH expression is driven by RAS mutation, we hypothesized that pan-RAS-GTP inhibition may relieve angiosuppression. Indeed, treatment of genetically engineered KPC mice with autochthonous pancreatic tumors led to a wave of angiogenesis in tumor tissues, even while the tumors themselves were regressing. This finding was validated in murine and human PDAC tissue explant cultures. scRNAseq analysis and IHC indicate that pan-RAS-GTP inhibition promotes maturation of endothelial cells into mature arterioles and venules. Mechanistic studies confirm that RAS inhibition downregulates the hedgehog-driven paracrine cascade that enforces angiosuppression. In ongoing work, we are now examining whether the increased vasculature leads to increased perfusion and drug delivery, as anticipated. Citation Format: Marie C. Hasselluhn, Ileana Murazzi, Lorenzo Tomassoni, Tanner Dalton, Allison C. Hess, Jayden McDonald, Stephen A. Sastra, Carmine F. Palermo, Andrea Califano, Kenneth P. Olive. pan-RAS-GTP inhibition relieves angiosuppression in PDAC by repressing Hedgehog paracrine signaling abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B097.
Hasselluhn et al. (2025) studied this question.