215 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which has been attributed to high interstitial pressure and poor drug delivery. In nonclinical studies, M402 affected multiple growth factors, adhesion molecules, and chemokines, inhibiting tumor progression, metastasis, and angiogenesis by clearing heparin-binding factors from the tumor microenvironment. We hypothesized that M402 could modulate tumor-stroma interactions in an orthotopic pancreatic cancer model (rich in desmoplasia), decreasing the fibrotic response and in turn increasing tumor perfusion and drug delivery. Methods: Capan-2 human PDAC cells were injected into the pancreata of nude mice. M402 (40 mg/kg/day, s.c.) or saline began Week 5. Gemcitabine (GEM; 30 mg/kg, i.p. biweekly) started Week 7. At different time points, primary tumors were analyzed for mRNA arrays, immunohistochemistry (ECM components, CD31), and functional tumor vasculature. GEM tumor uptake was evaluated by quantifying the incorporation of dFdC into tumor DNA by LC-MS/MS. M402 tumor uptake was visualized using HyLite-750-labeled drug in a Xenogen system. Results: M402 readily targeted pancreatic tumors with long residence time. Alone and particularly in combination with GEM, M402 significantly reduced tumor size and fibrosis, which was accompanied by down-regulation of SHH, PDGF, and TGF-β signaling in stromal cells. Tumors treated with M402 or M402+GEM showed perfusion and microvessel penetration into the tumor centers while vehicle or GEM treated tumors exhibited limited tortuous vessels surrounding the tumor rim. This translated into increased GEM incorporation into the tumor DNA when mice were pre-treated with M402 vs. saline (10.9±5.5 vs. 6.7±1.8 pg of dFdC/µg dG, respectively; p=0.037). Conclusions: M402 appears to inhibit stromal activation within the tumor microenvironment. Reduction in desmoplasia led to improved tumor perfusion, delivery of GEM, and tumor shrinkage. These and other promising nonclinical data support the rationale for the ongoing Phase 1/2 study evaluating the safety and tolerability of M402 in combination with nab-paclitaxel and GEM in patients with metastatic pancreatic cancer.
Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?
