Abstract 5326: Cholecystokinin receptor antagonist decreases fibrosis in pancreatic cancer microenvironment to improve uptake and efficacy of chemotherapy

Abstract

Abstract Background: Although pancreatic cancer cells respond to chemotherapeutic agents in cell culture, many of these drugs are less effective in vivo. This decreased response to chemotherapy in animal models and human subjects is in part attributed to the dense stroma of the pancreatic tumor microenvironment (TME) that impedes penetration of drugs. Pancreatic stellate cells and tissue fibroblasts have cholecystokinin (CCK) receptors and when these receptors are activated, they promote collagen deposition and increase fibrosis in the TME. We have previously shown that CCK receptor antagonists can decrease fibrosis and change the T-cell infiltrates of the TME in pancreatic tumors. We hypothesized that an oral CCK receptor antagonist, proglumide, would improve the efficacy of gemcitabine by decreasing fibrosis in the TME and improving uptake of chemotherapy. Methods: 500,000 mT3 murine pancreatic cancer cells were injected subcutaneously into the right flank of 40 C57/BL6 female mice. One week after the mice had measurable tumors (baseline), mice were divided into 4 groups (N=10 mice each) with equal mean tumor volumes. Treatment groups included: PBS control (100µl IP twice weekly); proglumide in drinking water (0.1 mg/ml); gemcitabine (100mg/kg, 100µl IP twice weekly); and combination of gemcitabine and proglumide. Tumors were measured weekly and the volumes were calculated. Mice were euthanized per protocol when the tumor diameter reached 20mm; tumors were removed, then flash frozen for gemcitabine measurement via mass spectrometry. Results: Tumor volumes demonstrated a rapid growth rate in the PBS control mice with a slope of 184.2±2 (mm3/week), whereas growth rates for proglumide (75±2) and gemcitabine monotherapy (72±14) were 2.6-fold slower, and also 3.4-fold slower for mice treated with both gemcitabine and proglumide (55.6±12; p<0001). By day 62, when all of the control PBS mice had died, survival in the other groups was: 70% for proglumide, 90% for gemcitabine only, and 100% for the combination-treated mice. On day 87, survival was as follows: control 0%; proglumide 40%, gemcitabine 50%, and the combination group 70%. Mean gemcitabine drug uptake, as measured by mass spectrometry, was 4-times higher in the tumors of mice treated with combination therapy (729 pg/ml) compared to the gemcitabine concentration in tumors of mice treated with monotherapy (173pg/ml). Kaplan Meier survival curve revealed significant improved survival in mice treated with the combination of gemcitabine and proglumide (p=0.001) compared to PBS. Conclusion: CCK receptor blockade with proglumide decreases fibrosis in pancreatic cancer TME allowing greater tumor uptake of gemcitabine and improving efficacy by slowing tumor growth and improving survival. Strategies to improve first-line therapies for patients with pancreatic cancer may improve overall survival of this disease. Citation Format: Zoe X. Malchiodi, Hong Cao, Martha Gay, Sunil Bansal, Benjamin A. Weinberg, Amrita Cheema, Narayan Shivapurkar, Jill P. Smith. Cholecystokinin receptor antagonist decreases fibrosis in pancreatic cancer microenvironment to improve uptake and efficacy of chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5326.