Abstract B035: Pre- and post-tumor engraftment treatment with propranolol reduces early- and late-stage tumor burden in a syngeneic murine model of high-grade serous carcinoma

Abstract Background: Chronic stress-related α- and β-adrenergic receptor (AR) activation is associated with increased high grade serous carcinoma (HGSC) tumor burden. The latter is proportional to disease lethality, so there is an urgent need for interventions that delay or prevent the transition from localized to metastatic state. Use of β-AR antagonists is associated with improved outcomes, but the unique effects of pre- and post-HGSC establishment AR inhibition have not yet been delineated. Stress is a ubiquitous experience, so characterization of such can lead to novel treatment strategies for HGSC. Here we utilized a syngeneic murine model of HGSC (ID8 Tp53-/-) to delineate the effects of β-AR and/or α1-AR antagonism administered either pre- or post-ID8 engraftment. Methods: We treated C57BL/6J mice daily via oral gavage with vehicle, the β-AR antagonist, propranolol (Pro, 20 mg/kg) and/or the α1-AR antagonist, prazosin (Prz, 2 mg/kg) either pre- or post-engraftment. Pre-engraftment mice were euthanized at either early- or late-stage disease, and post-engraftment mice were euthanized at late-stage. At necropsy, omenta and disseminated solid tumors (mets) were weighed and processed for immunohistochemistry (IHC). Results: Pre-engraftment: Early-stage omentum weight was reduced by Pro (avg. control, 0.015g vs. 0.01g, p=0.045, -40.9%) but not Prz (avg., 0.018g, p=0.46) or Pro+Prz (avg., 0.015g, p=0.9998). Early-stage metastatic spread was not observed in any group. Pro also reduced late-stage omentum weight (avg. control, 0.164g vs. 0.115g, p=0.0393, -30.01%) and met weights (avg. control, 0.136g vs. 0.052g, p=0.0047, -61.52%) and number (avg. control, 34.8 vs. 12.8, p=0.0063, -63.22%). Prz reduced omentum weight only (avg., 0.109g, p=0.0205, -33.56%). Pro+Prz did not reduce any late-stage tumor burden measure. Post-engraftment: Omentum weight was reduced by all treatments (avg. control, 0.1424g vs. Pro, 0.097g, p=0.0001, -31.74%; Prz, 0.116g, p=0.0227, -18.25%; Pro+Pra, 0.116g, p=0.024, -18.6%). Met weight was reduced by Pro (avg. control, 0.103g vs. Pro, 0.042g, p<0.0001, -59.41%) and Prz (0.058g, p=0.0001, -43.31%) but not Pro+Prz (avg. 0.08g, p=0.0615). A similar effect was observed with met number (avg. control, 23 vs. Pro, 9.444, p<0.0001, -58.93%; Prz, 15.9, p=0.0111, -30.87%). IHC analysis of the tumor immune microenvironment is currently underway. Conclusions: In the ID8 Tp53-/- syngeneic murine model of HGSC, tumor burden is differentially modulated by adrenergic signaling in a timing-dependent manner. Namely, β-AR activation appears to prime the pre-metastatic niche and promote in situ tumor development, as evidenced by the reduction in tumor burden observed in pre- and post-engraftment Pro-treated mice, respectively. Notably, HGSC development appears to only be sensitive to α1-AR modulation after tumors have established, as only post-engraftment Prz reduced final tumor burden. These data support targeting adrenergic signaling in both HGSC patients and at-risk individuals, particularly with beta blockers such as Pro. Citation Format: Elizabeth R. Woodruff, Maia Zoller, Benjamin G. Bitler, Nicole A. Marjon. Pre- and post-tumor engraftment treatment with propranolol reduces early- and late-stage tumor burden in a syngeneic murine model of high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B035.