Abstract LB407: Propranolol may enhance long term survivorship in a subset of dogs with hemangiosarcoma when combined with doxorubicin chemotherapy
Authors: Dickerson Erin B. , Chacón Jeremy , Husbands Brian D. , Henson Michael S. , Modiano Jaime F. , Stuebner Kathleen M. , Winter Amber , Pracht Sara , Chehadeh Andrea , Bergsrud Kelly , Feiock Caitlin , Medland Julia , Scavello Heather , Salah Pascale C. , Mahoney Jennifer , Childress Michael O. , Brown David R. , Borgatti Antonella 
Published: April 2024

Abstract
Angiosarcomas are rare (fewer than 300 cases each year), highly aggressive sarcomas of blood vessel-forming cells with an unfavorable prognosis. We and others have previously reported that propranolol, a beta adrenergic receptor antagonist commonly used to treat heart disease and anxiety, increased the overall survival of patients with advanced angiosarcoma when used alone or incorporated into chemotherapy regimens. Treatment of angiosarcoma has been hampered by the relative lack of suitable models to analyze molecular responses to treatment. To overcome this hurdle and understand the vulnerability of angiosarcoma to propranolol, we capitalized on the similar morphological and clinical characteristics between human angiosarcoma and canine hemangiosarcoma, which occurs in thousands of dogs each year. The objectives for the PRO-DOX clinical trial were to assess tolerability and clinical benefit of propranolol in dogs with hemangiosarcoma when given as an adjunct to chemotherapy. We conducted a phase I study using a continuous reassessment model with three dose cohorts (0.8, 1.0, and 1.3 mg/kg PO q 8 hrs) in dogs diagnosed with stage 1 or stage 2 splenic hemangiosarcoma. Following splenectomy, propranolol was onboarded using a dose escalation strategy over 12 days prior to the start of doxorubicin (30 mg/m2 intravenously every three weeks, five rounds). Twenty dogs were enrolled and distributed across the dose cohorts based on the study design. One dog in the highest cohort experienced acute hypotension after six months on propranolol, which resolved with dose reduction. Although a statistically significant survival benefit was not seen in this study when compared to historic controls, a subset of dogs (n=8 or 40%) exceeded the expected survival of 4-6 months. Notably, three dogs diagnosed at or below age five survived over two years. Gene expression analysis of tumors obtained from the short-, mid-, and long-term survivors revealed sets of genes associated with immune responses (e.g. lymphocyte activation, positive regulation of T cell activation), antigen processing, cell adhesion, and mitochondrial metabolism in the long-term survivor group. Our findings suggest that age (&lt; 6 years) may predict a favorable outcome, and immune mediated responses differ between the short and long-term survivors. Ongoing experiments seek to define the specific molecular properties and immune responses contributing to these outcomes, with potential implications for human angiosarcoma.
Citation Format: Erin B. Dickerson, Jeremy Chacón, Brian D. Husbands, Michael S. Henson, Jaime F. Modiano, Kathleen M. Stuebner, Amber Winter, Sara Pracht, Andrea Chehadeh, Kelly Bergsrud, Caitlin Feiock, Julia Medland, Heather Scavello, Pascale C. Salah, Jennifer Mahoney, Michael O. Childress, David R. Brown, Antonella Borgatti. Propranolol may enhance long term survivorship in a subset of dogs with hemangiosarcoma when combined with doxorubicin chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB407.