Abstract 5167: Development of advanced preclinical models for an in-depth characterization of cardiac angiosarcoma

Abstract Cardiac angiosarcoma (CAS) is a rare and highly aggressive tumor that originates from the endothelial cells lining the heart's blood vessels, with the right atrium being the most common site of occurrence. There are no effective treatments, and the five-year survival rate is under 10%. The absence of reliable preclinical models has also slowed progress in understanding its biology. To address this gap, we have developed a somatic mosaic genetically engineered mouse model (smGEMM) that faithfully recapitulates angiosarcoma features, including lung dissemination. Using an endothelial-specific CRE recombinase and CRISPR/Cas9, we engineered endothelial cells to express tdTomato and spCas9, enabling tissue-specific fluorescence and targeted mutation of CAS drivers. Primary endothelial cells from the cardiac tissue of our smGEMM were isolated and transduced with specific AAV particles in vitro and then transplanted orthotopically via ultrasound-guided injection. Primary and metastatic tumors were extensively characterized and closely mimic the features observed in CAS patients. Additionally, cell lines derived from both primary and metastatic tumors were established and comprehensively analyzed. Whole genome and RNA-seq were performed in all CAS samples and integrated with available patient data. Copy number profiling revealed whole genome duplication and loss of heterozygosity (LOH), further highlighting the complex genetic landscape of our CAS models in tumor tissues and cell lines. The comparison between our CAS samples and patient data displayed a similar mutation profile, highlighting the relevance of our model in replicating key genetic features of human cardiac angiosarcoma. To identify novel context-specific dependencies we conducted in vitro genome-wide CRISPR-Cas9 screens which revealed both common and unique hits across preclinical models. Several key pathways were identified and validated using different pharmacological tools. The results revealed critical therapeutic dependencies, not only when targeted with single agents but, more significantly, when these targets were evaluated in combination. This underscores the potential for developing novel, more effective therapeutic strategies for treating this rare and aggressive disease. Citation Format: Rosalba Minelli, Luigi Perelli, Benjamin J. Bivona, Sanjana Srinivasan, Desiree Catania, Bianca E. Amador, Frederick S. Robinson, Johnathon L. Rose, Christopher J. Terranova, Alejandro Hernandez Martinez, Charles E. Deckard, Courtney Le, Kuo-Shun Hsu, Michael Peoples, Aparna Subramaniam, Hannah C. Beird, Ningping Feng, Joseph R. Daniele, Christopher Vellano, Joseph Marszalek, Vinod Ravi, Alexander J. Lazar, Andrew Futreal, Timothy P. Heffernan, Giannicola Genovese, Virginia Giuliani. Development of advanced preclinical models for an in-depth characterization of cardiac angiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5167.