Abstract 1447: Development of advanced preclinical modeling for a comprehensive characterization of cardiac angiosarcoma biology
Authors: Minelli Rosalba , Perelli Luigi , Bivona Benjamin J. , Srinivasan Sanjana , Catania Desiree , Amador Bianca E. , Robinson Frederick S. , Rose Johnathon L. , Terranova Christopher T. , Martinez Alejandro Hernandez , Deckard Charles E. , Le Courtney N. , Hsu Kuo-Shun , Peoples Michael , Subramaniam Aparna , Beird Hannah C. , Feng Ningping , Daniele Joseph R. , Vellano Christopher , Marszalek Joseph , Ravi Vinod , Lazar Alexander J. , Futreal Andrew , Heffernan Timothy P. , Genovese Giannicola , Giuliani Virginia 
Published: March 2024

Abstract
Cardiac angiosarcoma (CAS) is an extremely rare malignant cardiac tumor known for its propensity for early metastasis and poor prognosis. CAS frequency is around 1-2% of all angiosarcoma cases and mostly arise in the right atrium. At present, there are no effective treatments and the survival rate is less than 10% at 5 years. Furthermore, the dearth of preclinical models has limited the advancement of biological insights into CAS. To address this challenge, we developed a somatic mosaic genetically engineered mouse model (smGEMM) with the aim of accurately mirroring the biological features of CAS. This model will be a crucial instrument for acquiring in-depth insights into the disease and steering the development of impactful therapeutic strategies. To develop a CAS smGEMM, we leveraged an endothelial-specific CRE recombinase to activate a fluorescent reporter in a tissue-dependent manner and CRISPR/Cas9 technology to engineer somatic drivers of CAS tumorigenesis. Using this strategy, all endothelial cells express tdTomato fluorescent reporter and spCas9. We then administered adeno-associated viral (AAV) particles carrying selected tandem sgRNAs with two different approaches: a direct approach where AAV particles were administered by ultrasound-guided injection in the cardiac wall of the smGEMM; and an ex-vivo approach where primary endotheliocytes derived from cardiac tissue of our smGEMM were first transduced with AAV particles in vitro, and then transplanted orthotopically by ultrasound-guided injection. With the latter strategy, we successfully generated the first cardiac angiosarcoma model that faithfully recapitulates angiosarcoma features, including lung dissemination. Cell lines from primary and metastatic tumors were also established, characterized and utilized for genome-wide CRISPR Cas9 screening. Current efforts are focused on prioritizing hits for validation, aiming to glean insights that can inform potential therapeutic strategies.
Citation Format: Rosalba Minelli, Luigi Perelli, Benjamin J. Bivona, Sanjana Srinivasan, Desiree Catania, Bianca E. Amador, Frederick S. Robinson, Johnathon L. Rose, Christopher T. Terranova, Alejandro Hernandez Martinez, Charles E. Deckard, Courtney N. 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 modeling for a comprehensive characterization of cardiac angiosarcoma biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1447.