Abstract P5-08-14: Blockade of CD47/Thrombospondin-1 signaling increases glycolytic metabolism as a protective mechanism against chemotherapy-associated cardiac injury in a model of Triple-Negative Breast Cancer
Authors: Bronson Steven M. , Mackert Jessica D. , Kooshki Mitra , Wilson Adam S. , Cruz-Diaz Nildris , Triozzi Pierre L , Thomas Alexandra , Cook Katherine L. , Soto-Pantoja David R. 
Published: March 2023

Due to advances in diagnosis and treatment, cancer–related mortality has decreased, and by the year 2030, there will be 22 million cancer survivors in the United States. This success comes with an increased incidence of serious adverse effects, mainly in the cardiovascular system. While new treatment modalities are emerging for Triple-negative breast cancer (TNBC), most current strategies include anthracycline-based regimens to manage disease. Therefore, novel strategies are needed to overcome anthracycline-induced cardiotoxicities in this patient population. Activation of the TSP1/CD47 signaling axis is implicated in the progression of heart failure, with reported increases in TSP1 levels following myocardial infarction. Therefore, we examined the potential of CD47 blockade as a strategy to prevent cardiac injury as a consequence of cancer chemotherapy. Our data in a syngeneic orthotopic breast cancer model shows that blockade of CD47 using an in vivo anti-sense phosphodiesterase morpholino (PMO) preserved ejection fraction, fractional shortening, and cardiac output when compared to DOX treatment while preserving oncologic efficacy of chemotherapy. To determine a potential mechanism of cardioprotection, hearts of control and CD47 PMO-treated mice were subjected to RNA sequencing. Gene set enrichment analysis (GSEA) showed significant positive enrichment for metabolic pathways including pyruvate metabolism (NES= 2.3 , p&lt; 0.002), and oxidative phosphorylation (NES=2.0, p&lt; 0.01). During cardiac insult, metabolic flexibility of cardiomyocytes results in metabolic reprogramming from fatty acid oxidation to a glycolytic mechanism to overcome injury. Thus, DOX-associated cardiotoxicity may be mediated by an increase in TSP1 and a decrease in glycolysis, leading to the inability to overcome acute cellular stress. In vitro cellular bioenergetics, analysis revealed that TSP1 caused a dose-dependent reduction in glycolytic flux and glycolytic capacity in cardiac myoblast. This, coupled with preserved cardiac viability of cardiac cells treated with CD47 PMO in the presence of DOX, suggests that TSP1 may act through CD47 to prevent cardiac cell metabolic reprogramming needed to overcome injury. Furthermore, anti-sense experiments with siRNAs to Glut-4 and Hexokinase-II showed that the protection conferred by CD47 is mediated by activating these proteins. Therefore our studies suggest that the TSP1/CD47 axis may be central to the interplay of metabolism to preserve cardiac tissue integrity; thus, targeting this pathway may prevent the onset of chronic cardiac disease due to chemotherapy in cancer patients.

Citation Format: Steven M. Bronson, Jessica D. Mackert, Mitra Kooshki, Adam S. Wilson, Nildris Cruz-Diaz, Pierre L Triozzi, Alexandra Thomas, Katherine L. Cook, David R. Soto-Pantoja. Blockade of CD47/Thrombospondin-1 signaling increases glycolytic metabolism as a protective mechanism against chemotherapy-associated cardiac injury in a model of Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-08-14.