Research Projects

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, that lacks molecular therapeutic target. Anthracycline-based chemotherapeutic drugs such as doxorubicin (Dox) are widely used in the treatment of TNBC. However, its clinical use is severely limited due to life-threatening cardiotoxic effects. The mechanisms underlying Dox-induced cardiomyopathy and heart failure remain unclear but are thought to be associated with oxidative stress and mitochondrial dysfunction which disrupts energy production, impairs calcium homeostasis, and triggers apoptotic signaling pathways in cardiomyocytes. Our published findings show that RGS6 plays a critical role in mediating Dox-induced cardiomyopathy by acting as an upstream activator of NADPH oxidase (Nox)-dependent ROS generation. ROS oxidatively modifies CaMKIIδ (M281/282), leading to its activation and subsequent cardiomyocyte apoptosis. Therefore inhibition of the RGS6-ROS-ox-CaMKII axis offers a rational means to circumvent Dox-induced cardiotoxicity in TNBC patients. Dexrazoxane is currently the only FDA-approved drug specifically designed to protect against chemotherapy-induced cardiotoxicity in breast cancer patients. However, its clinical utility is limited by its potential to compromise the anticancer efficacy of Dox. To address this challenge, there is an urgent need for cardioprotective agents that could mitigate or prevent Dox-induced cardiotoxicity through inhibition of the RGS6-ROS-ox-CaMKII axis without impeding the antitumor activity of Dox. Published studies from our lab and others have demonstrated that Disulfiram (DSF) and alpha lipoic acid (ALA) have cardioprotective in preclinical animal models of heart failure, as well as antitumor activity in breast cancer models, primarily through their ability to modulate oxidative stress. Therefore, we hypothesize that DSF and ALA will mitigate Dox-induced cardiotoxicity without compromising its anti-tumor effect in TNBC. The primary objective of this proposal is to investigate the efficacy of ALA and DSF in mitigating chemotherapy-induced cardiotoxicity while enhancing the anticancer efficacy of Dox in TNBC. Specifically, we will utilize (1) TNBC animal models to evaluate the therapeutic potential of DSF and ALA in protecting cardiac function while enhancing the tumor suppressive effects of Dox and (2) human induced pluripotent stem cell (hiPSC)-derived cardiac organoids generated from the peripheral blood mononuclear cells (PBMCs) of TNBC patients to assess the cardioprotective effects of ALA and DSF against Dox-induced cardiotoxicity and their signaling mechanisms. This comprehensive approach will shed light on the role of ALA and DSF as promising therapeutic agents in the context of Dox-based chemotherapy. If successful, DSF and ALA can be safely co-administered with Dox as a rescue factor to improve the therapeutic index of Dox along with better clinical outcomes.