Therapeutic Strategies to Mitigate Toxicities of Anthracycline-Based Therapeutics

Abstract Anthracycline-based chemotherapeutics such as doxorubicin (Adriamycin) are among the most widely used anticancer agents in oncology for the treatment of multiple solid tumors and leukemias. The clinical use of doxorubicin is associated with a dose-limiting, potentially lethal cardiotoxicity for which no effective preventative treatments are presently available. In addition, the mechanism by which doxorubicin accumulates into cardiomyocytes remains to this day unknown. Using a technique based on human induced pluripotent stem cell-derived cardiomyocytes from cancer patients receiving doxorubicin, we recently found that uptake transporter OCT3 is highly upregulated in patients experiencing cardiotoxicity. Functional validation studies in OCT3-deficient mice and heterologous overexpressed models confirmed that doxorubicin is transported into cardiomyocytes by OCT3. Furthermore, deficiency of OCT3 protected mice from acute and chronic doxorubicin-related changes in cardiovascular function and genetic pathways associated with cardiac damage, and these findings were confirmed using cardiac MRI-based methods. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we found that pharmacological targeting of OCT3 can also preserve cardiovascular function following treatment with doxorubicin without affecting its plasma levels and its cytotoxic potential against multiple leukemia and breast cancer cell lines. Finally, we identified a previously unrecognized, OCT3-dependent pathway of doxorubicin-induced cardiotoxicity that results in a downstream signaling cascade involving the calcium binding proteins S100A8 and S100A9, and we validated this observation in a mouse model with S100A8 and S100A8 deficiency. Based on these preliminary findings, we now outline three sets of related studies that will further test and refine the validity of our central hypothesis that targeted inhibition of OCT3 function can specifically affect accumulation of doxorubicin in cardiomyocytes and affect downstream toxic events without negatively influencing its plasma pharmacokinetic profile or antitumor properties: (i) identification, validation, and mechanistic characterization of novel OCT3 inhibitors from a library screen that includes FDA-approved agents in novel humanized knock-in and conditional knock-out mouse models; (ii) functional validation of endogenous and exogenous cardiac-specific OCT3 biomarkers that could serve as a companion diagnostic to guide dose selection of OCT3 inhibitors; and (iii) safety, toxicokinetic, and efficacy analyses of optimized combinatorial regimens of OCT3 inhibitors with doxorubicin (acute and chronic), including simultaneous assessment of cardiac protection and antitumor properties in established experimental models of breast cancer and acute leukemias. It is expected that these studies will shed new light on the etiology of doxorubicin-induced cardiotoxicity and provide a rationale for the future implementation of novel targeted intervention strategies to prevent this debilitating side effect.