Identifying non-cardiotoxic drug combinations for patients with relapsed sarcoma

Summary Standard-of-care treatments for most sarcomas and other childhood cancers include high-doses of anthracyclines, in particular doxorubicin (DOXO). DOXO causes irreparable damage to normal tissues, especially the heart, and late-onset cardiomyopathy is one of the leading causes of death among childhood cancer survivors. In addition, relapse is common in patients with sarcoma and fewer than 20% of patients who relapse can be cured. Experimental therapies are often their only option but the cardiotoxicity of primary therapy creates a major clinical challenge for these patients: investigational drugs and drug combinations for relapsed disease cannot incur additional cardiotoxic effects. Unfortunately, a priori knowledge about the potential cardiotoxicity of investigational agents and combinations is almost never available. Thus, there is a critical need to develop preclinical models that can reliably assess the cardiotoxic effects of experimental therapies before they are advanced to clinical trials in patients. In this proposal, we will combine our multi-disciplinary expertise in oncology and cardiology to develop less cardiotoxic treatment options for patients with relapsed Ewing sarcoma (EwS). We will combine mouse xenograft models with zebrafish small molecule screening to (1) improve our ability to predict cardiotoxic effects of combination therapies, (2) accelerate the identification and translation of effective combination drug therapies, and (3) identify small molecule combinations with anti-tumor activity but decreased cardiotoxicity. EwS is an aggressive tumor that peaks in adolescence. Tumors are critically dependent on epigenetic reprogramming and abundant preclinical data from our own group and others have shown the promise of epigenetic modifiers as investigational agents for EwS patients. However, epigenetic agents are not effective as single agents and combination approaches are needed. The potential cardiotoxic effects of most epigenetic drugs, either alone or in combination, is yet unknown. Studies in this project will focus on testing epigenetic agents alone and in combination with aclarubicin (ACLA), a minimally cardiotoxic anthracycline with equivalent anti-tumor efficacy to DOXO. The combination of bromodomain inhibition (BETi) with ACLA will be investigated as a priority in both mouse and zebrafish. Anti-tumor efficacy will be specifically evaluated in mice and cardiotoxicity will be assessed in both animal models. Demonstration of added anti- neoplastic activity in the absence of added cardiotoxicity will support advancing BETi plus ACLA to clinical trials for patients with relapsed EwS. Beyond BETi, this proposal will take advantage of large-scale screening in zebrafish to systematically test a large epigenetic small molecule library for cardiotoxicity in combination with anthracyclines. By cross-validating the activities of epigenetic compounds in our two in vivo models, we will accelerate the path to clinical trials and increase the likelihood that new potential drug therapies will have less cardiotoxicity and increased impact for patients.