Mentor Name: Jay Sarthy

Sarcomas are aggressive malignancies that disproportionately affect children, adolescents, and young adults, and systemic therapy remains essential for patients with high-risk or metastatic disease. Anthracyclines, particularly doxorubicin, are among the most effective agents used to treat sarcomas, yet their benefit is constrained by cumulative, dose-dependent toxicities such as cardiomyopathy and secondary malignancies. These long-term effects limit treatment intensity and impose lifelong morbidity on survivors. Although anthracyclines are classically thought to act through DNA damage via topoisomerase II poisoning, this model does not fully explain their exceptional efficacy relative to other genotoxic agents or the variability in toxicity across closely related compounds, underscoring the need for alternative mechanistic approaches that preserve efficacy while reducing harm. Di-methyldoxorubicin (DMD) is a modified anthracycline designed to markedly reduce DNA damage while maintaining antitumor activity. Emerging evidence suggests that DMD acts primarily through non-genotoxic mechanisms, including disruption of chromatin structure and transcriptional and translational programs required for malignant cell survival. These mechanisms may be particularly relevant in sarcomas, which often rely on high biosynthetic output and transcriptional dysregulation rather than defects in DNA repair. This project will evaluate the therapeutic potential of DMD in pediatric and young adult sarcomas by comparing its activity to conventional doxorubicin and defining molecular determinants of response. By testing whether antitumor efficacy can be uncoupled from genotoxicity, this work aims to advance safer anthracycline-based treatment strategies with reduced long-term toxicity for young sarcoma patients.