Pre-clinical Evaluation of LSD1 Inhibitors for the Treatment of Pediatric Ewing sarcoma: Defining the Biomarkers of Sensitivity and Mechanisms of Resistance
The development of drug resistance to both traditional chemotherapeutic and new targeted agents remains a major impediment and primary challenge in the quest to treat Ewing sarcoma, a highly aggressive pediatric solid bone malignancy. Despite significant advances in our understanding of the drivers of Ewing sarcoma oncogenesis, treatment strategies remain restricted to non-specific multi-modal regiments encompassing chemotherapy, radiotherapy and surgery. Five-year overall survival rates for patients with the metastatic disease remain at 10-20%. In addition, current chemotherapeutic treatment regimens are associated with significant cumulative and late toxicities. Given the modest efficacy of current sarcoma therapeutic modalities, there is a major unmet clinical need for the translation of novel agents to tackle the global burden of pediatric sarcoma.
Several studies have documented lysine-specific demethylase 1 (LSD1) overexpression in highly malignant tumors including Ewing sarcoma. Our laboratory has recently shown that the treatment of Ewing sarcoma cell lines with the novel LSD1 inhibitor HCI-2509 induces potent cell death and disrupts the global transcriptional function of EWS-FLI, the defining translocation associated with Ewing sarcoma.
As HCI-2509 will enter Phase I clinical testing in 2016, the primary objective of this study is to elucidate the biomarkers of response and mechanism(s) of resistance to LSD1 inhibitors prior to clinical trial evaluation. Our findings will provide a clear strategy for the incorporation of LSD1 targeted therapies into the treatment armamentarium for Ewing sarcoma and how we can circumvent drug resistance to achieve the maximal therapeutic effect.
"As an early career researcher, funding from Alex's Lemonade Stand Foundation will allow me to undertake pioneering research in collaboration with leading experts to decipher the mechanisms by which Ewing sarcoma cells develop drug resistance to inhibitors of LSD1, a promising therapeutic target for the treatment of pediatric cancers." - Kathleen Pishas, PhD
Project Update - 2020
With the support of the Alex’s Lemonade Stand Foundation, our preliminary findings have shown that Ewing sarcoma (pediatric bone cancer) cells undergo rapid cell death following treatment with a small molecule inhibitor that targets LSD1, a critical Achilles’ heel of Ewing sarcoma. We are currently studying how drug resistance to LSD1 inhibitors will occur and how we can use complementary drugs to overcome resistant cell populations. We hope that our findings will significantly improve the survival outcomes for these pediatric cancer patients.