Development and translation of novel therapies for pediatric sarcoma

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Tumor Metabolism Studies: Our lab is interested in identifying specific metabolic vulnerabilities in pediatric sarcomas. We have previously identified lactate dehydrogenase A (LDHA) as an oncogene-driven vulnerability in Ewing sarcoma, as well as PHGDH as an additional metabolic vulnerability in Ewing sarcoma. Our group has continued to study the mechanisms behind NAD metabolism in cancer cells. Specifically, we are using inhibitors of the rate-limiting enzyme in the NAD salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), in preclinical models of pediatric solid tumors. We initially identified the exquisite sensitivity of Ewing sarcoma cells to these inhibitors as part of a collaboration with The National Center for Advancing Translational Science (NCATS). Based on this work, we have continued our preclinical studies to better understand role of NAD and NAMPT in Ewing sarcoma and in other pediatric solid tumors. We have formed a collaboration with investigators in the Urologic Oncology Branch who also have an interest in targeting this pathway. To date, there have been no clinical studies of NAMPT inhibitors in any pediatric cancers. We are in the process of developing a pediatric trial for this patient population using OT-82, a clinical NAMPT inhibitor currently undergoing phase 1 evaluation in an extramural first-in-human study for hematologic malignancies. DNA Damage and Repair Studies: Project 1. In FY2021, the first-in-human trial of PEN-866, a novel HSP90 inhibitor-SN38 drug conjugate, which acts as to inhibit topoisomerase 1 and cause prolonged DNA damage in tumor cells, accrued additional patients. The rationale for this study, for which NCI was a lead site, was based in part on preclinical work done in our lab demonstrating superior activity and durability of PEN-866, as compared to other standard of care chemotherapy in models of pediatric sarcoma. The study was conducted in collaboration with the Developmental Therapeutics Branch at NCI to target an adult population for the first-in-human experience. Based on our preclinical data in sarcoma and the available phase 1 data generated by the study, we have developed a combination study using PEN-866 with chemotherapy which is we expect will be open shortly. This study incorporates disease-specific expansion cohorts for rhabdomyosarcoma and Ewing sarcoma. In the lab, we have continued to study PEN-866 in Ewing sarcoma and rhabdomyosarcoma, with a focus on identifying and overcoming potential mechanisms of resistance, as part of a collaboration with the Developmental Therapeutics Branch and the Urologic Oncology Branch. Project 2. Related to our work with the topoisomerase 1 inhibitor PEN-866, we are evaluating several novel topoisomerase 1 inhibitors (the indenoisoquinolines) in our pediatric sarcoma models, against the current standard of care topoisomerase agents for these diseases. This project is part of a collaboration with the Molecular Pharmacology Group in the Developmental Therapeutics Branch. Project 3. Our group has identified several potential new agents and combinations of agents that impact the DNA-repair machinery of cancer cells and are particularly effective in preclinical models of Ewing sarcoma. We are in the process of conducting in vivo studies to further describe the effects of these inhibitors.