Development and translation of novel therapies for pediatric sarcoma

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

The goal of our lab is to identify new targetable vulnerabilities in pediatric sarcomas, with an emphasis on those related to tumor metabolism and DNA repair. Preclinical Metabolism Studies: We have previously identified several NAD-dependent metabolic enzymes as vulnerabilities in Ewing sarcoma, specifically lactate dehydrogenase A (LDHA) and PHGDH (PMID 31431459, 32371575). Building on this work, our group has focused on the mechanisms behind NAD metabolism in cancer cells 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 NAMPT inhibitors as part of a collaboration with The National Center for Advancing Translational Science (NCATS) and have extended our preclinical studies to better understand the role of NAD and NAMPT in pediatric rhabdomyosarcoma, which we identified as an additional pediatric cancer demonstrating extreme sensitivity to perturbation of this pathway (PMID 28899971, 32908120, 37616468). In addition, we collaborated with investigators in the Urologic Oncology Branch to describe the effect of impairing NAD production in HLRCC (PMID 39397296). As there have been no clinical studies of NAMPT inhibitors in any pediatric cancers to date, we are actively developing a pediatric trial for this patient population using a clinical NAMPT inhibitor currently undergoing early phase evaluation. Preclinical DNA Damage and Repair Studies: A related area of study in my lab is the relationship between sarcoma metabolism and DNA damage repair, which was initially identified during our early work on NAMPT inhibitors. Since replication stress and impaired DNA repair are key biologically-driven features of Ewing sarcoma cells, we have become actively engaged in the preclinical evaluation of several novel clinical candidates that damage DNA either directly or indirectly through impairment of DNA repair. We have identified that the use of novel tumor-targeting agents called HSP90 inhibitor-drug conjugates (HDCs) in pediatric sarcoma models demonstrated antitumor activity that exceeded the effects of irinotecan, the standard of care TOP1 inhibitor for these cancers. Mechanistic studies confirmed that the enhanced activity was primarily the result of improved drug exposure and also revealed that HDCs had activity in irinotecan-resistant cancer models such as osteosarcoma (PMID 27608846). I am currently leading a clinical study using the HDC PEN-866 in combination with conventional chemotherapy for adolescent and young adult patients with sarcomas, a population for whom access to new experimental agents is lacking (NCT04890093). Related to our work with the topoisomerase 1 (TOP1) inhibitor PEN-866, we recently published a preclinical evaluation of several novel TOP1 inhibitors (the indenoisoquinolines) in a panel of diverse patient-derived xenograft (PDX) models of Ewing sarcoma, as part of a collaboration with investigators in the Developmental Therapeutics Branch at NCI (PMID 39512899). Additionally, in collaboration with colleagues in the Genetics Branch at NCI we recently published findings regarding a novel class of agents (DNA-PK inhibitors) that impact the DNA-repair machinery of cancer cells and that in combination with selected standard agents (doxorubicin and etoposide), are particularly effective in preclinical models of Ewing sarcoma (PMID 38657228).