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Therapeutic Targeting of PGBD5-induced DNA Repair Dependency in Pediatric Solid Tumors

Memorial Sloan-Kettering Cancer Center
Alex Kentsis, MD/PhD
Grant Type: 
Reach Grants
Year Awarded: 
Type of Childhood Cancer: 
Solid and Bone Cancers, Rhabdoid Tumor, General Pediatric Cancer
Project Description: 

While some human cancers occur as a result of the age-dependent accumulation of genetic mutations and others are caused by deficiencies in DNA replication or repair, the causes of many oncogenic mutations remain poorly understood. This conundrum is particularly true for solid tumors of children and young adults, as emphasized by their recent genome surveys, revealing a relative paucity of canonical tumorigenic gene mutations. Our current research now implicates the PGBD5 DNA transposase as an oncogenic mutator responsible for site-specific mutations in the majority of childhood solid tumors, including rhabdoid tumors, a lethal childhood cancer. 

Project Goal
This project aims to develop a new therapeutic strategy against PGBD5-expressing childhood solid tumors. Successful completion of this project is expected to lead immediately to clinical trials of improved therapies for the majority of children with refractory solid tumors.

Project Update 2020

Childhood solid tumors remain difficult to treat despite intensive chemotherapy, surgery, and radiation therapy. Many childhood solid tumors are known to be driven by abnormal regulation of gene expression, but its mechanisms remain elusive. Our recent work revealed an unanticipated requirement of an endogenous DNA transposase for the development of most childhood solid tumors. The current project aims to determine the mechanisms of aberrant cell survival in childhood solid tumors and develop chemical inhibitors with anti-tumor efficacy. This knowledge will be used to identify specific molecular dependencies that may be used for the development of improved targeted therapies of refractory childhood solid tumors and is expected to lead directly to clinical trials for patients.