Alex Kentsis, MD, PhD ‹ Back To 2019 Winners
2019 Winners, Mathers Foundation Fellow
Sloan Kettering Institute, Department of Pediatrics
Memorial Sloan Kettering Cancer Center
Genome sequencing efforts have revealed a surprising dearth of gene mutations in many human cancers, suggesting that alternative oncogenic mechanisms must be investigated to identify targets for improved therapy. Approximately half of the human genome originates from mobile DNA elements, or transposons, but their contributions to human disease and physiology remain almost completely unexplored. I intend to investigate mechanisms of tumorigenesis by DNA transposases activated in developing human tissues that cause both common and rare childhood cancers, many of which remain lethal and refractory to intensive chemotherapy. Successful completion of these studies promises to transform our ability to identify the essential drivers of human cancer, thus leading to improved targeted therapies for refractory pediatric tumors. This work will also establish powerful tools for the investigation of human genomic plasticity, with transformative applications in many areas of human biology and medicine.
Alex Kentsis, MD, PhD is a cancer biologist and pediatric oncologist. He treats children and young adults with leukemias and refractory solid tumors, and is interested in developing treatments that maximize the success of currently available therapies and devising new therapies that are precise, curative, and safe. In the laboratory, he is interested in understanding what causes cancer in young people, and what makes cancer cells “cancer” cells. This has led to discoveries about fundamental causes of childhood cancer, new therapeutic targets, mechanisms by which cancer cells can evade new treatments, and improved strategies to overcome treatment resistance, leading to new clinical trials for patients. This work has been recognized by the Scholar Award from the American Society of Hematology, Burroughs Wellcome Fund Career Award, Clinical Investigator Award from the Damon Runyon Cancer Research Foundation, Rita Allen Scholar Award, Society for Pediatric Research Young Investigator Award, and the St. Baldrick’s Arceci Innovation Award..
Understanding and Targeting DNA Transposition in Human Cancer
How do young people develop cancer? Most have not lived long enough to accumulate mutations due to aging or environmental exposure. And most do not have any apparent cancer predisposition from inheritance of cancer-causing gene mutations. Recently, my laboratory has discovered an unanticipated cause of human cancer, resulting from the aberrant activity of the PGBD5 molecule that can promote rearrangements of human genes. We reason that PGBD5 is normally controlled to promote development of healthy cells in early life, but becomes dysregulated in cells that give rise to tumors in children and young adults.
“Philanthropy remains crucial to advancing pediatric cancer care, and I am grateful for the continued support of my research to improve the understanding of the biological basis of childhood cancer and treatment of children with rare but devastating tumors. This Prize will allow me to advance ideas about the most fundamental mechanisms that cause cancer in otherwise healthy children, a venture that would be impossible to support using existing sources of research funding.”
We have now developed tools to model this activity in living cells and animals, and planned studies seek to elucidate the mechanisms by which PGBD5 causes cancer in accurate laboratory models using improved methods for human genome mapping. In turn, this knowledge will be used to develop new therapies to treat refractory human cancers, caused by similar cancerous “jumping genes.” Ultimately, this will not only enable us to understand how cancer can affect young people, but also consider potential strategies for its prevention.
“Support for this research project will allow my lab to explore both new technical approaches to define the cancer genomes, as well as new concepts for their therapeutic targeting.”
Alex Kentsis is a Pershing Square Sohn Prize Mathers Foundation Fellow. His project is funded in an exciting partnership with The G. Harold and Leila Y. Mathers Foundation, which aims to advance knowledge in the life sciences by sponsoring scientific research that will benefit mankind. Basic scientific research, with potential translational application, is central to this goal, and fundamental to its operating principles. For more information, please refer to the full press release.