Investigators led by Sidney Kimmel Cancer Center—Jefferson Health (SKCC) and their collaborators from Memorial Sloan Kettering Cancer Center, University of California, San Francisco and Celgene Corporation have generated new findings that suggest targeting DNA-PK might allow the development of effective strategies to some day prevent or treat aggressive, late-stage prostate cancer.
There is no cure for prostate cancer. And when it moves into an advanced, metastatic stage, there are no effective treatments. Within the United States, just in the year 2019, there will be about 174,650 newly diagnosed prostate cancer cases. An estimated 31,620 men will die from prostate cancer this year in the U.S. growing at a rate of 6%.
The research collaborative focused on an enzyme called DNA-PK (DNA-dependent protein kinase), a pivotal component of the cellular machinery that controls both DNA repair and influences gene expression. Previous studies revealed that DNA-PK is excessively active in metastatic prostate cancer and that its hyper-activation is associated with a poor outcome in prostate cancer patients. The team’s present work further clarified the functions of DNA-PK and identifies the protein as a master regulatory of gene networks that promote aggressive cancer behaviors.
The team found that DNA-PK modulates the expression of gene networks directing many important cancer-related cellular events. They include a developmental process called “epithelial-mesenchymal transition” as well as how the immune system responds to the metabolic pathways involved.
The team suggests that targeting DNA-PK could support the development of new approaches to treat and perhaps some day prevent late-stage prostate cancer. The team leveraged the generated data to assemble a clinical trial, including a combination of standard-of-care with a first-in-man DNA-PK inhibitor. Thus far, the results have been promising and research teams demonstrate in laboratory settings that an approach weaving in combinations may be more effective than a single treatment in drawing out anti-tumor effects. This clinical trial is still underway. The result of the clinical trial will be of interest in terms of strategic direction and a guide for the next wave of more targeted trials with the objective of understanding how DNA-PK regulates specific cellular pathways to promote more aggressive cancer behavior.
The work was orchestrated by the laboratory of Karen E. Knudsen, PhD, EVP Oncology Services and Enterprise Director of SKCC.
Emanuela Dylgieri, Study Lead