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Research Offers Deeper Understanding of Role of Retinoblastoma Gene in Aggressive Prostate Cancer

(BY RACHEL DERITA, PhD Candidate,Thomas Jefferson University, Department of Cancer Biology) In prostate cancer, there is a continual effort to better stratify patients. Current standards of care for all patients are identical, but each case is not. A recent study (published on December 4, 2017 in the Journal of Cl inical Investigation) from Thomas Jefferson University’s Sidney Kimmel Cancer Center (SKCC) identified loss of the retinoblastoma (RB) susceptibility gene as a cause of what senior author Karen Knudsen, PhD, Director of the SKCC, describes as “major reprogramming of gene expression, allowing induction of pathways that promote features that induce characteristics of lethal disease.” That article is titled “Differential Impact of RB Status on E2F1 Reprogramming in Human Cancer.” RB was the first “gatekeeper” gene (genes that are responsible for controlling cell growth and keeping it in check) discovered for cancer. Loss or damage to RB allowed cancer to thrive and be more aggressive, but the exact mechanism of how this happened remained unclear. The JCI -piublshed study involved tumor and cell-free DNA analysis of samples from patients with” advanced, lethal-stage” prostate cancer from multiple institutions across the US and international institutions in the UK, Italy, Belgium, Finland, and Sweden. RB function may be disrupted in several different ways, but it was found that complete loss of the RB gene, compared to inactivation, was associated with the transcriptional reprogramming linked to aggressive disease. This reprogramming, interestingly, was unique and different from the typical cell-cycle genes that RB controls as a gatekeeper. The group also found that this specific type of large-scale genetic change, caused only by complete loss of RB, could make cancer more resistant to therapy and more likely to spread.

Another aspect of this study that increases its clinical relevance is the fact that RB status can be tracked using cell-free DNA extracted from the blood of a patient, a process known as “liquid biopsy.” In a non-invasive way, patients may be analyzed and potentially better stratified into different treatment regimens based on their cancer subtype. There are multiple clinical trials underway just in Philadelphia evaluating RB as a potential guide to more efficient and precise therapy options for cancer patients. These studies involve evaluating response to current standards of care based on RB status. For example, a clinical trial study titled “Enzalutamide With and Without Ribociclib for Metastatic, Castrate-Resistant, Chemotherapy-Naive Prostate Cancer That Retains RB Expression” is being led by William Kevin Kelly, MD, leader of the TJU SKCC Prostate Cancer Program. Enzalutamide is an antagonist of the androgen receptor (often over-active in prostate cancer) and ribociclib is an inhibitor of the cyclin D1/CDK4 (or CDK6) complex, which, when active, pushes the cell cycle forward towards replication. Cyclin/CDK complexes phosphorylate RB, thereby inactivating it. It makes sense that in cancers with RB present, a CDK inhibitor like ribociclib may work. Further investigation should reveal more about exactly how RB status in prostate cancer will determine how prostate cancer patients will respond to different therapeutic strategies.

Image shows representation of retinoblastoma protein.

[Press release] [Journal of Clinical Investigation article] [Clinical trial description]