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Researchers Find Breakthroughs in Understanding Genetic Basis of Aggressive Prostate Cancer

Understanding Genetic Basis of Aggressive Prostate Cancer

Molecular alterations caused by the loss of the tumor suppressor RB in aggressive prostate cancer. Plot represents a circularized version of the human genome, while each subsequent inner ring represents novel findings in the study relevant to disease.

The retinoblastoma (RB) susceptibility gene was the first gatekeeper gene discovered for cancer. When it was removed or damaged, cancer thrived. Over the years, researchers have discovered methods that have allowed them to experimentally remove the RB gene in order to study it, but just how the gene’s loss made cancers more aggressive was poorly understood. By studying patient samples, researchers at the Sidney Kimmel Cancer Center at Jefferson (SKCC) found how one type of RB removal, but not another, caused large-scale genetic changes that could make cancer both resistant to treatment and more likely to spread.

“RB loss causes a major reprogramming of gene expression, allowing induction of pathways that promote features that induce characteristics of lethal disease,” said senior author Karen Knudsen, PhD, Director of the Sidney Kimmel Cancer Center at Jefferson. The study is the first to identify the molecular consequences of RB loss and illustrate the clinical relevance of RB loss-induced transcriptional rewiring.

The study involved a multinational collaboration between SKCC investigators and other US-based laboratories, as well as clinical and basic science researchers in the UK, Italy, Belgium, Finland and Sweden. The findings were published online December 4 in The Journal of Clinical Investigation.

The study, which was spearheaded by first author Christopher McNairPhD, a graduate student in the laboratory of Dr. Knudsen, undertook an extensive analysis of tumor samples and cell-free DNA samples from patients with advanced, lethal-stage prostate cancer. Although there are several ways to remove RB from the cellular machinery, the group found that complete loss, rather than inactivation, of the RB gene was associated with changes in gene networks closely linked to aggressive disease. Surprisingly, the cancer-promoting program that RB loss unleashed was distinct from the cell-cycle control genes that RB is best known for controlling.

The new findings hold great promise for further clinical development and application. First, the research demonstrates that RB status can be tracked using cell-free DNA samples, an approach referred to as “liquid biopsy,” in prostate cancer patient samples. This method will facilitate the analysis of patient tumors and the selection of the most appropriate therapy based on the individualized features of each patient’s cancer subtype. Multiple clinical trials are now underway in Philadelphia that will determine the impact of RB status as a means to guide more precise cancer therapy.

“Unlike breast cancer, all prostate cancers are currently treated in an identical fashion. This discovery, and the clinical trials we have underway, suggest that RB status might be used as means to stratify patients into more effective treatment regimens,” said Wm. Kevin Kelly, DO, Leader of the SKCC Prostate Cancer Program.

In addition to Drs. McNair and Knudsen, SKCC investigator Benjamin Leiby, PhD, contributed to the study.

The SKCC is one of only eight National Cancer Institute (NCI)-designated Cancer Centers with a Program in Excellence in Prostate Cancer. The research was funded by both the NCI and the Prostate Cancer Foundation in addition to foreign funding agencies.

Article Reference:  McNair C, Xu K, Mandigo AC, Benelli M, Leiby B, Rodrigues D, Lindberg J, Gronberg H, Crespo M, De Laere B, Dirix L, Visakorpi T, Li F, Feng FY, de Bono J, Demichelis F, Rubin MA, Brown M, Knudsen KE