Precision Medicine Principles Applied to Prostate Cancer

Cleveland Clinic Glickman Urological & Kidney Institute is leading the precision medicine charge against prostate cancer, and institute members have published a number of milestone studies.

Tumor resistance to CRPC drugs

Researchers discovered that increasing expression of the enzyme 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) can reverse tumor resistance to enzalutamide while sparing healthy tissue after chemical or surgical castration.

Physician-scientist Nima Sharifi, MD, described the effect of enzalutamide on suppressing a metabolic pathway in which 11β-HSD2 inactivates the tumor-proliferating cortisol hormone into cortisone via increased autocrine motility factor receptor expression and ubiquitin E3-ligase production. His team further showed that restoring 11β-HSD2 function by restricting AMFR expression restores tumor sensitivity to enzalutamide.

“Our findings reveal a surprising metabolic mechanism of enzalutamide resistance that may be targeted with a strategy that circumvents the need for systemic GR ablation,” says Dr. Sharifi.

Dr. Sharifi holds the Kendrick Family Chair for Prostate Cancer Research and co-directs Cleveland Clinic’s Center of Excellence for Prostate Cancer Research. He is a staff member of the Lerner Research Institute Department of Cancer Biology, Glickman Urological & Kidney Institute and Taussig Cancer Institute. In 2017 he received a Top Ten Clinical Research Achievement award from the Clinical Research Forum for his landmark discovery that men who carry the HSD3B1(1245C) variant are more likely to die from their disease.

Further reading on Dr. Sharifi’s research.

181 androgen receptor coregulators; 18 that matter

A team led by Hannelore Heemers, PhD, Associate Staff in the Lerner Research Institute Department of Cancer Biology, showed that of the 181 coregulators of the androgen receptor (AR), at least 18 could theoretically be modulated to interrupt androgen signaling.

“All therapies that target ligand activation of the AR eventually fail. We are attempting to target another point in the pathway,” says Dr. Heemers.

The study elucidated several previously unknown interactions between AR, coregulators and other proteins, the most important of which is the one between the AR, the coregulator WDR77 and the p53 protein. These WDR77-p35-AR interactions are enriched in prostate cancers, including those that do not respond to androgen deprivation therapy, where they promote cancer growth.

The findings lay the foundation to develop new drugs that interfere with these cancer-promoting interactions.

Further reading on Dr. Heemers’ research.

Next-generation risk stratification

Two new molecular tests in prostate cancer — Decipher® and IsoPSA — are a cornerstone of prostate cancer research and continue to show new utility in patient care.

A retrospective study of prostate tissue from men with 3+3=6 Gleason scores showed that up to 20 percent with favorable disease pathology have tumors with molecular alterations that put them at higher risk for metastatic disease.

The study, led by institute Chair Eric Klein, MD, showed that Decipher® accurately stratified patients with 3+3 Gleason disease into low (80 percent), intermediate (13 percent) and high-risk (7 percent) disease.

“Study after study has shown that active surveillance represents the best option for many men with low-grade prostate cancer,” says Dr. Klein. “The important thing is to make sure we select the right patients for deferred treatment to improve overall outcomes and reduce the chances that we miss an aggressive cancer.”

Similarly, a yearlong study of 261 men scheduled for biopsy showed that IsoPSA testing offered a 48 percent reduction in false-positive biopsies and a superior net benefit over no biopsy, all biopsy and the modified Prostate Cancer Prevention Trial Risk Calculator 2.0.

IsoPSA, developed at Cleveland Clinic, is serum-based assay that predicts prostate cancer risk by partitioning isoforms of prostate-specific antigen (PSA) with an aqueous two-phase reagent.

“We are optimistic that IsoPSA testing, once fully validated, will simultaneously reduce overtreatment and improve prognostication,” says Dr. Klein.