Targeting the Signaling Pathways in Prostate Cancer

Exploring a potential new prostate cancer therapy

For men, the leading cancer diagnosis is prostate cancer. Though common, this form of cancer can be deadly when it begins to spread to other parts of the body — men whose cancer is metastatic have a 5-year survival rate of 30%. Successful life-extending treatments for these patients are limited due to a high rate of patients who build resistance to therapies.

Addressing the need for improved treatments, Richard Bonneau, Professor of Biology, Computer Science, and Data Science, Kent Kirshenbaum, NYU Chemistry, Jeffrey A. Schneider of the Department of Urology at NYU’s School of Medicine, and Timothy W. Craven of the NYU Department of Chemistry, contributed to a recent publication that takes its aim at a pathway at the center of many cancers, the Wnt signaling pathway. Researchers aim at the N-terminal TCF (beta)-hairpin binding pocket of (beta)-catenin, which plays a critical role in the Wnt signaling pathway, using the Rosetta suite of protein design algorithms. In the study, researchers evaluated the way in which different macrocycle structures bind a pocket on beta-catenin that associates with TCF.

Protein-protein interactions (PPIs) direct a wide variety of biological processes. Because certain PPIs can result in disease, research efforts have centered on using molecules or peptides to control and inhibit undesirable PPIs. Unfortunately, both molecules and peptides have shortcomings that make them less than ideal choices in addressing detrimental PPIs. A possible solution is designing peptidomimetics that target particular PPIs. This approach circumvents the main weaknesses of peptides and molecules, but challenges researchers to produce the ideal design.

The team used the “Rosetta suite of computational tools to generate a small library of peptoid-peptide macrocycles designed in in silico that are predicted to bind beta-catenin.” Then, researchers select a promising compound that inhibits binding between beta-catenin and TCF proteins, proliferation of prostate cancer cells, and Wnt signaling in vivo. Researchers chose macrocycle 13 after testing the efficacy of 12 oligomers with a TOP-Flash Wnt luciferase reporter. Their findings included the fact that macrocycle 13 inhibits prostate cancer cell growth and slows growth of prostate cancer spheroids. Although further testing on mice with macrocycle 13 is needed before it can be considered as another potential therapy for prostate cancer, the result stands as a key milestone in directed design of therapies (often many thousands or millions more compounds would need to be tested to find a compound with this affinity and biological potency).

By Sabrina de Silva