A First-in-Field Approach to Target a Previously Undruggable Oncogene Family in Prostate Cancer
Abstract
Despite significant advances in treatment options, more than 26,000 men die of prostate cancer in the US annually, making it the second leading cause of cancer death in US men. In order to develop more effective treatments, we need to address the mechanisms that allow prostate cancers to evade current therapies. Prostate cancer growth originally requires hormones called androgens (such as testosterone and dihydrotestosterone), which activate a protein called androgen receptor (AR) to drive prostate cancer growth. For the past seven decades, the main treatment for advanced prostate cancer has been to decrease testosterone production in the body. This treatment is usually effective initially, but eventually the cancer grows back, even though the testosterone levels in the body remain low. These treatment-resistant prostate cancer cells frequently produce high amounts of "normal" AR proteins or "abnormal" variants (referred to as "spliced variants") that can function under low-androgen conditions (called "androgen-independent" or "ligand-independent" ARs) and drive cancer growth. Unfortunately, even new drugs, such as abiraterone and enzalutamide, are inactive against prostate cancers that produce high amounts of "ligand-independent" and "splice variant" ARs. Even worse, many prostate cancers can grow completely independently of the AR and learn to adapt and hijack other proteins/receptors/survival pathways for their growth advantage. These pathways are numerous, complex, and mutually redundant, thus blocking only one of them is insufficient to achieve cancer cure. Therefore, more effective therapies that can block multiple oncogenic pathways simultaneously are urgently needed. One innovative way to accomplish this would be to take advantage of the existence of common critical components of these cancer-driving pathways. In recent years, we have learned a lot about how androgens work in prostate cancer cells and how cancers can achieve this regrowth after testosterone suppression. The O Malley lab at Baylor College of Medicine was the first to discover and study the Steroid Receptor Coactivators (called "p160 SRCs"), key proteins that cooperate with the androgen receptor and are necessary for androgens to function inside the prostate cancer cell and stimulate cancer growth. Prostate cancer cells, especially those that have developed resistance to conventional treatment, produce high amounts of these proteins and utilize them to promote their growth. Importantly, these p160 SRCs are critical for the activity of a large number of cancer-driving pathways beyond the AR. Fortunately, normal tissues tolerate the loss of SRCs generally well, and we have found that mice born without the p160 SRCs are viable and overall healthy. Thus, there is a therapeutic window that would make the p160 SRCs ideal therapeutic targets. We propose that by targeting the p160 SRCs, which are master regulators of multiple resistance mechanisms in prostate cancer, we will provide a new treatment option for our patients who are no longer benefiting from conventional therapies. Unfortunately, there is currently no available drug that can inhibit the SRCs. In fact, despite the acknowledgement of their importance, the scientific community has long believed that the SRCs are "undruggable." This notion was first challenged by work from our group when we reported a series of natural compounds that can suppress cellular p160 SRC protein levels. We have now synthesized an additional panel of novel, "first-in-class" inhibitors of the p160 SRCs and prostate cancer growth that have higher clinical potential. Our preliminary results demonstrate that our novel p160 SRC inhibitors are active against cancer cells and well-tolerated by mice. Our proposal aims to prove that these novel drugs can inhibit the function of SRCs in prostate cancer cells and, as a result, suppress cancer growth, thus leading to benefit for our patients. Ultimate applica
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710298
Entities
People
- Nicholas Mitsiades
Organizations
- Baylor College of Medicine
- United States Army