ELK1-Targeted Molecules as a New Paradigm for Prostate Cancer Treatment
Abstract
A dual challenge in prostate cancer treatment: The main weapon in the clinician?s arsenal for treating advanced prostate cancer is to deprive the tumors of the hormone testosterone (called ?androgen deprivation?). Testosterone works by binding to a protein called the androgen receptor (AR) and enabling it to turn on genes that promote tumor growth. Androgen deprivation is achieved by castrating the patient, most commonly by treating the patient with certain chemical drugs that suppress testosterone production in the body. Additionally, drugs called anti-androgens are available that either interfere with the actions of AR or cause its destruction. All of these therapies, however, pose the following two major challenges. First, no matter what mode of disrupting AR is chosen, prostate tumor cells are able to adapt and restore AR function by overproducing either testosterone, AR, or a variant form of AR. High levels of AR or its variants enable the tumor cells to utilize diminishing amounts of testosterone or to grow in the absence of testosterone. Second, testosterone and AR have roles unrelated to cell growth in the normal functioning of a variety of adult tissues. For this reason, prolonged androgen deprivation and use of anti-androgens have many undesirable side effects including a decline in cognitive function, thinning of bones, loss of muscle mass, and increase in percentage of fat body mass, sexual dysfunction, lowered ability of the blood to carry oxygen, swelling of the breast tissue, hot flashes, heart and blood vessel disease, and the general loss of wellbeing. Therefore, treatment strategies that deplete testosterone, or completely disable AR, burden patients with many undesirable side effects yet ultimately lose their effectiveness against the tumor. A dual solution: We have recently published findings that advance a new concept for treating prostate cancer by disrupting the ability of AR to support tumor growth in a manner that circumvents both the above problems. This concept is based on our finding that a protein called ELK1 acts as an ?anchor? to direct AR to crucial growth promoting genes in a variety of standard models of prostate cancer, including cancer that recurred after castration. AR binds directly and quite tightly to ELK1, and this binding requires two sites in the ELK1 protein. Standard prostate cancer model cells are ?addicted? to ELK1 in that they must have ELK1 for AR-dependent growth and tumor formation. Virtually all prostate tumors from patients have ELK1. We predict that drugs able to prevent ELK1 from associating with AR will have no effect on normal tissues in which testosterone is needed for functions other than stimulating growth; however, the drugs should strongly suppress growth of prostate cancer, including advanced tumors that have overcome castration. Indeed, such a treatment would not require androgen deprivation at all, allowing the patient to enjoy a normal level of testosterone. Execution of the new idea: Using stringent methods, we have screened a large collection of chemical compounds to look for any that could prevent AR binding to ELK1. One would expect such compounds could work by binding to either AR or to ELK1. Several candidates passed the screen and from the top candidates we prioritized those that could likely be developed as drugs for clinical use in the shortest time. One candidate molecule suppressed growth of various prostate cancer cell lines models including cells obtained from castration-resistant tumors. We have additionally picked five other compounds for further studies in this project. The proposal: We will study in detail just how selectively these six types of compounds disrupt the interaction of ELK1 with AR, to which partner they bind, how well they slow the growth of model prostate cancer cells in culture and how effective they are in protecting mice bearing advanced prostate tumors obtained from patients. In parallel, w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710243
Entities
People
- Peter E Shaw
Organizations
- United States Army
- University of Nottingham