Discovery of a First-In-Class MPP8 Antagonist to Reverse Lineage Plasticity in Treatment-Resistant Prostate Cancer
Abstract
Prostate cancer is a common and deadly disease. In the U.S., prostate cancer (PC) is the most commonly diagnosed malignancy and is the second leading cause of cancer-related death among men. Because nearly 80% of the active-duty population and the Veteran population are men, prostate cancer is a public health issue for the Servicemen, Veterans, and their families. Active-duty male Servicemen are at least twice as likely to be diagnosed with prostate cancer when compared to men in the general population. Clearly, this means that prostate cancer has a potentially negative impact on their ability to serve. In addition, Servicemen exposed to chemical agents, like Agent Orange during the Vietnam War, are at much higher risk for aggressive prostate cancer and prostate cancer-related death. In prostate cancer, a phenomenon called “lineage plasticity” or “epithelial to mesenchymal transition” (“EMT”) can occur, where cells lose their original identity and assume the identity of a different kind of cell. Then, they are able to escape the prostate and spread (or “metastasize”) to different parts of the body, which makes the disease extremely challenging to treat. Ultimately, EMT has been associated worsened survival among metastatic prostate cancer patients. Chromatin is a complex of DNA and proteins found in all of our cells. Modifications to the DNA without changing the actual DNA code are called “epigenetics,” and these modifications dictate how genes are expressed. Recently, scientists have begun to more fully appreciate how inappropriate epigenetic changes, or “epigenetic dysregulation,” can influence human diseases. Despite the fact that epigenetic dysregulation is a common feature of most cancers, understanding of epigenetic dysregulation is still in its infancy. Chemical biology and developmental therapeutics are poised to help advance scientific knowledge and create new therapeutics in this field. The oncology scientific community’s interest in epigenetic dysregulation has intersected with drug development, and numerous compounds for several classes of epigenetic regulatory proteins have made it from the laboratory to clinical trials over the past decade. In fact, some have even been FDA-approved in hematologic malignancies, while others having progressed past first-in-human clinical trials in solid tumors. Epigenetic dysregulation is common in treatment-resistant prostate cancer, and epigenetic changes to chromatin have been associated with EMT. In prostate cancer, a protective gene called CDH1 can be silenced, which leads to EMT, increased risk of metastasis, and changes to cells that cause a particularly lethal form of prostate cancer called “neuroendocrine prostate cancer.” However, mechanisms of CDH1 silencing and EMT are still not well understood, which has made developing new treatments challenging. MPP8 is an epigenetic protein that has been linked to EMT in many types of cancer and has been implicated in CDH1 silencing. Therefore, the goal of this FY20 PCRP Idea Development Award is to develop a potent and selective MPP8 antagonist compound to (1) validate MPP8 as a central regulator of EMT in prostate cancer and (2) develop as a potential therapeutic strategy in metastatic prostate cancer. In this research proposal, our team addresses with two of the FY20 PCRP Overarching Challenges: (1) Define the biology of lethal prostate cancer to reduce death and (2) Develop treatments that improve outcomes for men with lethal prostate cancer. We have assembled a multi-disciplinary research team with complementary expertise in basic and translational research experience in prostate cancer, medicinal chemistry, chemical biology, molecular biology, pharmacology, and developmental therapeutics. In this proposal, we plan to show that our MPP8 antagonist can be both potent and selective in cell and preclinical animal models. Despite the fact that we are at least 5 years from testing in humans, we believe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110748
Entities
People
- Daniel Crona
Organizations
- United States Army
- University of North Carolina at Chapel Hill