Regulation of Prostate Cancer Dormancy and Recurrence by Hippo Signaling
Abstract
Scientific Objectives and Rationale: With today’s technology, prostate cancer (PCa) is incurable after it is detectable at multiple sites, i.e., once it becomes metastatic. After a man is treated with radiation or surgery for localized PCa, he can have metastatic PCa develop months or decades after he thought he was cured. The capacity of a cancer to relapse many years after initial potentially curative therapy is often referred to as dormancy. PCa is a prime example of a cancer with a capacity for dormancy and subsequent recurrence, as about 25% of recurrences occur greater than 5 years after initial surgery or radiation. However, even though PCa has a continuing risk of recurrence after treatment, we know very little about how to prevent these recurrences. In this application, we propose to study how a group of proteins within PCa cells, called the hippo signaling pathway, controls whether and how PCa remains dormant vs. starts to grow. We decided to study the hippo pathway in this context because of three different types of evidence, which we present in the preliminary data for this proposal: (1) production of hippo pathway members in primary prostate tumors predicts the time to PCa recurrence; (2) different amounts of hippo pathway components are produced per cell when comparing rare PCa cells and large PCa tumors; and (3) different amounts of members of the hippo pathway are produced when comparing PCa cells that are preparing to divide vs. PCa cells that are quiescent. We then found that decreasing the production of some of the hippo pathway members affected cell growth in cultured PCa cells and formation of PCa bone tumors in mice. We will structure our investigations with the following specific aims. Specific Aims: Aim 1. Determine which hippo pathway components stimulate or inhibit PCa recurrence. We have data that the hippo pathway is involved in PCa recurrence, but do not know which members of the pathway are most important or whether the hippo pathway is more important in primary tumors or metastatic tumors. Aim 2. Delineate how tissue mechanics regulate PCa recurrence through the hippo pathway. In other situations, the hippo pathway responds to mechanical factors such as pressure and stretch, but it is unknown how they might apply to PCa recurrence. Aim 3. Investigate how non-coding RNAs regulate PCa recurrence through the hippo pathway. Ribonucleic acid (RNA) is the intermediary for transferring DNA code into protein sequence. However, novel studies outside of PCa show that some RNAs (non-coding RNAs) can control the hippo pathway as well. Research Applicability: This work is designed to ultimately lead to the development of medicines or other interventions to prevent the progression of PCa to fatal widespread metastatic disease. These studies will have their impact through a better understanding of regulation of PCa recurrence and therefore directly address the Overarching Challenge, “Define the biology of lethal PCa to reduce death.” Patients with localized PCa at high risk of recurrence are the main target population for these studies. Biological insight gained here will allow the rational design of therapy to prevent recurrence, i.e., “adjuvant therapy.” The biology of biochemical (PSA only) recurrence and oligometastatic (few metastases) PCa has commonalities with the initial recurrence, so patients with these conditions may be helped as well. Although laboratory-based research is essential for clinical progress in most cases, it is difficult to predict a time frame for direct patient impact. However, we think that identification of which hippo pathway member is most important for recurrence is a reasonable interim outcome. Drugs targeting the hippo pathway are in development. Therefore, identification of the most important pathway member will allow a drug to be chosen for a clinical trial. Career Goals: I am a medical oncologist and physician scientist with the long
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010394
Entities
People
- Frank C Cackowski
Organizations
- United States Army
- Wayne State University