Understanding the MIRO2/GCN1 Signaling Axis for Therapeutic Gain in Lethal Prostate Cancer
Abstract
Prostate cancer starts when cells in the prostate gland grow out of control. Some prostate cancers (PC) grow quickly and are able to move into new parts of the body, a process called metastasis. Hormone therapy is the most effective treatment for PC that has metastasized. However, nearly all patients develop resistance and progress to castrate-resistant prostate cancer (CRPC). Although new regimens initially reduce CRPC growth and extend patient survival, these gains are transient and invariably followed by resistance and disease progression. Compounding resistance, 30% of patients develop more aggressive and lethal forms of CRPC that spread to vital organs, henceforth called metastatic prostate cancer (mPC). A major barrier in developing more effective treatments is our limited understanding on how mPC cells grow and spread to vital organs, ultimately leading to poor quality of life for patients, and prostate cancer-related death. The overarching challenge of this project is to understand the biology of mPC and to translate this knowledge into novel therapeutic strategies to prevent prostate cancer-related death. Our project proposes a novel way in which mPC can be stopped. The key to this novel idea is that mPC cells need a continuous fuel supply to grow and spread. All cells have small energy factories called mitochondria, which help to break down food into fuel and small components that can be used by the cells to build up structures, grow and move around the body. Our project will study the importance of mitochondria in mPC, focusing on aggressive mPC that do not respond to hormone therapies. Specifically, we will study a protein whose expression is excessive in mPC tumors and that increases the risk of death of prostate cancer patients. This protein is named MIRO2 (for Mitochondrial Rho GTPase). Our preliminary studies show that MIRO2 works together with two other important proteins named GCN1 and GCN2 (for General Control Non-derepressible 1 and 2). Together, these three proteins help mPC cells tolerate conditions where growth of normal cells would be prevented—for example, whether nutrients are limiting. Importantly, by reducing MIRO2 levels, we are able to suppress growth and the spreading ability of mPC cells. Our first aim is to examine the impact of MIRO2, GCN1, and GCN2 on the aggressiveness of mPC using preclinical models of mPC that spreads to bone, lung, and liver (the major sites where mPC spreads in the body). This is important given the upregulation of MIRO2 and GCN1 in metastatic tumors and the correlation between higher MIRO2 expression and poor patient survival. Furthermore, we have identified mutations on MIRO2 that abolish tumor invasiveness and suggest a potential way to target MIRO2. We will examine the impact of these mutations on the aggressiveness of mPC using preclinical models as before. From a translational standpoint, these studies may reveal novel ways to treat mPC. Our second aim seeks to identify vulnerabilities of mPC that expresses high MIRO2 levels. We show that combination of a GCN2 inhibitor with an agent that reduces the levels of nutrients can kill mPC cells in culture. Here we will test if these drug regimens can reduce or prevent the metastatic dissemination of mPC, using preclinical models of mPC that spreads to bone, lung, and liver. Furthermore, we will test the clinical relevance of our proteins by examining the expression and activation of MIRO2, GCN1, and GCN2 in biospecimens from patients diagnosed with localized or metastatic prostate cancer. These experiments have a higher risk associated with them, but if successful, we will establish a novel way to treat mPC. In the short term, we aim to understand how MIRO2 helps cancer cells survive, grow, and spread to other organs. In addition, we will investigate whether mPC can be killed by inhibiting GCN2. In the long term, we aim to use this basic knowledge to develop novel ways to treat pros
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110408
Entities
People
- Maria Caino
Organizations
- United States Army
- University of Colorado Denver