Defining the Role of PIM Kinases in Hypoxia-Induced Invasion and Metastasis
Abstract
Rationale: Prostate cancer (PCa) patients have a good outcome if the tumor remains confined to the primary organ. When the tumor cells escape the prostate (metastasis), there is a dramatic decrease in 5-year survival (from nearly 100% to 30%). Over 80% of metastatic PCa will establish in the bone, and these secondary tumors do not respond to therapy and are ultimately what kill patients. Therefore, two of the most important factors that determine outcome in PCa patients are invasion out of the primary organ and therapeutic resistance in established bone metastasis. Clinical evidence indicates a strong correlation between low oxygen (hypoxia) and decreased progression-free survival in PCa patients, suggesting that hypoxia plays a significant role in PCa metastasis. Hypoxia is known to cause drug resistance, and tumors located in the bone are exposed to extensive hypoxia. Therefore, the successful identification and targeting of hypoxia-inducible pathways that control invasion and survival will lead to more effective treatment strategies for PCa patients. Our research group recently identified the Proviral Integration site for the Moloney murine leukemia virus (PIM) kinase as a pro-survival protein that is turned on in hypoxia. PIM expression increases with PCa disease progression and is known to promote tumor growth and survival. Importantly, my research group discovered that drugs that block PIM selectively kill hypoxic cancer cells and reduce metastasis in mouse models of PCa. Based on these findings, we will test the hypothesis that PIM activation in response to hypoxia promotes the initial invasion of cancer cells out of the prostate as well as resistance to therapy in patients with bone metastatic disease. Objective: The overall goal of this research is to gain a better understanding of how hypoxia impacts PCa progression and resistance to therapy. We identified PIM activation as a new mechanism responsible for the ability of hypoxia to promote tumor cell invasion and drug resistance, both of which represent lethal steps in PCa progression. The proposed research aims will yield valuable information about the role of hypoxia in driving PCa progression while testing a new therapeutic strategy to treat patients with bone-metastatic PCa. Specific Aims: Aim 1. Hypoxia predicts metastasis in PCa patients, but the biological mechanisms responsible are not known. For tumor cells to leave the primary organ, they must initiate signaling pathways that allow the cells to increase motility and invade tissue. Data in this proposal link PIM activation to the biological processes that are required for cells to become more motile. This aim will define the biological mechanisms by which PIM promotes cell migration in response to hypoxia. These results will improve our understanding of how hypoxia promotes metastasis and define a new role for PIM as a driver of cancer cell invasion. Aim 2. Our research group has developed several new models to test the ability of hypoxia to promote cancer cell invasion out of the prostate. Importantly, these models mirror the environment encountered by cancer cells as they metastasize out of the prostate and establish in the bone. Therefore, our results will accurately depict what is occurring in PCa patients as their disease progresses and will provide a useful platform for testing PIM inhibitors and new therapies. The goal of this aim is to test whether PIM is necessary for PCa invasion in hypoxia and evaluate the ability of PIM inhibitors to block metastasis. Aim 3. The vast majority of PCa metastases arise in the bone. Preliminary data from our group show that PIM1 is highly upregulated in PCa bone metastases due to increased hypoxia. Therefore, PIM expression in bone-resident tumors could provide cancer cells with the ability to escape current therapies. In this aim, we will combine PIM inhibitors with drugs that are currently being used to treat advanced PCa patie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910455
Entities
People
- Noel A Warfel
Organizations
- United States Army
- University of Arizona