Novel PTEN Regulatory Pathway for Prostate Cancer Therapy
Abstract
Scientific Objective/Rationale: The PTEN (phosphatase and tensin homolog) gene makes a protein that blocks an important process called the PI3K/AKT/mTOR pathway within a cell. This suppresses cell growth and division, survival, and movement. In the absence of PTEN, cells can grow and divide faster than normal. Loss of at least one copy of the PTEN gene is found in about 40% of prostate cancers. PTEN deletions are often found in more aggressive tumors and indicate poorer prognosis, increased tumor metastases, and greater chance of recurrence after treatment. Emerging evidence has also shown that, much like the genomic disruptions that inactivate a given PTEN allele, the pathological mechanisms that repress PTEN protein levels are associated with prostate cancer. Thus, identifying novel mechanisms that directly control PTEN protein stability and activity for therapeutic purposes has become a high priority for prostate cancer researchers. Yet there are no Food and Drug Administration (FDA)-approved prostate cancer therapies that specifically target PTEN. Therapies that target other proteins in the PI3K/AKT/mTOR signaling pathway could potentially compensate for PTEN inactivation by switching off the pathway. However, the efficacy of these therapies has been limited to partial responses in patients with PTEN-related prostate cancer, suggesting that combination treatment modalities are necessary to maximize the efficacy of these therapies. The rationale for our proposed research is that, once we know how PTEN protein levels are regulated in prostate cancer, the activity of PTEN regulators can likely be manipulated pharmacologically to fully restore PTEN expression, resulting in new and innovate approaches to the prevention and treatment of prostate cancer. We have recently identified a novel, specific PTEN regulator and demonstrated that its activity is tightly controlled in prostate cancer. We here propose to define, in knockout mice, the critical roles of this novel PTEN regulator in vulnerabilities of prostate cancer, and exploit these insights to optimize patient stratification for the rational design of cancer therapies. We are dedicated to the goal of ultimately bringing this research to clinical fruition in the quest to eradicate prostate cancer, initially by evaluating the therapeutic implication of this novel, specific PTEN regulator in clinically relevant knockout mouse models for prostate cancer. Ultimate Applicability of the Research: PTEN is one of most frequently mutated tumor suppressor gene in human cancers, including glioma, melanoma, endometrial cancer, breast, colon, prostate, and lung tumors. Thus, this approach could be used to treat prostate cancer and have the potential to treat the common cancers. Our focus is on aggressive and advanced prostate cancers, which preferentially strike down men worldwide. This approach, if it works, will open up a new platform for prostate cancer therapy. By coupling the identification of the key PTEN regulator and preclinical evaluation of its therapeutic potential in clinically relevant mouse models of prostate cancer, this study will not only shed light on prostate cancer progression in humans, but also help bolster diagnostic, prognostic, and therapeutic approaches. The successful completion of this project will identify the novel and critical tumor suppressor that modulates PTEN dosage in vivo, paving the way for stratifying patients for the rational design of novel cancer therapies towards a full restoration of PTEN function. If our cell line feasibility studies and comprehensive animal testing are completely successfully, we believe that our work will prevent the treatment of men with therapies that had little benefit for their disease and provide new treatment opportunities for patients whose tumors do not respond to conventional chemotherapy and for which new options are urgently needed. Likely Contributions to Advancing Prostate Cancer Resear
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510662
Entities
People
- Min Sup Song
Organizations
- United States Army
- University of Texas at Austin