A Novel Regulator of Cancer Stem Cell Plasticity and Its Roles in Prostate Cancer Resistance and Metastasis
Abstract
Metastasis and resistance to chemotherapy (chemo-resistance) are hallmarks of lethal prostate cancer, and TGF-ß is the single most potent known cytokine in the promotion of these processes. More than a decade of efforts in directly targeting TGF-ß or its receptors has not been successful in developing therapies that suppress metastasis or overcome chemo-resistance in advanced prostate cancer, and further understanding of how TGF-ß promotes prostate cancer progression at the molecular level is crucial for developing novel therapies. Our published and unpublished studies have identified a novel process in which acetylated KLF5, a molecule that regulates the expression of other genes, acts as an essential functional effector of TGF-ß in the development of bone metastasis and chemo-resistance (BMCR). In this project, we will further test the roles of KLF5 in prostate cancer metastasis and chemo-resistance and identify partners and functional mediators of KLF5 required for the development of BMCR. Completion of these studies will firmly establish Ac-KLF5 as a key player in the development of BMCR in prostate cancer; identify proteins whose interactions with Ac-KLF5 are necessary for these processes; identify functional mediators of Ac-KLF5 in the induction of these processes; provide proof of concept for targeting different components of the TGF-ß/Ac-KLF5 signaling axis in the suppression of BMCR; and generate novel preclinical models of BMCR. What Types of Patients Will It Help, and How Will It Help Them? As described above and in other sections, this proposal will help prostate cancer patients who have developed bone metastasis or resistance to chemotherapies. Although additional drug development work will be needed after the completion of this project, identifying Ac-KLF5-partner interactions and Ac-KLF5’s functional meditators will provide therapeutic targets for the development of new drugs that suppress BMCR. Once developed and clinically proven to be effective, such drugs will help to treat metastatic and/or chemo-resistant prostate cancers, which are virtually incurable at present. The need for such effective therapies is urgent. What Are the Potential Clinical Applications, Benefits, and Risks? Although the outcomes of this project will not directly result in clinical applications or benefits, they represent a crucial step in developing novel therapies to treat bone metastasis and overcome chemo-resistance. Once therapeutic targets are established in this project, drug development efforts will be initiated, which will likely result in novel drugs for the treatment of prostate cancer BMCR in the future. What is the Projected Time It May Take to Achieve a Patient-Related Outcome? We expect that the drug development effort to target molecules discovered in this project will start during the time period of this project. Supported by our extensive preliminary studies, we further expect that lead compounds will become available, and clinical trials will likely begin in about 5 years to achieve a patient-related outcome. If the Research is Too Basic for Clinical Applicability, Describe the Interim Outcomes: Immediate outcomes of this project include the discovery of drug targets and the development of preclinical models of BMCR. Molecules that are needed for the development of BMCR can be used for drug development, and the preclinical models can be used for testing agents from other studies for their therapeutic effects on BMCR. What Are the Likely Contributions of This Study to Advancing the Field of Prostate Cancer Research? It has been well known for a long time that TGF-ß is a potent promoter of prostate cancer metastasis and chemo-resistance, but therapeutically targeting TGF-ß or its receptors has not been successful so far. Further understanding the molecular mechanisms underlying TGF-ß’s promoting effect on prostate cancer progression is a crucial step in the effort of targetin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810526
Entities
People
- Jin-Tang Dong
Organizations
- Emory University
- United States Army