A Single Missense Mutation in 77% of Prostate Cancer Bone Metastases: Novel Opportunity for Genetic Biomarker and Novel Therapeutic Mitochondrial Target
Abstract
The lethal form of prostate cancer almost always includes spread (metastases) to multiple places in the patient s bones. At this advanced stage, there is no highly effective treatment and a painful death is the usual outcome. The purpose of this grant is to leverage a recent finding in our lab about prostate cancer bone metastases to ultimately benefit patients. This year we published our findings that three-quarters of all bone metastases sampled from patients that died of prostate cancer have the exact same DNA mutation. This mutation occurs in the mitochondria, the "powerhouse" of the cell where most of the energy for the cell is generated ("mitochondrial DNA" or "mtDNA"). This extremely high frequency of a single mutation is literally unprecedented and unique in all of cancer biology and strongly suggests that it is critical for the successful spread of prostate cancer to the bone and the ability of prostate cancer to grow once it has spread there. The research proposed in this application will therefore identify the precise molecular changes that this mutation causes in human prostate cancer (both in actual patient samples obtained immediately after death and in human prostate cancer cells manipulated in the laboratory and in mice) in order to allow us to identify the critical processes that occur when prostate cancer spreads to the bone so that these mechanisms can be targeted or disabled. This application brings together three institutions that each contribute unique expertise and resources to solve this problem. Emory has an extensive experience with mtDNA mutation in prostate cancer and was the first to report that mtDNA mutations were important in developing prostate cancer and in how fast the cancer grows. The University of Washington-Fred Hutchinson Cancer Center has an invaluable tissue resource because it has been performing a rapid autopsy soon after people die of their prostate cancer and it harvests and stores multiple pieces of the cancer, including the bone metastases. Cold Spring Harbor Laboratory in New York has developed the "RapidCaP" mouse model of prostate cancer metastasis that will uniquely identify mechanisms of metastasis in prostate cancer cells with the mutation and allows the rapid testing of genes and mutations involved in the spread of prostate cancer. The first specific aim of the application will do experiments on patient tissue specimens, the second specific aim will perform laboratory experiments using human prostate cancer cells implanted in mice, and the third specific aim will perform experiments in genetically modified mice that develop prostate cancer. The potential clinical translation of this research involves two separate but related opportunities. The first will be to identify truly novel targets for the treatment of advanced prostate cancer. The patient with bone metastasis has relatively few therapeutic options: androgen deprivation, chemotherapy, and focal radiotherapy. None of these result in cure, perhaps because the most common genetic alteration in actual patient-derived bone metastasis has never before been identified. We have identified it and just published this remarkable finding: that 75% of all bone metastases studied to date have the exact same DNA base change that results in the exact same protein change. This situation is exactly analogous to the finding in a mouse model of lung cancer where a mitochondrial DNA mutation was the sole cause of metastasis and the finding that these metastases could be stopped by either fixing the mutation or treating the mice with specific antioxidants. The successful completion of the research proposed in this application will allow us to focus in on specific molecules to target for the development of new treatments for patients. While drug development is not part of this application, new drugs cannot be designed until the new targets are identified, and that is the focus of this research. The second is
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610584
Entities
People
- John Petros
Organizations
- Emory University
- United States Army