Prostate cancer is a highly heterogeneous disease, and mortality from prostate cancer is due to metastases, and thus, understanding the mechanisms of metastasis is essential for improving patient outcomes. In this proposal, we plan to leverage the resources of an ongoing NIH-funded clinical trial of patients with high-risk prostate cancer who have had extensive dissection of surrounding lymph nodes and imaging with the FDA-approved radiotracer [18F]-fluciclovine, a biomarker of amino acid transport, which is upregulated in prostate cancer cells. We hypothesize that genomic analysis of multiple foci within the primary tumor, and lymph nodes positive and negative for [18F]-fluciclovine uptake and metastatic disease, will provide new insights into the mechanisms of the earliest steps in metastasis and help identify key driver mutations and signal transduction pathways. We plan to test this hypothesis via the following specific aims:
Aim 1) perform whole exome sequencing of multiple primary foci and corresponding lymph nodes to identify somatic mutations associated with LN mets;
Aim 2) perform RNAseq analysis of multiple primary foci and corresponding lymph nodes to identify gene expression changes associated with LN metastasis;
Aim 3) determine RNA and DNA signatures associated with the presence and degree of uptake of fluciclovine in LN mets. This proposal is innovative in that we will be using multiple samples from the same patients to interrogate the heterogeneity of primary prostate tumors and the genomic and gene expression changes that drive the initial step of metastasis as they migrate to the lymph nodes. In addition, we will generate new understandings of the changes that are associated with uptake of the radiotracer [18F]-fluciclovine, which reflects upregulated amino acid metabolism in tumor cells. Discoveries from this project could lead to new approaches for treatment of advanced disease by identifying the genomic changes essential to the first steps of metastasis and defining the biology of lethal prostate cancer. New drug targets that are critical for metastasis may be identified from the knowledge gained through this study.
We hypothesize that genomic analysis of matching primary and metastatic prostate cancer tissue samples will provide new insights into the mechanisms of the earliest steps in metastasis and help identify key driver mutations and signal transduction pathways. Discoveries from this project could lead to new approaches for treatment of advanced disease by identifying the genomic changes essential to the first steps of metastasis and defining the biology of lethal prostate cancer. New drug targets that are critical for metastasis may be identified from the knowledge gained through this study.
