Development of Personalized Cancer Therapy for Men with Advanced Prostate Cancer
Abstract
Bone metastases typically develop in patients with advanced prostate cancer (PCa). We have previously reported that the fibroblast growth factor (FGF) axis is implicated in the pathogenesis of PCa bone growth, and that FGFR blockade has clinical activity in advanced PCa and bone metastases.2 In an RNA sequencing study of human PCas we found that different samples express different FGFR1 transcripts. We then mined TCGA PCa database to determine the expression profile associated with two well-characterized FGFR1 splice variants, alpha and beta, which represent the most abundant protein coding transcripts found in PCa. We discovered that each isoform is associated with the expression of different genes. Also, in gene set enrichment analysis, we found that FGFR1 beta (but not alpha) is associated with many different pathways. In particular, FGFR1 beta is significantly associated with MAPK signaling cascade, signaling by FGFR in disease, and pathways in cancer, among others. In vitro studies of FGF signaling activation in PCa cells expressing FGFR1 isoforms alpha, beta, or empty vector (EV) confirmed these results. Therefore, these results suggest that FGFR1 alpha and beta induce different genes. Importantly, when compared to PCa cells expressing EV, PCa cells expressing FGFR1 isoforms produce significantly more metastasis and reduced survival of mice injected intracardially with the cells. In summary, our studies suggest that FGFR1 alpha and beta activate different genes and pathways in PCa cells, thus conferring different phenotypes. We further propose that FGFR1 expression in PCa cells favors its metastatic dissemination to bone, and this may be mediated at least partially by activating PCa cell-bone cell interaction. Our studies provide the framework to move forward with clinical trials targeting FGFR in men with advanced PCa.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2018
- Accession Number
- AD1070334
Entities
People
- Arul Chinnaiyan
- Nora M. Navone
Organizations
- University of Texas at Austin