A Systems Biology Approach to Link Nuclear Factor Kappa B Activation with Lethal Prostate Cancer
Annual rept. 1 May 2013-30 Apr 2014
DANA-FARBER CANCER INST BOSTON MA
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It is appreciated that NF B activation can either promote cancer cell death or cancer cell survival the outcome being dependent on the context of parallel biological processes. Notably, the presence of tumor suppressors influences the outcome. Our bioinformatic approach to define a cancer promoting NF B gene activation signature is well suited for accounting for the varied and opposing roles of NF B activation. Our prostate cancer specific work has identified absence of a unique set of tumor suppressors that leads to cancer cell survival and ultimately lethal prostate cancer. It is also now appreciated that indiscriminate inhibition of NF B activation may be problematic as this may block the anti-cancer effect of NF B activation. As such the increased understanding of NF B activation s context dependency adds further support for the work we are doing. In year one and two of the project we have found elevated cytokines and presence of T. Vaginalis at time of diagnosis of prostate cancer are not associated with higher grade disease nor risk of relapse after prostatectomy. In Year 3 of this grant we have curated the publically available gene expression profile GEP data of lethal vs non-lethal prostate cancer and also completed the preparation of the 26,000 GEP data from the Harvard School of Public Health cohorts relapsed vs not relapsed post prostatectomy. We have also identified a SNP that was associated with lethal disease using a SNP selection process called dense module GWAS . We have also been collecting TRUS biopsies of patients who progressed on surveillance vs no progression and relapse vs not relapse post prostatectomy to test our SNP and gene sets. In the year 4 no cost extension we will assess whether our candidate SNP and gene set associated with NF B can reliably identify patients with Gleason 6 low volume prostate cancer not in need of therapy.
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