Grants and Contracts Details
Public abstract: Radio-sensitizing effects of novel histone de-acetylase inhibitors in prostate cancer Seema Gupta, Ph.D. The current therapies used for the treatment of prostate tumors have limitations. It is often observed that there is relapse in prostate cancer patients who respond to androgen (a hormone required for growth of cells) depleting drug therapy initially. To achieve better results there is an ongoing search for novel therapeutic strategies. One such approach could be to induce cell death (one of them is apoptosis) and inhibit cell growth. However, modalities used for treatment of prostate cancer may themselves lead to release of certain factors that often confer resistance for subsequent treatment. Thus, we hypothesize that treatment of prostate cancer cells with radiation will induce genes that have both killing functions as well as induce genes that have cell survival functions. For example, genes that functions for cell killing and induced by treatment are Bax and others and the gene that induces cell proliferation is NFkappaB. Hence, strategies that can block selectively the signaling pathways responsible for growth and induce expression of genes responsible for cell death will be beneficial for complete eradication of prostate cancer. This could be obtained by inhibiting NFkappaB signaling which is responsible for cell growth (i.e. pro-survival) using histone de-acetylase (HDAC) inhibitors and inducing expression of Bax and other downstream proteins that are responsible for apoptosis (i.e. anti-survival/pro-apoptotic). This proposal will be tested in both androgen dependent and independent prostate cancer cell lines and prostate tumor bearing mice by inhibiting radiation-induced NFkappaB by HDAC (an enzyme that is required for chromatin remodeling and thus changes the expression of certain genes) inhibitors: VAD-18 and VAD-20. Some of the HDAC inhibitors are already undergoing clinical trials without radiation. Thus, the three specific aims of this proposal will help in examining which genes are affected by radiation and HDAC inhibitors treatments and relate that to cell death. The results will also help in understanding the molecular mechanisms responsible for enhanced radio-sensitivity in the presence of these inhibitors. This project takes an innovative approach of combining the radiation with HDAC inhibitors in inducing enhanced cell death and tumor regression. The results of these experiments will be the basis for future clinical trials in patients utilizing this combined treatment.
|Effective start/end date||9/1/04 → 4/30/05|
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