During the course of tumorigenesis, cancer cells overcome genomic instability by constitutively up-regulating multiple signaling pathways pertinent to cell proliferation and survival. This tumor heterogeneity poses challenges to the clinical management of cancer patients and to the development of effective preventive and therapeutic strategies. A rational strategy to address this issue is the concomitant targeting of different molecular abnormalities with a potent pleiotropic agent to improve clinical outcomes. This rationale constitutes the molecular basis for our structural optimization of indole-3-carbinol to develop potent antitumor agents with pleiotropic modes of mechanism, which has culminated in the generation of an acid-stable derivative, OSU-A9. OSU-A9 exhibits a 100-fold higher antitumor activity and striking similarities in its effects on targeting multiple signaling targets in cancer cells. Despite this complex mode of mechanisms, nonmalignant cells were less susceptible to the antiproliferative effect of OSU-A9. This project thus tests our hypothesis that use of a pleiotropic agent that targets multiple signaling pathways associated with oncogenesis and tumor progression represents an effective strategy for cancer prevention, of which the aim is twofold.
Aim 1 is to continue the structural modification of OSU-A9 and mechanistic validation of optimal derivatives. Two series of derivatives will be generated, in which the indole ring of OSU-A9 is substituted with substituents with different stereoelectronic properties. We expect that this Aim will generate 3 optimal derivatives with low to sub-5M potency in antitumor activity for mechanistic validation and in vivo testing.
Aim 2 is to assess the in vivo efficacy of the optimal OSU-A9 derivatives on blocking prostate tumorigenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. We hypothesize that the optimal OSU-A9 derivative can block prostate tumorigenesis in vivo at clinically attainable concentrations.
This Aim consists of three parts. First is to determine the oral maximum tolerated doses of OSU-A9 and its optimal derivatives in nude mice. Second is to determine the in vivo efficacies and to identify potential toxicities of these agents in the PC- 3 xenograft tumor model. Third is to evaluate their chemopreventive activities in the TRAMP model. We expect that these optimal derivatives will provide considerable advantages relative to indole-3-carbinol and other phytochemicals in fostering potentially successful strategies to block or delay prostate tumorigenesis and/or tumor progression.
Project narrative In men, prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer death. Our overall research goal is to develop novel agents that target the specific molecular and cellular defects in prostate cancer cells that make the clinical management and development of preventive strategies for this disease so challenging. We expect that this project will ultimately yield new drugs that will block or delay the development and/or the progression of prostate cancer.
