Delaying the onset of cancer may be a viable cancer prevention strategy, but until now research efforts on this aspect are indeed limited. To this end, we are relatively advanced because our published results establish that organ specific delivery of eRapa (a novel formulation of rapamycin) can delay the development of intestinal tumors in a mouse model of familial adenomatous polyposis (FAP) and thus extended life as well as health span. The potential for broad application of this approach is also illustrated by results in genetically heterogeneous wild type mice by the NIA Intervention Testing Program, where eRapa extends maximum survival in nine replicate published experiments, the last of which shows a dose response in survival. Reductions in cancer are posited to contribute to survival in this setting. Very importantly, our comprehensive studies on the immunological effects of long-term use of rapamycin did not identify any specific detrimental effects rather we observed many potentially beneficial effects. For example, long-term rapamycin likely promotes immunological health in the aged, who are most susceptible to cancer. Published meta-analysis of cancer patients and results from healthy elders indicate rapalogs have a low association with fatal adverse events and minor adverse effects, respectively. Altogether these data represent strong evidence for the safety of chronic eRapa treatment in a cancer-delaying setting. We will use intestine cancer as a model to test the general proposition that long-term mTORC1 inhibition extends life span (and health span) by delaying cancer.
Aim 1 tests if our 42 ppm eRapa diet prevents malignant degeneration of colon polyps in established DSS or AOM colon cancer promotion ApcMin/+ models (males and females), and comprehensively examines its effects on mTOR and Wnt/?-catenin signaling in tumors and tissues. We will also assess in vivo eRapa responses in tissues and tumors by ribosome profiling experiments with an emphasis on mTORC1 regulation of ribosome biogenesis. Our rapamycin-DNA methylation studies identified Slc38a3, which encodes a neutral amino acid transporter. Because of its mTORC1 regulatory potential, we will study Slc38a3 using cell-based and in vivo approaches.
In Aim 2, we investigate if mTORC1 and mTORC2 separately contribute to tumorigenesis and exert differential responses to chronic eRapa exposure. We will use ApcMin/+ mice with intestine crypt stem cell (ICSCs) knockout of either raptor (for mTORC1) or rictor (for mTORC2). In each model, eRapa treatment (or control diets) will start first (4 weeks beginning at 6 weeks of age) followed by conditional knockouts in ICSC in the large bowel. eRapa treatment will be the same as aim 1, and the same assessments of spontaneous tumor development (with and without eRapa treatments), growth and conversion to malignancy will be determined, including comprehensive responses of mTORC1 and mTORC2 to chronic eRapa. Since our studies have not revealed any detrimental effects of chronic rapamycin treatments, the major impact of our proposed studies, if positive, will shift the paradigm by raising the possibility of a normal life or FAP patients.
The major impact of our proposed work would be a deeper understanding of intestinal cancer development through addiction to increased macromolecular biosynthesis and to develop eRapa as an cancer chemo- delaying agent by down regulation of these systems. As a proof of principle, ours is a viable approach toward realization of Dr. Sporn's vision of a successful cancer chemopreventive, which makes reverting to a normal life a possibility.
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