The goal of this proposal is to develop 15-PGDH, and/or its partner genes in the pathways that regulate PGE2 degradation and PGE2 synthesis, as a powerful biomarker for reducing deaths from colorectal cancer (CRC), by enabling personalized strategies to improve risk-based screening and to improve aspirin chemoprevention. Groundbreaking studies from my group have shown that 15-PGDH is a colon cancer suppressor that, by mediating degradation of PGE2, acts as a metabolic suppressor of the oncogenic activity of COX-2. In studies published in Science, we have moreover shown that 15-PGDH acts in the colon, and in other organs, as a negative regulator of the proliferative response of stem like cells to tissue injury. We furthermore have shown that colon 15-PGDH levels vary by 12-fold over the human population, and, in genetics studies, have indirectly linked 15-PGDH deficiency (or deficiency of PGT, a gene that partners with 15-PGDH in the pathway of PGE2 degradation) with increased human risk of CRC.
Our first aim i s to now directly test colon 15-PGDH as a biomarker for recognizing humans at high CRC risk, who thus need more intensive CRC screening, and to then test our hypothesis that an integrated analysis of expression of the 6 genes that partner with 15-PGDH to mediate PGE2 degradation and synthesis (i.e. a genetic signature of inferred PGE2) will be an even stronger predictor of individuals at high CRC risk. Moreover, in landmark studies, published in Science Translational Medicine, we have shown that 15-PGDH is also determinative of individuals in whom using aspirin prevents CRC, with aspirin only effective in lowering CRC risk in individuals who have high colon 15-PGDH, and ineffective in individuals who have low colon 15-PGDH levels (i.e. effective CRC prevention requires the synergistic activity in lowering PGE2 of a COX inhibitor (aspirin) acting together with high colon 15-PGDH).
Our second aim i s to now provide a practice changing clinical replication of colon 15-PGDH as a biomarker of sensitivity versus resistance to aspirin chemoprevention in a new, larger, human validation population, and further, to test our hypothesis that the 6- gene signature of inferred PGE2 will be an even stronger predictor for recognizing individuals who will benefit from using aspirin to reduce CRC risk. Last, in studies published the Journal of Clinical Investigation, we have shown that inflammatory pathways potently suppress colon 15-PGDH expression.
Our third aim now tests the hypotheses that i) lifestyle factors that are linked to both CRC risk and to inflammatory tone (e.g. obesity, lack of exercise, and dietary red meat) act by regulating 15-PGDH and its 6 partner genes of the inferred PGE2 signature; and ii) that modifying these lifestyle factors can shift the signature of inferred PGE2 toward a profile predictive of greater aspirin sensitivity. We interrogate this hypothesis by i) testing for association of lifestyle factors to human colon expression of 15-PGDH and the signature of inferred PGE2, and ii) functional testing in mouse models for these factors ability to: iia) alter gene expression (inferred PGE2), iib) alter colon PGE2, and iic) potentiate NSAID's activity in lowering colon PGE2.
Colorectal cancer (CRC) is the second leading cause of cancer death in America. Our team has discovered 15- PGDH is a colon cancer suppressor gene, which acts by targeting the same pathway of inflammation as aspirin. This proposal will perform definitive clinical studies to test our initial pilot findings that individuals with low levels of colon 15-PGDH are: i) a population with high colorectal cancer risk; ii) a population that are resistant to aspirin for CRC prevention (i.e. that high colon 15-PGDH is a predictive marker for identifying those who can reduce their CRC risk by using aspirin). Moreover, in both humans and mice, we test the ability to increase colon 15- PGDH (and thus increase sensitivity to aspirin like drugs) by anti-cancer strategies that reduce inflammatory tone, including: weight loss, exercise, and avoidance of red meat.
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