Patients with chronic inflammatory bowel diseases (IBD) affecting the colon have increased risk for colorectal cancer (CRC), accounting for nearly 10-15% of deaths in IBD patients. CRC developed as a consequence of chronic colonic inflammation is referred to as colitis-associated cancer (CAC). Due to the well-established association of chronic inflammation with CRC development, the use of anti-inflammatory agents to impede carcinogenesis is considered an effective strategy for CRC chemoprevention. In search of a novel anti- inflammatory agent to prevent CAC, I utilized FL3, a novel compound synthetically produced from natural compounds named flavaglines found in medicinal Aglaia plants. My preliminary data demonstrate that FL3 reduces tumor development in a mouse model of CAC. FL3 treatment of 3D cultures of tumors (tumoroids) from these mice increased tumor cell death and induced genes that inhibit the Wnt/?-catenin pathway, a pathway that is commonly activated in intestinal tumors. Based on these data, the hypothesis for the proposed study is that FL3 exhibits anti-cancer properties in the intestine via inhibition of Wnt/?-catenin signaling.
Specific aims are: 1) determine whether FL3 alters oncogenic properties via inhibition of Wnt/?-catenin signaling in CRC cell lines and tumoroids carrying activating mutations in the Wnt/?-catenin pathway, 2) determine whether FL3 alters oncogenic properties via inhibition of Wnt/?-catenin signaling in vivo in the APCMin/+ mouse model. Recently, NIH expressed interest in early phase clinical trials of natural products, which have a specific mechanism of action as shown in preclinical studies. My approach will elucidate FL3?s ability to combat tumorigenesis in preclinical models via the specific mechanism of enhanced ?-catenin inactivation and degradation through induction of Axin1. Results from these studies are intended to provide information to accelerate the translation of preclinical findings about FL3 into early stage clinical testing, which is of intense interest to NIH.
FL3, a synthetic compound belonging to the flavagline family which is found in medicinal Aglaia plants, exhibits anti-tumorigenic potency in the intestine. The proposed experiments aim to determine the therapeutic response and mechanism of FL3 in prevention of intestinal tumorigenesis. Understanding FL3 effects on intestinal tumor development will offer a strong pre-clinical justification for FL3 to be examined in colorectal cancer clinical studies.
