Abstract 2950: Targeting chemo-resistant colon cancer by inhibiting embryonic resistance pathways

Colorectal cancer (CRC), with an estimated 2.1 million worldwide new cases, and 610,000 deaths in 2014, is the second-leading cause of cancer death in developed countries. While early detection (e.g., via colonoscopy, occult fecal blood tests) or prevention (removal of premalignant polyps) generally allows complete disease elimination, metastatic and drug-resistant disease is uniformly fatal. Even so FDA-approved, life-extending CRC chemotherapies such as camptothecin-derived alkaloidal quinolones (e.g., irinotecin, topotecin) have demonstrated potent inhibition of the DNA synthesis enzyme topoisomerase-1, although the use of these drugs is limited due to specific adverse effects and resistance mediated by ATP-dependent membrane transporters. Consequently, to improve the efficacy (e.g., specificity, attenated toxicity, chemosensitivity, etc.) of these topoisomerase inhibitors, we designed and synthesized (based on structure-activity relationships, molecular docking, and in silico studies) eight distinct analogues, based on a pyrimido[1,2:1,5]-pyrazolo[3,4-b]quinoline (PPQ) (“IND-2”) structure. One of these, “IND-2,” demonstrated robust anticancer efficacy, selectivity to colon cancer cells, negligible toxicity to normal cells, high water-solubility, and absent cellular efflux via multidrug transporters, but remained vulnerable to metabolic inactivation and poor bioavailability. Resultantly, based on our preliminary microarray and bioinformatics analyses of over 47,000 genes, and our findings of IND-2-facilitated transcriptional downregulation of several gene members of the embryonic WNT/EMT signaling axis, we further bioinformatically optimized and synthesized 14 IND-2 derivatives that we herein set forth to characterize in in vitro and in vivo CRC models, specifically assessing the abovementioned vulnerabilities. We hypothesize that embryonic signal pathways (e.g., WNT-β catenin, EMT, etc.) play an important role in colorectal tumorigenesis and can be successfully targeted for the development of safe and efficacious drugs for eventual human CRC treatment. Presently, we are assessing these analogs in numerous normal and cancerous CRC cell lines, to select the most promising of these candidates (based on efficacy and selectivity) for scaled-up synthesis and extensive in vivo testing, using the highly aggressive mouse APC/Min/+ CRC model. We strongly believe that the proposed work will validate embryonic signal cascades as targetable pathways that could lead