Discovery and Development of Natural Products for Interception of CRC

Naturally occurring bioactive compounds are extensively studied as anticancer agents, particularly for therapeutic intervention. It is estimated that about 25% of all newly approved anticancer drugs are derived from natural products. Although, several bioactive natural products were studied and proven to be efficacious in preclinical models, their progress to clinic remains elusive due to lack of specificity toward one desired clinically relevant interceptive target(s). Thus, UG3/UH3 RFA “Discovery and Development of Natural Products for Cancer Interception and Prevention” takes the advantage of the world’s largest, most diverse libraries of pre-fractionated natural products from NIH-NCATS resources to screen and identify bioactive fractions which target clinically relevant interception pathways of colorectal cancer (CRC). These targets are microsomal prostaglandin E synthease-1 (mPGES-1), 5-Lipoxygease (5-LOX) and ornithine decarboxylase (ODC). mPGES-1, 5-LOX, and ODC are highly over-expressed in colonic preneoplastic lesions and their metabolites PGE2, 5-HETE/Leukotrienes, and polyamines play a critical role in tumor progression. The rationale to select these clinically relevant targets is based on the fact that, i) there is a lack of highly selective natural agents which target mPGES-1, 5-LOX, and ODC at non-toxic doses; ii) targeting mPGES-1/5-LOX may spare PGI2 (antithrombotic) and avoid cardiovascular risk; and iii) combining inhibitors of PGE2 and polyamines would provide synergistic inhibition of CRC. Based on the above rationale, we propose the following Aims/goals for UG3 and UH3 phases. Goals of UG3: 1. Establish optimal HTS assays for mPGES1, 5-LOX, and ODC using purified proteins and ~1,500 natural product fractions from NCATS; 2. Establish and test secondary assays for selectivity, and activity, using cell-based assays and further validate targets and growth inhibition in organoid assays; and 3. Evaluate the off-targets and cellular toxicites associated with natural product selective inhibitors mPGES-1, 5-LOX, and ODC. Goals of UH3: 1. Conduct full scale evaluation of the Natural Products Libraries in collaboration with NCATS through NCI assistance (350,000 - 500,000 natural product samples/fractions) in HTS as potential cancer interception agents; 2. Isolation and structural elucidation by MicroED of active natural compound(s) based on selective inhibition of mPGES-1, 5-LOX, and ODC. Followed by scaling up of lead molecules; and 3. Determine the Ex-Vivo and In-Vivo inhibitory effect of bioactive natural product compounds on mPGES-1, 5-LOX, ODC and its metabolism and efficacy in CRC interception.