Abstract 942: Target validation and high-throughput screening assay development for natural product discovery for cancer prevention and interception

Le résumé fourni par la source

Abstract Background Natural products (NPs) represent a rich source of bioactive compounds with cancer prevention/interception potential. NPs offer unique chemical diversity and a history of safe human use, making them attractive candidates for long-term use. High-throughput screening and mechanistic studies are key to discovering promising leads and translating them into effective and safe cancer prevention and interception strategies. To support the Discovery and Development of Natural Products for Cancer Interception and Prevention (DDNP-CIP) Initiative, we aimed to validate potentially clinically relevant molecular targets (SKP2, TEAD2, 5-LOX and RUNX1) and establish and optimize assays to enable high-throughput NPs library screening for cancer prevention. Methods Target validation was performed using tissue microarrays. SKP2, a component of the SKP2-SCF E3 ligase complex, and TEAD2, a DNA-binding transcription factor, were evaluated for their expression levels in TMAs of prostate and liver cancer, respectively. In addition, cell-based platforms were developed or adapted to identify NPs exhibiting immune-modulating activity or targeting either 5-LOX, a lipid-peroxidizing enzyme, or RUNX1, a transcription factor critical for hematopoietic differentiation and frequently mutated in hematologic malignancies. These assays utilized stably expressing reporter cell lines. Results SKP2 was significantly over expressed in 68.6% of prostate hyperplasia, 97.6% of prostate intraepithelial neoplasia, and 81.9% of adenocarcinoma compared with normal tissue. TEAD2 was highly expressed in liver hyperplasia and significantly upregulated in hepatitis (p = 0.0041), hepatocellular carcinoma (p = 0.0012), and intrahepatic cholangiocarcinoma (p < 0.0001). To identify NPs with immune-modulating activity, an assay using the THP-1 ISRE FRET reporter cell line was adapted and optimized. Reference compounds and initial challenge plates were tested, with several samples eliciting positive responses. A cell line expressing 5-LOX was generated and validated. An inhibition assay using a positive compound nordihydroguaiaretic acid demonstrated dose-dependent inhibition (29% at 0.1uM to 92% at 1uM) upon arachidonic acid treatment without toxicity. To screen NPs for splicing modulating activity, nano-luciferase reporter cell lines with RUNX1 mutations identified in patients with familial platelet disorder with associated myeloid malignancy were generated. Several reference compounds showed positive responses in selected mutations. Summary Validated targets and assay platforms establish a foundation for high-throughput NPs screening. These efforts advance the DDNP-CIP’s mission to identify and develop NPs for cancer prevention and interception. Funded partly by the National Cancer Institute under Contract No. HHSN261201500003I Citation Format: Yurong Song, Brandon Somerville, Kajal Biswas, Karim Baktiar, Liankun Song, Sara Sanders, Tanja Grkovic, Ligia A. Pinto, Ana Catarina Menezes, Paul P. Liu, Matthew J. Hart, Chinthalapally V. Rao, Shugeng Cao, Xin Chen, Xu Wu, Xiaolin Zi, Mark J. Henderson, Barry R. O'Keefe, Altaf Mohammed, Robert H. Shoemaker. Target validation and high-throughput screening assay development for natural product discovery for cancer prevention and interception [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 942.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.