Novel Approach To Colorectal Cancer Drug Target Discovery In Human Ffpe Tissue Using The Adaptive Dynamic Artificial Polyligand Targeting System

Identification of novel biomarkers and drug targets for colorectal cancer remains a critically unmet medical need. Target identification has historically been driven by preclinical models which poorly recapitulate the complex biology of human cancers. We describe a unique approach to drug target identification and comprehensive profiling directly in clinical specimens. Using the Adaptive Dynamic Artificial Polyligand Targeting (ADAPT) system, we aimed to identify such disease specific drug targets using a highly complex library of single-stranded oligodeoxynucleotides (ODNs). To generate the library, the ODNs were enriched using FFPE tissue specimens from pathologically determined colorectal cancer (CRC) and counter-selected against normal adjacent tissue (NAT) regions. Once the specificity of the library was verified via differential binding on independent CRC cases, it was used to affinity purify cognate biding partners from 393 CRC FFPE lysates with appropriate representation of cases with either KRAS, NRAS or BRAF mutations. Greater than 700 proteins were identified by mass spectrometry exclusively in the CRC FFPE tissue lysates and not in the NAT FFPE tissue lysates for all 393 CRC cases. Classification of these proteins into the druggable protein classes revealed G-protein coupled receptors, transporters, voltage-gated ion channels, proteases, and protein kinases. In addition, subsequent verification studies confirmed novel candidate cell surface protein targets appropriate for targeting by antibody-drug conjugates (ADC) or other biologic modalities. mRNA expression corresponding to the 700 potential targets was analyzed in over 1600 CRC FFPE tumor samples and \u003e9000 other cancer types as well as in a broad panel of normal tissues by Whole Transcriptome Sequencing (WTS) and immunohistochemistry (IHC). We conclude that the unbiased ADAPT platform provides a robust and novel approach to drug target discovery with highly selective expression profiles directly from FFPE clinical specimens. Citation Format: Stephanie Williams, Chao Sima, Tassilo Hornung, Matthew Rosenow, Teresa Tinder, Varun Maher, Michelle Kassner, Gerri Ortiz, Perrin Mok, Nicholas Helle, Stephen Logie, Heather ONeill, Mark Miglarese, David Spetzler. Novel approach to colorectal cancer drug target discovery in human FFPE tissue using the Adaptive Dynamic Artificial Polyligand Targeting System [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5165.