Abstract 4293: Development of SSTR2-peptide conjugated exatecan for therapy of advanced GEP-NENs

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Abstract Gastro-enteropancreatic neuroendocrine neoplasms (GEP-NENs) are a diverse family of tumors which can originate throughout the gastrointestinal tract. Despite a designation as a rare cancer, the incidence of GEP-NENs has increased over the last few decades. There has been difficulty in developing new therapies due to a lack of targetable mutations present in these tumors. One potential target is somatostatin receptor 2 (SSTR2), which is expressed in many of these cancers. Somatostatin analogues and peptide-targeted radiotherapies have been developed to target these tumors, but treatment acquired resistance is common and SSTR2 expression is often lost during progression from less aggressive, lower grade tumors towards more aggressive, higher-grade tumors. Due to this, additional therapies are needed to target these tumors to improve patient outcomes. To address this gap, we conducted a high-throughput screen of high grade pancreatic NEN cell lines BON-1 and QGP-1 to identify potentially therapeutic small molecules using the MIPE 5.0 library at the National Center for Advancing Translational Sciences (NCATS). The top 20 molecules from classes including proteosome inhibitors, BRAF/MEK inhibitors, NAMPT inhibitors, and topoisomerase inhibitors were further selected for repeat screening with the addition of two well-differentiated cell lines NT-18P and NT-3 and GEP-NEN patient tumor organoids (PTO, n=51 tumors). Results from these screens, comparison of targets to known mutation profiles of high-throughput models, and analysis of current conjugation methods were used to select exatecan, a topoisomerase 1 inhibitor, for usage as a payload for a conjugated therapy. Exatecan showed high statistically significant cytotoxicity with PTO grade (grade 1 IC50 average=331 nM, 206 nM for grade 2, 90 nM for grade 3, p=0.01), but not with origin (pancreatic NEN IC50=157 nM vs small bowel NEN=356 nM, p=0.10). Exatecan and its derivative deruxatecan has already been incorporated into the treatment paradigm for HER2+ breast cancer. In partnership with the Chemical Synthesis Center at the National Institute of Health, click chemistry to incorporate cleavable crosslinkers was used to create three SSTR2-targeted drug conjugates based on octreatate. Finally, each of the compounds were shown to effectively target cell lines with SSTR2 expression, while cell lines with no SSTR2 expression demonstrated significantly lower sensitivity towards the compounds. In conclusion, we have created a series of compounds which demonstrate optimal chemical characteristics and promising targeting of SSTR2+ GEP-NENs. Next steps include the analysis of binding affinity for SSTR2, as well as stability testing for usage as a therapy and the incorporation of SSTR2+ xenograft models for treatment efficacy. Citation Format: Steven Donald Forsythe, Srujana V. Yellapragada, Tracey Pu, Ken C. Cheng, Freddy E. Escorcia, Rolf E. Swenson, James P. Madigan, Samira M. Sadowski. Development of SSTR2-peptide conjugated exatecan for therapy of advanced GEP-NENs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4293.

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