(418f) Targeted Therapies to Treat Neuroendocrine Tumors

Neuroendocrine tumors (NETs), such as carcinoids, pancreatic islet cell tumors and medullary thyroid cancers, mostly metastasize at the time of being diagnosed. In addition to surgery, several chemotherapies (etoposide, everolimus, octreotide) and radio­pharma­ceutical Lutathera that combines endoradiotherapy and diagnostic partner have been developed, but their therapeutic efficacies are limited on rapidly proliferating NETs. This study aims to develop a powerful targeted therapy to treat highly aggressive NETs. Clinical data and our patient tissue microarray showed somatostatin receptor 2 (SSTR2) is overexpressed in the surface of over 70% NET patients. We used hybridoma technology to develop murine anti-mouse SSTR2 monoclonal antibody (mAb) and constructed chimeric mAb with high circulation stability and half-life. The SSTR2 mAb was used to construct two targeted therapies for SSTR2⁺ NET treatment: 1) antibody-drug conjugate (ADC) by conjugating mAb with potent payload MMAE and DM1, and 2) mAb surface tagged exosomes (mAb-Exo) to deliver combined thermotherapies (DM1 and Ver-A). Their NET specific targeting was confirmed with flow cytometry, confocal microscope and In Vivo Imaging System. The in vitro anti-cancer cytotoxicity assay showed IC₅₀ values of 2-5 nM and in vivo studies demonstrated high tumor specificity and serum stability, minimal toxicity, and high anti-tumor efficacy (significantly reduced tumor growth) of the developed therapies in human NET xenografted mouse models. This study suggested that our SSTR2 mAb-based targeted therapies could provide an efficient strategy for NETs treatment.