ABSTRACT
Neuroendocrine (NE) cancers such as carcinoids, pancreatic islet cell tumors, and medullary thyroid cancer
(MTC) frequently metastasize to the liver. Despite various complex management strategies for NE liver
metastases, surgery is the only treatment that offers potential for cure. There is a critical need to develop new
therapeutic options to reduce NE cancer progression and excessive hormone secretion. Recently, we have
developed a new monoclonal antibody (mAb) that selectively targets the NE cancers’ epitope - somatostatin
receptor 2 (SSRT2), generated mAb tagged exosomes (mAb-Exo) as a delivery vehicle, and identified in the
high-throughput screening a natural compound originating from marine sponges (Verrucarin A, VC-A) capable
of inhibiting NE cancer cell proliferation and altering malignant phenotype. The preliminary studies using NE
cancer cell lines and human xenografts indicated that our anti-SSTR2 mAb can effectively and specifically bind
to NE cancer and the conjugation of SSTR2 mAb with the drug delivery vehicle – exosomes, did not change the
targeting efficacy. Moreover, we have shown that VC-A is capable to induce the apoptotic response in NE cancer
cells in low nanomolar concentrations. To achieve high therapeutic efficacy, we propose to further investigate
the antitumor properties of VC-A, delineate the mechanisms of prosurvival pathways inhibition, and formulate
the drug in exosomes which are equipped with our anti-SSTR2 mAb. Such anti-SSTR2 mAb-Exo-VC-A
therapeutic can selectively deliver the lethal agent to NE tumor cells and minimize side effects to patients. Both
the in vitro NE cancer cell lines and the in vivo preclinical mouse model of NE tumor liver metastases will be
used to evaluate the biodistribution, tolerated doses, pharmacokinetics, and antitumor efficacy of the targeting
delivered VC-A. If the anticancer efficacy will be confirmed in the preclinical model, this will be the first exosomes-
facilitated targeted therapy for NE cancers.