AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas

Abstract

Patients with inoperable or unresectable pancreatic neuroendocrine tumors (NETs) have limited treatment options. These rare human tumors often express somatostatin receptors (SSTRs) and thus are clinically responsive to certain relatively stable somatostatin analogs, such as octreotide. Unfortunately, however, this tumor response is generally short-lived. Here we designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide on the viral surface for ligand-directed delivery, cell internalization, and transduction of an apoptosis-promoting tumor necrosis factor (TNF) transgene specifically to NETs. These functional attributes of AAVP-TNF particles displaying the octreotide peptide motif (termed Oct-AAVP-TNF) were confirmed in vitro, in SSTR type 2-expressing NET cells, and in vivo using cohorts of pancreatic NET-bearing Men1 tumor-suppressor gene KO mice, a transgenic model of functioning (i.e., insulin-secreting) tumors that genetically and clinically recapitulates the human disease. Finally, preclinical imaging and therapeutic experiments with pancreatic NET-bearing mice demonstrated that Oct-AAVP-TNF lowered tumor metabolism and insulin secretion, reduced tumor size, and improved mouse survival. Taken together, these proof-of-concept results establish Oct-AAVP-TNF as a strong therapeutic candidate for patients with NETs of the pancreas. More broadly, the demonstration that a known, short, biologically active motif can direct tumor targeting and receptor-mediated internalization of AAVP particles may streamline the potential utility of myriad other short peptide motifs and provide a blueprint for therapeutic applications in a variety of cancers and perhaps many nonmalignant diseases as well.

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

“…In particular, given that IBC is often misdiagnosed because of its atypical disease presentation and/or is understaged because of the early onset of micrometastasis before distant disease can be documented (4,5), an effective molecular methodology for early tumor detection, staging, and serial monitoring of response and local or distant disease recurrence clearly remains an unmet medical need. Attesting to its inherent versatility, ligand-directed AAVPbased delivery of transgenes in preclinical settings has been demonstrated successfully in xenograft and transgenic models of soft-tissue sarcomas (10), glioblastomas (11), and neuroendocrine pancreatic tumors (12), in addition to the original new technology report in breast and prostate cancer in tumor-bearing mice a decade ago (9,19). Notably, one also could speculate that the described ligand-directed theranostic approach introduced here could also be used to determine the precise location of a lesion intraoperatively and/or to integrate the administration of tumor-directed treatments based on the recent report of an enabling AAVP-based nanotechnology platform (46).…”

“…We previously have developed targeted hybrids of adenoassociated virus and phage particles (AAVP), functional vectors that enable synchronous ligand-directed and transcriptional delivery of transgenes (9). In the decade since their introduction, we have validated the delivery of therapeutic genes via peptide-directed AAVP vectors to xenograft and transgenic models of tumors such as softtissue sarcomas (10), glioblastomas (11), pancreatic neuroendocrine tumors (12), and even to dogs with various native tumors (13).…”

Gene delivery by peptide-assisted transport

“…A total of 118 peptide-binding GPCRs have been identified and hence peptides mimicking their natural agonists or antagonists can be used for targeting the orthosteric binding site of the receptor for cargo delivery. For example, a group of researchers designed a hybrid adeno-associated virus and phage (AAVP) vector displaying biologically active octreotide (Oct) for ligand-directed gene delivery of tumor necrosis factor (TNF) [35]. Oct can emulate the specific binding to somatostatin receptor 2 (SSTR2) in pancreatic neuroendocrine tumor (NET) cells to enhance uptake.…”

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

“…Ligand-directed AAVP particles have been successfully evaluated in several preclinical transgenic and xenograft tumor-bearing mouse models, including carcinomas of the breast and prostate (22), soft-tissue sarcomas (26), and glioblastomas (27). Moreover, AAVP-mediated tumor vascular delivery of TNF has proven efficacy in human melanoma xenografts (28) and pancreatic neuroendocrine transgenic tumors (29), as well as in native tumors in dogs (30). Here we investigated the GRP78-targeting properties of SNTRVAP (10), exploiting its specific binding to cell surface GRP78 for tumor targeting in the MDA-PCa-118b PDX.…”