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

Tracey L. Smith, Ziqiang Yuan, Marina Cardó-Vila, Carmen Sanchez Claros, Asha Adem, Min-Hui Cui, Craig A. Branch, Juri G. Gelovani, Steven K. Libutti, Richard L. Sidman, Renata Pasqualini, Wadih Arap

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2466-2471
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number9
DOIs
StatePublished - Mar 1 2016

Fingerprint

Dependovirus
Octreotide
Neuroendocrine Tumors
Transgenes
Bacteriophages
Pancreas
Ligands
Tumor Necrosis Factor-alpha
Neoplasms
Therapeutics
Insulin
Neuroendocrine Cells
Somatostatin Receptors
Peptides
Somatostatin
Tumor Suppressor Genes
Virion
Transgenic Mice
Apoptosis

Keywords

  • AAVP
  • Neuroendocrine tumor
  • Pancreas
  • Phage display
  • Preclinical study

ASJC Scopus subject areas

  • General

Cite this

AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas. / Smith, Tracey L.; Yuan, Ziqiang; Cardó-Vila, Marina; Claros, Carmen Sanchez; Adem, Asha; Cui, Min-Hui; Branch, Craig A.; Gelovani, Juri G.; Libutti, Steven K.; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 9, 01.03.2016, p. 2466-2471.

Research output: Contribution to journalArticle

Smith, Tracey L. ; Yuan, Ziqiang ; Cardó-Vila, Marina ; Claros, Carmen Sanchez ; Adem, Asha ; Cui, Min-Hui ; Branch, Craig A. ; Gelovani, Juri G. ; Libutti, Steven K. ; Sidman, Richard L. ; Pasqualini, Renata ; Arap, Wadih. / AAVP displaying octreotide for ligand-directed therapeutic transgene delivery in neuroendocrine tumors of the pancreas. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 9. pp. 2466-2471.
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AU - Smith, Tracey L.

AU - Yuan, Ziqiang

AU - Cardó-Vila, Marina

AU - Claros, Carmen Sanchez

AU - Adem, Asha

AU - Cui, Min-Hui

AU - Branch, Craig A.

AU - Gelovani, Juri G.

AU - Libutti, Steven K.

AU - Sidman, Richard L.

AU - Pasqualini, Renata

AU - Arap, Wadih

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