Ligand-Directed Aavp to Deliver A Therapeutic Transgene to Neuroendocrine Tumors of The Pancreas

<p>Human pancreatic neuroendocrine tumors are rare tumors that form in the endocrine pancreas. Patients with these tumors have limited therapeutic options, and curative intervention is limited to surgical resection. These tumors do, however, consistently express somatostatin receptor type 2 (SSTR2) making them vulnerable to somatostatin analogs. Exploiting cell surface receptors overexpressed in tumors is a common avenue for ligand-directed delivery of imaging or therapeutic agents to tumors. In this regard, identification of novel ligand/receptor pairs with combinatorial peptide libraries has produced multiple candidates for clinical translation. Alternatively, here, we introduce a hybrid vector of adeno-associated virus and phage (AAVP) displaying a known, rationally chosen, biologically active peptide for the delivery of tumor necrosis factor (TNF). Our ligand, octreotide, is a somatostatin analog with specific affinity for SSTR2 that is currently used clinically for both imaging studies and the relief of symptoms associated with pancreatic neuroendocrine tumors. When displayed in AAVP, octreotide mediates selective internalization of the viral particles after systemic administration. We validated the internalization and transduction capabilities of the octreotide-targeted AAVP in a neuroendocrine tumor cell line expressing SSTR2. Additionally, we confirmed AAVP homing and TNF expression <em>in vivo</em> in a transgenic mouse model of pancreatic neuroendocrine tumor development that mimics human disease. With further investigation, therapeutic gene delivery using the octreotide/SSTR2 ligand/receptor pair could represent a viable clinical alternative for patients lacking adequate treatment options.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2013

Author dc:creator

• Smith, Tracey L.

Contributors dc:contributor

• Renata Pasqualini, Ph.D.
• Wadih Arap, M.D., Ph.D.
• Oliver Bogler, Ph.D.

• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/375

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1410