Targeted Treatment of Neuroendocrine Tumors of the Pancreas
Researcher: Renata Pasqualini, PhD Location: MD Anderson Cancer Center State: Texas Year: 2012 Status: Finished
This grant was issued in partnership with American Association for Cancer Research
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To develop components of a virus that will be designed to kill neuroendocrine cancer cells. The virus will be modified to attach to somatostatin receptors on pancreatic neuroendocrine tumor cells, limiting negative effects on healthy tissues.
Verify specific binding and gene delivery to evaluate the targeting properties in a bacteriophage system.
Assess anti-tumor activity of somatostatin peptide-analogue targeted AAVP delivering TNF-α in pancreatic NETs using the MEN1 mouse model.
Cell-surface receptors are optimal targets for exploitation in ligand-directed systems for the targeted delivery of therapeutics to tumors. Here, we introduce a strategy for capitalizing on the overexpression of one such receptor, somatostatin receptor type 2 (SSTR2), in neuroendocrine tumors (NETs) of the pancreas. We will prepare phage-based gene delivery constructs targeted by a somatostatin peptide-analogue known to selectively bind SSTR2 in pancreatic NETs. Our strategy utilizes a hybrid vector with genetic elements from adeno-associated virus (AAV) and an M13-derived phage, called AAVP, displaying somatostatin peptide-analogue to mediate selective internalization of the viral particles after systemic administration. Establishing AAVP for delivery of TNF-a (AAVP-TNF) would provide for the systemic, targeted delivery of an apoptotic agent directly to the vulnerable vasculature of pancreatic NETs with limited toxicity for normal tissues.
Research Progress and Results:
From pnas.org: We have demonstrated that a biologically active peptide can be successfully used as a displayed ligand in either phage or AAVP particles. We chose the peptide motif as a soluble cyclic octapeptide synthesized with natural residues (to enable incorporation of the encoding single-stranded DNA into viral particles), favorable pharmacologic attributes, and a very well established profile and track record for targeted drug delivery to NETs of the pancreas. The framework used here is suitable for a myriad of other known, short, biologically active peptide motifs that could enable in vivo tumor homing and/or receptor binding internalization of targeted AAVP particles to obviate or even eliminate several of the logistic requirements for combinatorial selection and validation from phage libraries in vivo. Click to read the full article.
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