avb6-directed molecular imaging and therapy

Project: Research projectResearch Project

Description

? DESCRIPTION (provided by applicant): The overall goal of this proposal is to further investigate the integrin subtype ?v?6 as a target for molecular imaging and therapy of cancer. The integrin ?v?6 is an epithelial-specific cell surface receptor that is undetectable in healthy
adult epithelium but is significantly up-regulated in a wide range of epithelial derived cancers. Previously indicated in pancreatic, ovarian, lung and squamous cell carcinoma, most recent reports indicate the expression of ?v?6 also predicts the transition from DCIS to invasive carcinoma in breast cancer, is indicative of a poor outcome for patients with colon cancers, and promotes osteolysis through the up-regulation of MMP2 in prostate cancer. Overall this makes ?v?6 a significant target for both molecular imaging and therapy. We propose a targeted-peptide based approach to develop both novel ?v?6 specific imaging agents and ?v?6 specific therapies. We will use multimerization approaches to further improve target affinity and albumin binding motifs to improve pharmacokinetic properties of our current ?v?6 targeting peptide PEG28-A20FMDV2 (K16R)-PEG28. All compounds will be screened in vitro and in vivo for affinity and selectivity in ELISA and cell binding studies, their serum stability will be assessed,
and the lead compounds taken forward to in vivo imaging studies in tumor-bearing mice based on ?v?6-affinity 1000 fold, ?v?6 (+) cell binding >50% at 1 h and serum stability >95% after 2 h. The lead compounds, based on murine pharmacokinetics and radiolabeling strategies, will also be investigated in nonhuman primates. We will use PEG28-A20FMDV2 (K16R)-PEG28 as a proof of concept delivery vehicle for two therapeutic strategies: i) D (KLAKLAK) 2 (a pro-apoptotic peptide) and, ii) a micelle-based nanocarrier formulation of paclitaxel (PTX). Efficacy will be assessed in vitro in DX3/mTFL/ITGB6 (?v?6-positive) and DX3/mTFL (?v?6-negative) cells prior to in vivo studies in mice. Positron emission tomography (PET) and bioluminescence imaging (BLI) will be used both to track in vivo biodistribution and measure therapeutic efficacy of these targeted therapies. This proposal brings together an interdisciplinary team of investigators with expertise in radiochemistry and molecular imaging (Sutcliffe, PI), biostatistics (Beckett), nonhuman primate imaging (Tarantal), physics and imaging instrumentation (Cherry) and surgical oncology (Bold), with a history of successful collaboration and productive research. This proposal will utilize the state of the art preclinical imaging resources (including nonhuman primate) as well as new radiochemistry and GMP resources to facilitate rapid translation to the clinic.
StatusActive
Effective start/end date12/1/1511/30/19

Funding

  • National Institutes of Health: $461,496.00

Fingerprint

Molecular Imaging
Radiochemistry
Primates
Integrins
Peptides
Therapeutics
Pharmacokinetics
Biostatistics
Neoplasms
Osteolysis
Carcinoma, Intraductal, Noninfiltrating
Physics
Cell Surface Receptors
Micelles
Paclitaxel
Serum
Positron-Emission Tomography
Colonic Neoplasms
Albumins
Squamous Cell Carcinoma

Keywords

  • Medicine(all)