Patched targeting peptides for imaging and treatment of hedgehog positive breast tumors.

Daniel Smith,Fanlin Kong,Wendy A Woodward,David Yang,Richard Larson,Jennifer Sims-Mourtada

doi:10.1155/2014/525680

Abstract

High tumor hedgehog expression is correlated with poor prognosis in invasive ductal carcinoma. Peptides which bind the patched receptor have recently been reported to have a growth inhibitory effect in tumors with activated hedgehog signaling. We sought to examine growth inhibition with these peptides in breast cancer cells and use these peptides as molecular imaging probes to follow changes in hedgehog expression after chemotherapy. Significant growth inhibition was observed in breast cancer cell lines treated with PTCH-blocking peptides. Significant in vitro uptake was observed with both FITC- and 99mTc-EC-peptide conjugates. In vivo imaging studies displayed greater accumulation of 99mTc-labeled peptides within tumors as compared to adjacent muscle tissue. Patched receptor expression increased after treatment and this correlated with an increase in tumor radiotracer uptake. These studies suggest that peptides which bind the sonic hedgehog docking site in patched receptor correlate with patched expression and can be used to image patched in vivo. Further, our data suggest that radiolabeled peptides may enable us to examine the activity of the hedgehog signaling pathway and to evaluate response to anti-cancer therapies.

Highlights

The hedgehog (Hh) signaling pathway plays a critical role in embryonic development and wound healing, and its aberrant activity is associated with several malignancies
Recent studies implicate Hh signaling in breast cancer growth and metastasis, and high tumor sonic hedgehog (SHh) expression is correlated with poor prognosis in invasive ductal carcinoma
We show that in vivo imaging with 99mTc-PTCH peptides may offer an alternative method to follow treatment response and allow for tumor-specific imaging prior to and immediately after chemotherapy treatment

Summary

Introduction

The hedgehog (Hh) signaling pathway plays a critical role in embryonic development and wound healing, and its aberrant activity is associated with several malignancies. We demonstrated strong detection of tumor xenografts using an iodinated derivative of the PTCH-1 binding ligand, sonic hedgehog [1]. This agent was capable of delineating tumor tissue, its clinical utility is limited due to poor stability and pharmacokinetics. Imaging with radiolabeled peptides has been shown to improve pharmacokinetics and the targeting of other tumor-based receptors. Nakamura et al previously reported the synthesis of several peptides targeting the PTCH-1 receptor [2]. These peptides were shown to bind to the PTCH-1 receptor on the surface of pancreatic tumors and decrease tumor growth

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