Research Project
7748058
DESCRIPTION (provided by applicant): The American Cancer Society estimates that in 2008 there will be more than 1.4 million new cases of cancer in the United States and that it will claim the lives of more than 500,000 Americans. The vast majority of these cases will be solid tumors, and overt metastatic disease will be present in many of these patients over the course of their disease. The expression of distinct proteins on the surface of tumor cells offers the opportunity to diagnose and characterize disease by probing the phenotypic identity and biochemical composition of the tumor. Radioactive molecules that selectively bind to specific tumor cell surface proteins allow the use of noninvasive imaging techniques, such as molecular imaging or nuclear medicine, for detecting the presence and quantity of tumor associated proteins, thereby providing vital information related to the diagnosis and extent of disease, prognosis and therapeutic management options. In addition, as radiopharmaceuticals can be prepared that are not only capable of imaging disease but also delivering a therapeutic radionuclide to the diseased tissue, cancer therapy may be realized. The goal of this proposal is to develop a series of novel techenium-99m (99mTc) based molecular imaging pharmaceuticals that target the cell surface protein, seprase (FAP1) for imaging by single photon emission computed tomography (SPECT). The expression of seprase is normally restricted to fetal mesenchymal tissue and sites of wound healing, but is selectively overexpressed in cancer-associated fibroblasts in greater than 90% of human primary epithelial tumors including breast, lung, colorectal, gastric, cervical and ovarian cancers, making it an attractive target to exploit for noninvasive imaging as well as targeted radiotherapy. Since stromal support, and therefore seprase involvement, is critical to the initiation of metastatic growth, seprase expression will serve as a molecular marker to detect tumor metastases based on a cancer specific biochemical event at an early stage of development. The research plan combines high affinity targeting molecules with the conjugation of a chelator for coordination of a diagnostic or therapeutic radionuclide. Analogs of seprase inhibitors will be synthesized first as non- radiolabeled rhenium complexed molecules and tested to verify binding to seprase in biochemical and cellular assays. Compounds demonstrating high affinity binding to seprase will then be radiolabeled with 99mTc and examined for cell binding, and tumor uptake and retention in mice bearing human cancer xenografts. As seprase is a cell surface protein, the target will be readily accessible, with a straightforward pharmacokinetic analysis. The use of 99mTc will lead to widespread application through kit preparation and the prevalence of SPECT scanners in medical institutions. We believe that the 99mTc labeled seprase radiotracers could be exploited for the diagnosis, staging, prognosis and potential treatment of patients with solid tumors and metastases. PUBLIC HEALTH RELEVANCE: The American Cancer Society estimates that in 2008 there will be more than 1.4 million new cases of cancer in the United States which will claim the lives of more than 500,000 Americans, and the vast majority of these cases will be solid tumors with the presence of overt metastases over the course of their disease. The goal of this proposal is to develop a series of novel imaging radiopharmaceuticals targeting seprase, a protein that is normally restricted to fetal expression and sites of wound healing, but is selectively overexpressed in cancer- associated fibroblasts of greater than 90% of human primary epithelial tumors, making it an attractive target to exploit for noninvasive imaging, as well as targeted radiotherapy. We believe that the seprase radiotracers could be exploited for the diagnosis, staging, prognosis and potential treatment of patients with solid tumors and metastases.
