Noninvasive Assessment of Cancer Responsiveness to Therapy by use of .....

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Central Hypothesis: These aims will test the hypothesis that non-invasive imaging of cancer response can be achieved by use of recombinant peptides selected from phage-displayed libraries that bind within tumor blood vessels following treatment with tyrosine kinase inhibitors (TKIs). GOAL: The goal of this research is to assess cancer response to molecular targeted therapy by use recombinant peptides that bind to responding cancers. Specific kinase inhibitors, including receptor tyrosine kinase (RTKs) antagonists, are effective as single agents and enhance the cytotoxic effects of radiation and chemotherapy. RTK inhibitors interrupt signal transduction which is required for cell viability and thereby improve cancer susceptibility to cytotoxic therapy (Geng et al., 2001; Schueneman et al., 2003). RTK inhibitors have now been approved for many neoplastic diseases including renal cell carcinoma and gastrointestinal stromal tumors. Presently, cancer response is measured by the assessment of tumor volumes or by repeated biopsy to analyze pharmacodynamics. These methods of monitoring cancer response are inefficient because volume changes typically require therapy for prolonged time intervals. Neoplasms within the brain, lung or abdomen are not amenable to sequential biopsies. Furthermore, biopsies can result in sampling error so that the response to therapy is not accurately assessed. One other consideration is the re-evaluation of the development of resistance in cancer as resistant cells repopulate a neoplasm. Although peptide ligands such as Annexin V have been used to assess apoptosis, noninvasive imaging to assess cancer responsiveness to therapy has not developed a useful imaging tool for assessment of cell death. We have therefore utilized phage displayed peptide libraries (over a billion peptide ligands) to select peptides that bind to responding tumors but not to nonresponding tumors. One peptide, HVGGSSV, is effective at assessing cancer response to RTK inhibitors. This peptide maintains selective binding to responding cancers when linked to gamma emitters. We will study the HVGGSSV peptide which rapidly assesses tumor vascular response to VEGF RTK inhibitors. This new paradigm in cancer management promises to improve our ability to tailor therapy specifically to an individual patient in a manner that is more analogous to the management of bacterial pathogens in that susceptibility to therapy can be predetermined. This is platform technology that will prove the principle that peptide biomarkers are effective at rapidly assessing cancer susceptibility to molecular targeted therapy.