The limitation of present assessment of response to therapy is that patients are treated for 2 months before tumor volumes are measured to reassess effectiveness of the drug. The goal of this research is to develop systems for the rapid assessment of cancer responsiveness and susceptibility to tyrosine kinase inhibitors (TKIs) by use of recombinant peptides that bind to responding cells.
These aims will test the central hypothesis that non-invasive imaging of cancer response can be achieved by use of recombinant peptides selected from a phage-displayed libraries that bind within tumor blood vessels following treatment with TKIs and cytotoxic therapy. PET, SPECT and gamma camera imaging will be used to rapidly monitor the response of cancer to TKIs. One model includes VEGF receptor TKIs that enhance the cytotoxic effects of radiation in the tumor microvasculature. This results in apoptosis of the tumor endothelium and subsequent activation of inflammation and thrombotic cascades. Our preliminary data indicates that VEGF receptor TKIs enhance the effects of radiation within tumor microvasculature resulting in improved tumor control. Cancer susceptibility to TKIs has been evaluated primarily by tumor tissue sectioning and staining. This pharmacodynamic approach is not entirely feasible in patients with brain tumors and lung cancer primaries. For that reason, we have developed the hypotheses that recombinant peptides from phage-displayed peptide libraries can be selected that bind to apoptotic endothelium and to receptors activated in response to therapy. These peptides in turn can be labeled with internal emitters to provide a means of non-invasive monitoring of responsiveness to therapy. The physiologic response to therapy is seen within 24 hours of therapy, which provides a rapid assessment using non-invasive means. We utilized phage displayed peptide libraries to select peptides that bind within treated tumor blood vessels. We will study these peptides with the intention of monitoring tumor blood vessel response during therapy with RTK inhibitors and radiation. We hypothesize that recombinant peptides will bind to cells undergoing apoptosis and provide a means to non-invasively assess cancer response to TKI therapy. The studies of the RGD peptide pneumatic imaging of tumor vasculature response has shown that this simple amino acid sequence binds to activated receptor that is non-specific and achieves binding to other tissues in addition to tumor [Hallahan, 2001]. For that reason, we have developed recombinant peptide that binds more specifically to irradiated tumor blood vessels. In the present investigation, we will test the hypothesis that these recombinant peptides bind selectively to microvasculature of treated tumors.
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