Project 4 is dedicated to the development of methods for imaging the in vivo effects of selective inhibitors of components of activated signal transduction pathways in cancer and the translation of these methods to the clinic. A major obstacle to the implementation of targeted therapy is the inability to determine the pharmacodynamics and biologic effects of the drug in the tumor, quantitatively and as a function of time. We have developed a method for the imaging of the pharmacodynamics of Hsp90 inhibitors, drugs that induce the degradation of various oncoproteins including HER2. We constructed an F(ab')2 fragment of trastuzamab chelated to positron emitting isotopes such as 68Ga. This reagent allowed the quantitative imaging in tumor xenografts of the loss of HER2 expression in animals treated with the HspQO inhibitor 17- AAG. We now propose to use this reagent to determine the pharmacodynamic effects of 17-AAG and other HspQO inhibitors in clinical trials and to plan combination trials with this drug based on these pharmacodynamic data. This method provides a platform for imaging the effects of other drugs. This will comprise identifying proteins with extracellular domains, the expression of which changes rapidly in cells treated with the targeted drug, developing an antibody, peptide or other molecule that binds selectively and tightly to this protein and chelating the binding molecule to an imageable isotope. We propose to test this concept by attempting to develop reagents for imaging the effects of selective inhibitors of the MEK and mTOR kinases. This technology allows us to correlate the pharmacodynamics of the drug with the biologic consequences of target inhibition. We propose to use imaging to correlate, as a function of time, changes in HER2 expression with changes in tumor metabolism (FDG PET, choline NMR) and inhibition of DMA synthesis (FLT PET). Inhibition of certain targets may have specific, profound cellular effects. Using traditional techniques, we have determined that MEK kinase inhibitors inhibit tumors with BRAF mutation selectively and potently and that inhibition is associated with completed arrest. We have imaged this effect with FLT PET and are now planning to incorporate this method into Phase 2 trials of the inhibitor. The broad, long-term focus of the work is the use of this technology to probe the biologic effects of pathway inhibitors and to accelerate their clinical translation.
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