Project 4 is dedicated to the development of methods for imaging the in vivo effects of selective inhibitors ofcomponents of activated signal transduction pathways in cancer and the translation of these methods to theclinic. A major obstacle to the implementation of targeted therapy is the inability to determine thepharmacodynamics and biologic effects of the drug in the tumor, quantitatively and as a function of time. Wehave developed a method for the imaging of the pharmacodynamics of Hsp90 inhibitors, drugs that inducethe degradation of various oncoproteins including HER2. We constructed an F(ab')2 fragment oftrastuzamab chelated to positron emitting isotopes such as 68Ga. This reagent allowed the quantitativeimaging 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 otherHspQO inhibitors in clinical trials and to plan combination trials with this drug based on thesepharmacodynamic data. This method provides a platform for imaging the effects of other drugs. This willcomprise identifying proteins with extracellular domains, the expression of which changes rapidly in cellstreated with the targeted drug, developing an antibody, peptide or other molecule that binds selectively andtightly to this protein and chelating the binding molecule to an imageable isotope. We propose to test thisconcept by attempting to develop reagents for imaging the effects of selective inhibitors of the MEK andmTOR kinases. This technology allows us to correlate the pharmacodynamics of the drug with the biologicconsequences of target inhibition. We propose to use imaging to correlate, as a function of time, changes inHER2 expression with changes in tumor metabolism (FDG PET, choline NMR) and inhibition of DMAsynthesis (FLT PET). Inhibition of certain targets may have specific, profound cellular effects. Usingtraditional techniques, we have determined that MEK kinase inhibitors inhibit tumors with BRAF mutationselectively and potently and that inhibition is associated with completed arrest. We have imaged thiseffect with FLT PET and are now planning to incorporate this method into Phase 2 trials of the inhibitor. Thebroad, long-term focus of the work is the use of this technology to probe the biologic effects of pathwayinhibitors and to accelerate their clinical translation.
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