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Harnessing Hsp90 tumor biology in the development of novel PET tracers
Hsp90 is a molecular chaperone with important roles in maintaining malignant transformation and there is currently increasing interest to develop inhibitors of its function as cancer therapeutics. We have pioneered the discovery of synthetic small-molecule Hsp90 inhibitors, the purine-scaffold (PU) agents, whose representative CNF2024 is currently in Phase I clinical evaluation in patients with advanced cancers. When administered in vivo, these PU-agents preferentially bind tumor Hsp90 and accumulate in viable tumor mass while being rapidly cleared from blood and normal tissue. We hypothesize that such characteristics make them ideal positron emission tomography (PET) imaging agents for breast cancer and propose here to develop them for such use. In Aim1 we propose to chemically tailor them for imaging by increasing their affinity for tumor Hsp90. The crystal structure of a PU in complex with Hsp90 will be used to guide further chemical modifications. All designed agents will be computationally analyzed to predict favorable pharmacologic features. Compounds generated in Aim1 will be analyzed in Aim2 for their affinity and specificity for MDA-MB-231 cell-specific Hsp90. For this purpose we will use a fluorescence polarization assay developed by our laboratory to assess binding of inhibitors to cell-specific Hsp90. Ten most promising agents will be further evaluated for their suitability to generate new radioligands by assessing their ability to compete 131I-PU/MDA-MD-231 tumor Hsp90 binding. In Aim3, selected five best candidates will be used to generate SnMe3 precursors for iodo-radiolabeling. These precursors will be 124/131I-labeled by our collaborators, Drs. Larson and Smith-Jones and their biodistribution and ability to image metastasis evaluated in a MDA-MB-231 derived metastatic breast cancer mouse model. We propose several important clinical applications for these agents. First, these novel PET imaging technologies could significantly accelerate the development of novel Hsp90 inhibitors by reducing the number of patients needed to identify the optimal dose and schedule for use in phase II and III studies. These agents would be useful for the screening of patients who might best benefit from Hsp90-targeted therapy, for monitoring tumor accessibility to the Hsp90 inhibitor and not lastly, tumor responsiveness to these inhibitors during clinical trials. Second, due to preferential uptake in viable tumor mass, these PET tracers may be useful tools in differentiating viable from necrotic tumor mass before, during and at the end of treatment. Third, these agents are not P-glycoprotein (P-gp) substrates and we envision their use in imaging metastasis, including at organs protected by P-gp such as the brain. Thus this work will introduce to clinic novel imaging agents that may have a major impact in the development of agents towards successful therapies in breast cancer.
Molecular imaging of breast cancer continues to rapidly expand and promises earlier diagnosis and better management of metastatic breast cancer patients. A highly sensitive non-invasive technology that is ideally suited for clinical imaging of cancer biology is positron emission tomography (PET). By using radiolabelled tracers, which are injected in very low non-pharmacological doses, three-dimensional images can be reconstructed by a computer to show the concentration and location(s) of the tracer of interest, and concordantly of the tumors, without exposing the patient to unnecessary radiation such as in the case of CT. Finding an appropriate imaging agent for selective functional and dimensional imaging of tumors is however not an easy task. The agent must concentrate only in tumors, and it must clear rapidly from the blood and normal tissue, so that a high contrast can be obtained between the tumor and surrounding tissues. To resolve these issues we propose here to take advantage of the specific biology of Hsp90, a protein abundantly expressed in breast cancer cells. For this purpose we have developed small molecules that bind to Hsp90 and are selectively retained in viable tumor mass while rapidly cleared from blood and normal tissues. We propose that such agents will have several clinical applications in breast cancer. First, they will help the physician determine whether a tumor is responsive to chemotherapy long before anatomical imaging such as CT scan shows any change. This will allow a timely change in treatment and thus increase the probability of finding an efficacious therapy. Second, these agents are not P-glycoprotein (P-gp) substrates and we envision their use in imaging brain metastasis, frequently found in breast cancer. Third, Hsp90 inhibitors themselves, such as 17AAG, are in clinic in the treatment of patients with advanced cancers. At MSKCC, HER2 positive patients who progressed after several trastuzumab-containing combinations responded to 17AAG treatment. Improved inhibitors such as CNF2024, an orally available Hsp90 inhibitor developed by the efforts of our laboratory and those of Conforma Therapeutics have recently also entered Phase I clinical evaluation. Our novel PET imaging technologies could significantly accelerate the development of these drugs by reducing the number of patients needed to identify the optimal dose and schedule for use in phase II and III studies. These agents would be useful for the screening of patients who might best benefit from Hsp90-targeted therapy, for monitoring tumor accessibility to the Hsp90 inhibitor and not lastly, tumor responsiveness to these inhibitors during clinical trials. In conclusion, our proposed imaging agents represent much needed tools in the management of metastatic breast cancer patients that also promise to facilitate and accelerate the rational clinical development of Hsp90 inhibitors.