Bio Contact Education Research Teaching Clinical CV
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Hyunsuk Shim, Ph.D.

Research Interests

Short Description: Molecular Imaging and Drug Discovery

Long Description: The chemokine receptor, CXCR4 is one of critical factors for breast cancer metastasis by interacting with its ligand, stromal cell derived factor 1 (SDF-1). SDF-1 is expressed in destinations of breast cancer metastasis, including lymph node, lung, liver, and bone marrow. CXCR4 expression is low in normal breast tissues and high in malignant tumors. Dr. Shims laboratory developed CXCR4 antagonist, which inhibits CXCR4/SDF-1 mediated invasion with high specificity. Using an experimental animal model for metastasis, the CXCR4 antagonist blocked metastasis completely. Biotin-labeled TN14003 can detect the CXCR4 receptors on cultured cells and paraffin-embedded patient tissue samples. They hypothesize that CXCR4 is required for breast cancer metastasis and can be used to detect metastasis because all metastasized tumors should have a high expression of CXCR4. Therefore, they plan to use CXCR4 antagonist as an imaging probe to detect primary tumors with high metastatic potential and their metastasis by non-invasive F18-Positron Emission Tomography (PET). This work is pursued in collaboration with Dr. Mark Goodman. In addition, they are in a process of developing small molecules against CXCR4/SDF-1 and new assays to screen drugs specific for CXCR4/SDF-1 interaction. The long-term outcome that we hope to achieve is the identification of a small molecule that will attenuate tumor metastasis in-vivo while demonstrating a sufficient pharmacokinetic and toxicological profile to merit advancement into human, clinical evaluation. Presently, we have identified several small molecules, including WZ40 which is currently the most advanced, that bind potently to CXCR4 and thus block the CXCR4/SDF-1 signaling process in collaboration with Drs Liotta/Snyder. We have followed this discovery by demonstrating that WZ40 inhibits tumor metastasis through this mechanistic pathway in both in vitro and in vivo studies. We now plan to build on these data and advance WZ40, or a mechanistically equivalent analog, toward human clinical evaluation. Early stage studies within 6 months will expand our current pool of active, CXCR4 antagonists, identify the most suitable lead for preclinical progression, and initiate advancement studies. A medicinal discovery program will be maintained throughout the screening and progression process in order to sustain a continuous escalation of novelty and efficacy. Specific screening studies that have been established for the selection process include in-vitro binding potency, a matrigel tissue penetration model, a calcium flux assay, anti-antiogenic efficacy, and pharmacokinetic stability screening. We have established and validated a number of in-vivo models of cancer metastasis that will be used to establish a proof of efficacy and dose dependency for our lead molecule. We will also study the specificity or cross-reactivity of our compounds against other chemokine recepors. Future aims will include advancement through preclinical development and IND application.

Associated Keywords:

Drug Development

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Last Update: 04/18/2014