SCIENCE AT THE EDGE – INTERDISCIPLINARY PHYSICS

11:30a.m. Friday February 26, 2016, room 1400 BPS Bldg.

Richard Neubig

Pharmacology and Toxicology, Michigan State University

Precision medicine for human and animal diseases through pharmacologic profiling

Abstract

Rational drug discovery through target-based screening starts with the assumption that we know enough about disease pathology to predict which genes or proteins would make good therapeutic targets. Many diseases, however, are complex or poorly understood which probably contributes to the high failure rate in late-stage clinical trials due to lack of efficacy. In my presentation, I will introduce the MSU Assay Development and Drug Repurposing Core (http://bit.ly/1ToQfWw) which can help MSU faculty and students design and implement high throughput screening projects using both targeted biochemical assays or phenotypic cell-based assays. The ADDRC also can provide over 1000 known clinical drugs for testing in these HTS assays to facilitate drug repurposing – finding new uses for existing drugs.

Two examples of ongoing projects will be presented. We are profiling human melanoma cell lines using a collection of over 500 inhibitors of protein kinases (GSK kinase inhibitor collection) to see which kinases are critical for growth or survival in human melanoma. The overlapping activity of different inhibitors and differential biological properties of the melanoma lines makes the deconvolution of these data a complex informatics problem. At least two distinct populations of melanomas have been identified by their biological responses to these kinase inhibitors – and this does not simply correlate with the known mutant oncogenes present in the cell lines. This same approach is being applied in other human and animal cancers. Second, scleroderma or systemic sclerosis (SSc) is one of the most serious rheumatologic diseases and effective targeted therapies are lacking. One critical step in the pathogenesis of SSc and other diseases of fibrosis is fibroblast activation to the proliferative and synthetic myofibroblast state in which cells deposit abundant, pathological extracellular matrix. We are developing methods for rapid, in vitro high-throughput screening of the myofibroblast phenotype of skin cells from scleroderma patients. Ultimately, we will test 1000s of  clinically approved and/or pharmacologically defined compounds to identify those that reverse the myofibroblast activation state. By testing multiple individuals with scleroderma, we should be able to define pharmacological subtypes among patients to help develop precision therapeutics of systemic sclerosis and potentially other diseases of fibrosis such as cirrhosis, diabetic nephropathy, and others. By letting the patient’s own cells define which drug targets can effectively be hit to interrupt disease pathology, we hope to rapidly repurpose known drugs into the clinic and don’t have to guess about the most relevant targets in disease.

http://confrooms.pa.msu.edu/cgi-bin/cal?Op=UserLogin

Refreshments at 11:15 am.

Shawna Prater / Secretary

Astrophysics Group

Michigan State University

567 Wilson Road, Room 3261

Biomedical Physical Sciences Bldg

East Lansing, MI 48824-2320

Ph: (517) 884-5601 Fax (517) 432-8802

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