Keith Skubitz, MD

My clinical research centers on biology and treatment of sarcomas, including genetics and drug development. I have directed multiple clinical trials, many of which I designed.  Our laboratory work, with similar work from scientists in Australia, provided the rationale for a treatment of giant cell tumors of bone that involved interfering with paracrine signaling from normal cells that was quite effective. We have also developed a number of infusional chemotherapy regimens that simplify the patient experience, offer less toxicity, and potentially greater efficacy. We are also interested in useful methods to detect and predict cardiotoxicity from anti-cancer drugs. My basic science research centers mostly on immunology. Our work has demonstrated several important concepts: 1) that the kinetics of antibody-hapten interactions are diffusion limited (done as a medical student working with Dr. Thomas Smith at Harvard), 2) that exposure of neutrophils to stimuli can selectively desensitize them in vitro and in vivo, 3) that some membrane active drugs can alter the kinetics of ligand binding to cell surface receptors primarily by altering dissociation kinetics, and 4) that some drugs that alter ligand receptor binding of stimuli can prevent neutrophil activation but allow desensitization to further stimulation by the ligand in question after drug has been removed. We were among the first to report evidence suggesting the existence of a protein kinase on the cell surface and also characterized a secreted form of an ecto-protein kinase from neutrophils. We lead the CD15, CD66, and CD67 working groups in the Leukocyte Differentiation Antigen Workshops, defining the CDs; in this process we became interested in CEACAMs which is one of our current laboratory interests. We have made several important observations including:

1. CD66a, CD66b, CD66c, and CD66d can each independently stimulate neutrophils
2. CD66a, b, and c associate with tyrosine kinase activity
3. CD66 signaling is via a transient, calcium-dependent activation complex
4. we identified several active sites of the surface of CEACAMs that are critical in function by use of synthetic peptides