department of pharmacology

Clark Distelhorst, M.D.

distelhorst

Charles S. Britton II Professor of Hematology/Oncology

Departments of Medicine and Pharmacology
Case Western Reserve University School of Medicine
Cleveland, Ohio
Wolstein Research Building
WRB3-301

Phone: (216) 368-4546
Fax: NA
E-mail: cwd@case.edu

Background and Training

Dr. Distelhorst earned BA and MD degrees Summa Cum Laude at Ohio State University. He then trained in Internal Medicine at Yale, followed by training in Internal Medicine and Hematology/Oncology at Washington University School of Medicine in St Louis. Here he received intensive basic research training under Professors Stuart Kornfeld and Philip Majerus. Most of his research career has been at Case Western Reserve University School of Medicine in Pharmacology, Hematology/Oncology and the Case Comprehensive Cancer Center. In 2003 he worked at the Babraham Institute, Cambridge, UK, with Sir Michael Berridge, Martin Bootman and Llewelyn Roderisk. This work enabled the Distelhorst lab to employ single cell digital imaging in their discovery of Bcl-2-IP3R interaction. In collaboration with Jan Parys and colleagues in Leuven, Belgim, we established the importance of targeting Bcl-2-IP3R interaction to treat Bcl-2 positive maligncies.

The Distelhorst Lab Group and Collaborators

The Distelhorst lab is a highly collaborative and productive research group including research assistants and both PHD and MD/PHD trainees. Numerous collaborators at Case Western Reserve and both nationally and internationally play critical roles in this research program.

Major Research Priorities

  • Mechanism by which the Bcl-2 protein regulates calcium signaling and cell death, with novel approaches to target the Bcl-2 protein to induce cell death in cancer cells
  • Mechanism of glucocorticosteroid hormone induce apoptosis in malignant lymphocytes
  • Most recent discovery, providing novel insight into the role of pyruvate kinase in cancer cells

Key Bcl-2 Discoveries

Discovery of Bcl-2-IP3R interaction

Rong Y, Aromolaran AS, Bultynck G, Zhong F, Li X, McColl KS, Herlitze S, Matsuyama S, Roderick HL, Bootman MD, Mignery GA, Parys JB, De Smedt H, Distelhorst CW. Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2's inhibition of apoptotic calcium signals. Molecular Cell 31:255-265, 2008. PMCID: PMC3660092

Rong Y, Bultynck G, Aromolaran AS, Zhong F, Parys JB, De Smedt H, Mignery GA, Roderick HL, Bootman MD, Distelhorst CW.  The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor. Proc Natl Acad Sci USA 106:14397-14402, 2009. PMCID: PMC2728114

Targeting Bcl-2-IP3R interaction to kill cancer

Zhong F, Harr MW, Bultynck G, Monaco G, Parys JB, De Smedt H, Rong Y-P, Molitoris JK, Lam M, Ryder C, Matsuyama S, Distelhorst CW. Induction of Ca2+-driven apoptosis in chronic lymphocytic leukemia cells by peptide-mediated disruption of Bcl-2-IP3 receptor interaction. Blood 117:2924-2934, 2011. PMCID: PMC3062302
Lavik AR, Zhong F, Chang M-J, Greenberg E, Choudhary Y, Smith MR, McColl KS, Pink J, Reu FJ, Matsuyama S, Distelhorst CW.  A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2. Oncotarget 6:27388-402 2015. PMCID: PMC4694997

Greenberg, E.F., McColl, K.S., Zhong, F., Wildey, G., Dowlati, A., Distelhorst, CW. Synergistic killing of human small cell lung cancer cells by the Bcl-2-inositol 1,4,5-trisphosphate receptor disruptor BIRD-2 and the BH3-mimetic ABT-263. Cell Death and Disease 6:e2034, 2015. PMCID: PMC4720890

How Bcl-2 regulates IP3R calcium signals

Chang MJ, Zhong F, Lavik AR, Parys JB, Berridge MJ, Distelhorst CW. Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival. Proc Natl Acad Sci USA 111:1186-1191, 2014 PMCID: PMC3903247