Dr. Orlowski

Here’s some information about Dr. Orlowski at UNC:

Robert Z. Orlowski, MD, PhD
Assistant Professor, Department of Medicine, Division of Hematology and Oncology
Molecular Therapeutics Program; Clinical Research Program

Clinical Interests
Dr. Orlowski’s clinical areas of focus include the treatment of patients with hematologic malignancies, including multiple myeloma, acute and chronic leukemias, and Hodgkin’s and non-Hodgkin’s lymphomas, and also Phase I clinical trials, which apply novel agents or drug
combinations to the therapy of patients with refractory malignancies.

Research Interests
The research being pursued by members of our laboratory focuses on three goals:

1.) To evaluate the mechanisms by which inhibitors of the multicatalytic proteinase complex (proteasome) induce apoptosis, with a focus on human malignancies in which the oncogene c-myc is involved, such as Burkitt’s lymphoma and breast cancer. Work performed in our laboratory has revealed that proteasome inhibitor-mediated programmed cell death occurs in part through effects on the p44/42 mitogen-activated protein kinase pathway. Current and future studies will evaluate other signal transduction pathways involved in this process, including the c-Jun-N-terminal kinase (JNK).

2.) To determine the potential therapeutic benefit of modulation of proteasome activity for patients with refractory malignancies. Our previous work in this field has included a Phase I clinical trial of the proteasome inhibitor PS-341 in patients with hematologic malignancies, which was the first study to show the activity of this agent in patients with multiple myeloma. Based on an understanding of the mechanisms of action of other chemotherapeutic drugs on cell death and survival associated pathways, novel drug regimens will be evaluated for their anti-tumor efficacy, and those which prove promising will be translated into clinical trials. This approach is exemplified by a current trial of the combination of PS-341 with pegylated liposomal doxorubicin (Doxil).

3.) To examine the potential impact of dietary agents which influence apoptosis-associated signal transduction pathways on the efficacy of cancer chemotherapy. This line of investigation led to our previous demonstration that the dietary additive curcumin can inhibit chemotherapy-mediated apoptosis, generation of reactive oxygen species, activation of JNK, and mitochondrial release of cytochrome c in both in vitro and in vivo models of human breast cancer. Future studies will evaluate the possibility that other factors may also inhibit, or in some cases promote, the anti-tumor efficacy of chemotherapeutic drugs.

Training
Yale University Ph.D. 1990 Molecular Biophysics and Biochemistry
Yale University Ph.D. 1990 Medicine

Board Certifications
Internal Medicine 1994
Oncology 1997

Publications
Small, G.W., Chou, T.-Y., Dang, C.V., and Orlowski, R.Z. Evidence for involvement of calpain in c˝Myc proteolysis in vivo. Arch. Biochem. Biophys. 400: 151-161, 2002.

Somasundaram, S., Edmund, N.A., Moore, D.T., Small, G.W., Shi, Y.-Y., and Orlowski, R.Z. Dietary curcumin inhibits chemotherapy˝induced apoptosis in models of human breast cancer. Cancer Res. 62: -, 2002. In press.

Orlowski, R.Z., Small, G.W., and Shi, Y.Y. Evidence that inhibition of p44/42 mitogen activated protein kinase signaling is a factor in proteasome inhibitor-mediated apoptosis. J. Biol. Chem. In press.