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Irene M. Ghobrial, MD

Associate Professor, Department of Medicine, Harvard Medical School

Active Medical Staff, Myeloma Program, Dana-Farber Cancer Institute

Contact Info

Irene Ghobrial
Dana-Farber Cancer Institute
450 Brookline Avenue

Boston, MA, 02215
Mailstop: D1B30
Phone: 617-632-4198
irene_ghobrial@dfci.harvard.edu

Assistant

Not Available.

DF/HCC Program Affiliation

Lymphoma and Myeloma
Angiogenesis, Invasion and Metastasis

Research Abstract

My research focuses on understanding the regulation of homing and migration in Waldenstrom Macroglobulinemia (WM) and Multiple Myeloma (MM), and on identifying dysregulated signaling proteins that can be specifically targeted with novel therapeutic agents, specifically focusing on the role of the PI3K and PKC pathways in WM and MM.

The main focus of this research is understanding mechanisms of trafficking of B cells into and out of the bone marrow. We first used the chemokine SDF-1 and its receptor CXCR4 as a model of understanding migration, homing and egression of MM and WM cells into and out of the marrow. We are currently testing inhibitors of CXCR4 such as AMD3100 on MM and WM migration in vitro and homing in vivo using in vivo confocal microscopy. We are also identifying the role of CXCR4 on adhesion of B cells to the bone marrow stromal cells. These studies will lead to novel therapeutic interventions in MM and WM by disrupting adhesion and homing of malignant B-cells and leading to their mobilization out of the BM.

In addition, the PI3K and PKC are critical regulators of proliferation as well as migration in B-cell malignancies. We have been studying the role of these two pathways in WM and MM and the effect of inhibitors of these pathways on the proliferation, apoptosis and migration of MM and WM cells in vitro and in vivo. Some of the inhibitors being tested are the AKT inhibitor perifosine, the mTOR inhibitor rapamycin and the PKC inhibitor enzastaurin. Based on these studies, we have developed a clinical trial using the AKT inhibitor, perifosine in WM based on the first in vitro studies of efficacy of a novel therapeutic agent in WM. We have also developed clinical trials using the mTOR inhibitors CCI-779 and RAD001 in MM and WM. We are currently developing clinical trials for the use of enzastaurin in MM and WM. We plan to identify the mechanisms of resistance/response to these agents in vivo using samples obtained from the clinical trials, taking the data back again from the clinic to the laboratory.

In addition, we are performing multi-level characterization of molecular regulators of progression and response/resistance to therapeutic agents using molecular profiling with miRNA, transcription profiling (ChIP on chip) and signaling profiling with proteomic techniques. These studies will help improve our understanding of the pathogenesis of WM and MM, as well as the development of methods to overcome resistance to therapy in these diseases.

Publications

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