• Researcher Profile

    Margaret A. Shipp, MD

     
    Chief, Division of Hematologic Neoplasia; Program Director, Lymphoma Program
    Senior Physician


    Professor of Medicine, Harvard Medical School

    Center/Program

    Hematologic Oncology

    Office phone: 617-632-3874
    Fax: 617-632-4734
    Website: Shipp Lab

    Preferred contact method: office phone

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    Research Department

    Medical Oncology/Hematologic Neoplasia

    Interests

    Bone marrow transplantation, Lymphoma, Hodgkin disease

    Area of Research

    Research interests

    Dana-Farber Cancer Institute
    450 Brookline Avenue
    Mayer 513
    Boston, MA 02215

    Biography

    Dr. Shipp received her MD in 1979 from Washington University School of Medicine, St. Louis, where she also completed an internship and residency in internal medicine at Barnes Hospital. Her research focuses on the biology of normal and malignant B cells and aggressive B-cell lymphomas. Dr. Shipp is the Chief of the Division of Hematologic Neoplasia at DFCI, the Director of the Lymphoma and Myeloma Program of the Dana-Farber/Harvard Cancer Center and a Professor of Medicine at Harvard Medical School.

    Recent Awards

    • Distinguished Woman in Medicine and Science, Northwestern University School of Medicine, 2007
    • Association of American Physicians,, 2005
    • Doris Duke Distinquished Clinical Scientist Award, 2001
    • Stohlman Scholar, Leukemia Society of America, 2000
    • American Society of Clinical Investigation, 1996
    • Scholar, Leukemia Society of America, 1995

    Research

    Research interests

    Our clinical and basic research group focuses on the pathogenesis and treatment of aggressive B-cell lymphomas, particularly the most common lymphoid malignancy, diffuse large B-cell lymphoma (DLBCL) and related variants and Hodgkin lymphoma. We previously led an international effort to identify highly reproducible clinical prognostic factors in patients with aggressive lymphoma (primarily DLBCL) and develop a model to predict patient outcome. Investigators from 16 major centers in the United States, Canada and Europe contributed data on over 3,000 patients to the International Prognostic Factors project and the subsequent development of the International Prognostic Index (IPI). The IPI is now used worldwide to assess the probability that a DLBCL patient will be cured with standard therapy or require more intensive, investigational treatment. In fact, most recent studies of risk-related therapy in DLBCL are based on IPI-defined patient subgroups. The IPI has also been widely applied to other lymphoid neoplasms.

    Our laboratory is also characterizing molecular bases for the recognized clinical heterogeneity in DLBCL. Earlier studies focused on specific genes and pathways implicated in biology of normal and malignant lymphoid progenitors. For example, our group cloned and characterized one of the first lymphoid differentiation antigens associated with germinal center B-cells and a good risk subtype of DLBCL, CD10. We demonstrated that CD10 was a neutral endopeptidase that regulated peptide-mediated signaling, stromal cell dependent lymphopoiesis and B-cell reconstitution and maturation in vivo. More recently, our group has identified and characterized novel risk-related genes in DLBCL, including the B-cell protein tyrosine phosphatase, PTPROt, which regulates spleen tyrosine kinase (SYK) activity and is itself a BCL6 target, and 2 partner proteins, BAL and BBAP, which play unique roles in DNA damage repair. In addition, we have developed genome-wide approaches to define the unique molecular signatures of specific DLBCL subtypes and more rational therapeutic targets. Our pilot studies identified several signaling pathways associated with resistance to standard therapy. Two of these pathways (PKCbeta and PDE4B/cAMP) have now been credentialed as rational therapeutic targets in DLBCL. Clinical trials of an oral PKCbeta inhibitor in relapsed/refractory DLBCL are completed and studies in newly diagnosed DLBCL are underway.

    Additional comprehensive analyses of the molecular signatures of large B-cell lymphoma subtypes led to the identification of discrete disease subtypes. In initial studies, we defined the unique molecular signature of MLBCL, an unusual disease primarily affecting young women. These studies uncovered an unanticipated molecular link between MLBCL and classical Hodgkin lymphoma and a shared NFkappaB survival pathway.

    Thereafter, we defined three discrete subsets of DLBCLs: Oxidative Phosphorylation; B-cell Receptor/Proliferation (BCR); and Host Response (HR) tumors. HR tumors which were largely defined by their inflammatory/immune cell infiltrate and shared multiple features of histologically defined T-cell histiocyte-rich BCL. BCR-type DLBCLs, which overexpress BCL6 and have more frequent BCL6 translocations, exhibit coordinate regulation of BCL6 target genes and selective sensitivity to BCL6 inhibitors. BCR-type DLBCLs are reliant upon tonic B-cell receptor signaling and uniquely sensitive to targeted inhibition of this critical survival pathway with a spleen tyrosine kinase (SYK) inhibitor. These preclinical observations led to a recently completed national phase I/II clinical trial of an oral SYK inhibitor which exhibited clinical activity in relapsed/refractory DLBCL.

    Our observations regarding the shared molecular features of MLBCL and classical Hodgkin lymphoma (cHL) prompted additional analyses of the defining features of cHL. In cHL, small numbers of malignant Reed-Sternberg (RS) cells reside within an extensive inflammatory infiltrate. We found that Hodgkin RS cells exhibit AP-1 dependent overexpression of galectin-1 (Gal1), a carbohydrate-binding lectin that selectively inhibits the apoptosis of cytotoxic T cells and Th1 cells, skews the balance toward a Th2 type cytokine profile and favors the expansion/retention of Treg cells. Gal1 represents a novel therapeutic target for restoring immune surveillance in cHL and several additional malignancies. For these reasons, we have now developed neutralizing Gal1 monoclonal antibodies for further clinical evaluation.

    Investigators

    • Juszczynski, Przemyslaw, MD, PhD

    Trainees

    • Chapuy, Bjoern, MD
    • Chen, Linfeng, PhD
    • Yansheng, Hao, Ph.D
    • Wang, Zhe, PhD
    • Ouyang, Jing, PhD
    • Green, Michael, PhD
    • Yan, Qingsheng, PhD
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