Güllü Görgün

Dana-Farber Cancer Institute, Boston, MA, United States

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Publications (5)31.72 Total impact

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    ABSTRACT: Myeloid derived suppressor cells (MDSCs) are a heterogeneous, immature myeloid cell population with the ability to suppress immune responses. MDSCs have been characterized in infections, inflammatory diseases, and solid tumors; however, their presence and role in the tumor promoting, immune suppressive microenvironment in hematologic malignancies remains unclear. Here we assessed the presence, frequency, and functional characteristics of MDSCs in patients with newly diagnosed, relapsed and relapsed/refractory multiple myeloma (MM), compared to healthy donors. Additionally, we evaluated the immunomodulatory effects of lenalidomide and bortezomib on MDSCs in MM. CD11b(+)CD14(-)HLA-DR(-/low)CD33(+)CD15(+) MDSCs were significantly increased in both PB and BM of patients with active MM compared to healthy donors. Furthermore, MDSCs induced MM growth, while suppressing T cell mediated immune responses. Conversely, MM cells induced development of MDSCs from healthy donor PBMCs, confirming a bidirectional interaction between MDSCs and MM cells and immune effector cells. Our results further suggest that MDSCs may be associated with activity of disease in MM. Importantly, our studies suggest that inhibition of the tumor promoting and immune suppressive functions of MDSCs in MM may represent a promising novel immune-based therapeutic strategy.
    Blood 01/2013; · 9.78 Impact Factor
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    ABSTRACT: Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed and refractory myeloma. The most common adverse events associated with lenalidomide include fatigue, skin rash, thrombocytopenia, and neutropenia. In addition, when lenalidomide is combined with dexamethasone or other conventional cytotoxic agents, there is an increase in the incidence of venous thromboembolic events. There is now evidence that continued treatment with lenalidomide has a significant impact on survival by improving the depth and duration of response. This highlights the value of adverse event management and appropriate dose adjustments to prevent toxicity, and of allowing continued treatment until disease progression. In this review, we will discuss the different lenalidomide-based treatment regimens for patients with relapsed/refractory myeloma. This is accompanied by recommendations of how to manage and prevent adverse events associated with lenalidomide-based therapy.
    Cancer Management and Research 01/2012; 4:253-68.
  • Güllü Görgün, Kenneth C Anderson
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    ABSTRACT: Advances in tumor biology have demonstrated a point of critical importance: tumor are established as an intersection of malignant clone cells and surrounding stromal cells. The stroma is composed of nonhematopoietic cells, including connective tissue cells, blood vessels, nerves, fat and smooth muscle cells, in the extracellular matrix niche. Recent studies have demonstrated that stromal cells regulate immune responses by: coordinating lymphocyte homing, differentiation, activation and antigen responses; inducing tolerance; and maintaining immunologic memory. Hence, elucidation of the interaction between stromal cells and lymphocytes is essential for generating effective immunotherapies. In this article, we summarize what is currently known about the interactions between stromal cells and lymphocytes in the tumor microenvironment, as well as potential immunotherapeutic approaches targeting stroma-lymphocyte interactions; both in the context of our work on multiple myeloma, and of recent literature in both solid tumors and hematologic malignancies.
    Immunotherapy 10/2011; 3(10):1253-64. · 2.39 Impact Factor
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    ABSTRACT: The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferonγ, and IL-6 regulator suppressor of cytokine signaling (SOCS)1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing-MM cells than unmodified MM cells. These data therefore demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM.
    Blood 10/2010; 116(17):3227-37. · 9.78 Impact Factor
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    ABSTRACT: Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P = .007) and overall survival was significantly increased (P < .005) in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay. MLN8237 is currently in phase 1 and phase 2 clinical trials in patients with advanced malignancies, and our preclinical results suggest that MLN8237 may be a promising novel targeted therapy in MM.
    Blood 04/2010; 115(25):5202-13. · 9.78 Impact Factor