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Richmond, VA, United States

Bhatia S.,Virginia Commonwealth University | Emdad L.,Virginia Commonwealth University | Das S.K.,Virginia Commonwealth University | Hamed H.,Virginia Commonwealth University | And 4 more authors.
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: Melanoma is one of the most aggressive forms of cutaneous malignancies displaying a substantial mortality rate among the various forms of skin cancers. The management of patients with advanced melanoma poses a significant challenge considering that the disease is refractory to most conventional therapies. Areas covered: This review highlights some of the genes and signaling molecules that are mutated in melanoma patients. The authors also discuss protein kinase inhibitors targeting non-BRAF mutations that are now being evaluated in Phase II clinical trials. Expert opinion: In light of several preclinical and clinical studies, it is clear that targeting single-gene mutations may not provide a desired therapeutic gain in the context of melanoma. Consequently, research will need to focus on rational combinations of novel therapeutic agents targeting multiple genetic aberrations or deregulated pathways to achieve a desired maximum clinical benefit. There is certainly a need for a better understanding of the complex and redundant molecular signatures associated with melanoma development; this would open up new avenues for creating the next generation of targeted and effective therapeutics. © 2014 Informa UK, Ltd. Source

Li Y.-J.,University of Toronto | Li Y.-J.,Jilin University | Liu G.,University of Toronto | Li Y.,University of Toronto | And 12 more authors.
Molecular Cancer Research | Year: 2013

Melanoma differentiation-associated gene (MDA)-7)/interleukin (IL)-24, a member of the IL-10 family of cytokines, inhibits growth of various human cancer cells, yet the underlying mechanism is largely unknown. Here, we report that mda-7/IL-24 efficiently suppresses the development of rat mammary tumors in vivo. Microarray analysis for genes differentially expressed in rat mammary tumor cells overexpressing MDA-7/IL-24 compared with those that do not express this cytokine identified growth arrest-specific gene-3 (gas3) as a target for mda-7/IL-24. Upregulation of gas3 by mda-7/IL-24 was STAT3 dependent. Induction of gas3 inhibited attachment and proliferation of tumor cells in vitro and in vivo by inhibiting the interaction of β 1 integrin with fibronectin. A mutated GAS3, which is unable to bind β 1 integrin, was also unable to inhibit fibronectin-mediated attachment and cell growth both in adherent and suspension cultures, suggesting that GAS3 exerts its effects through interaction with and regulation of β1 integrin. Thus, mda-7/IL-24 inhibits breast cancer growth, at least in part, through upregulation of GAS3 and disruption of β1 integrin function. Importantly, the expression of the mda-7/IL-24 receptor, IL-20R1, is highly correlated with GAS3 expression in human breast cancer (P= 1.02 × 10-9), and the incidence of metastases is significantly reduced in patients with HER2 breast cancer expressing high-levels of IL-20R1. Together, our results identify a novel MDA-7/IL-24-GAS3-β 1integrin - fibronectin signaling pathway that suppresses breast cancer growth and can be targeted for therapy. © 2013 American Association for Cancer Research. Source

Yi H.,Virginia Commonwealth University | Yi H.,VCU Institute of Molecular Medicine | Yi H.,Massey Cancer Center | Yu X.,Virginia Commonwealth University | And 11 more authors.
Cancer Immunology, Immunotherapy | Year: 2011

In this study, we report a novel treatment strategy that could potentially be used to improve efficacy of adoptive cell therapy for patients with prostate cancer. We show that female C57BL/6 mice are able to effectively reject two syngeneic prostate tumors (TRAMP-C2 and RM1) in a T cell-dependent manner. The protective antitumor immunity appears to primarily involve T cell responses reactive against general prostate tumor/tissue antigens, rather than simply to male-specific H-Y antigen. For the first time we show that adoptive transfer of lymphocytes from TRAMP-C2-primed or naïve female mice effectively control prostate tumor growth in male mice, when combined with host pre-conditioning (i.e., non-myeloablative lymphodepletion) and IL-2 administration. No pathological autoimmune response was observed in the treated tumor-bearing male mice. Our studies provide new insights regarding the immune-mediated recognition of male-specific tissue, such as the prostate, and may offer new immunotherapy treatment strategies for advanced prostate cancer. © 2010 Springer-Verlag. Source

Yu X.,VCU Institute of Molecular Medicine | Yu X.,Virginia Commonwealth University | Guo C.,VCU Institute of Molecular Medicine | Guo C.,Virginia Commonwealth University | And 5 more authors.
Advances in Cancer Research | Year: 2015

Scavenger receptors constitute a large family of evolutionally conserved protein molecules that are structurally and functionally diverse. Although scavenger receptors were originally identified based on their capacity to scavenge modified lipoproteins, these molecules have been shown to recognize and bind to a broad spectrum of ligands, including modified and unmodified host-derived molecules or microbial components. As a major subset of innate pattern recognition receptors, scavenger receptors are mainly expressed on myeloid cells and function in a wide range of biological processes, such as endocytosis, adhesion, lipid transport, antigen presentation, and pathogen clearance. In addition to playing a crucial role in maintenance of host homeostasis, scavenger receptors have been implicated in the pathogenesis of a number of diseases, e.g., atherosclerosis, neurodegeneration, or metabolic disorders. Emerging evidence has begun to reveal these receptor molecules as important regulators of tumor behavior and host immune responses to cancer. This review summarizes our current understanding on the newly identified, distinct functions of scavenger receptors in cancer biology and immunology. The potential of scavenger receptors as diagnostic biomarkers and novel targets for therapeutic interventions to treat malignancies is also highlighted. © 2015 Elsevier Inc. Source

Das S.K.,VCU Institute of Molecular Medicine | Das S.K.,Virginia Commonwealth University | Bhutia S.K.,VCU Institute of Molecular Medicine | Bhutia S.K.,National Institute of Technology Rourkela | And 17 more authors.
Cancer Research | Year: 2013

Melanoma differentiation-associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma, and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, chorioallantoic membrane (CAM) assays and xenograft tumor animal models. Gain-of-function and loss-offunction experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several proangiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/ syntenin in which MDA-9/syntenin interacts with the extracellular matrix (ECM), activating Src and FAK resulting in activation by phosphorylation of Akt, which induces hypoxia inducible factor 1-a (HIF-1a). The HIF-1a activates transcription of insulin growth factor-binding protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell nonautonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (nonautonomous). © 2012 AACR. Source

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