I am a cancer biologist interested in studying the potential of ‘stem cell signaling pathways’, such as hedgehog/notch-signaling pathways as therapeutic targets in cancer.
My graduate study in the Department of Physiology at the All India Institute of Medical Sciences (AIIMS), India initiated my research career. The focus of my study was to understand the mechanism(s) of trophoblast cell invasion in the feto-maternal interface towards development of a functional placenta, a well studied physiological model of cellular invasiveness. Subsequently my research interest shifted towards understanding the biology of cancer metastasis. I joined the Department of Pathology at the Johns Hopkins University, Baltimore, MD, USA, in the year 2003 as a postdoctoral fellow working on gastrointestinal cancers. The research interest of my lab was the identification of novel therapeutic targets in pancreatic cancer which included the developmentally important signaling pathways (or “stem cell signaling pathways”), like hedgehog-, notch- and Wnt- signaling pathways. My research was mostly on the Hedgehog (Hh-) signaling pathway. This signaling pathway was originally discovered as an essential signaling pathway for embryonic development in fruit-fly, Drosophila melanogaster in the year 1980 by Christiane Nüsslein-Volhard and Eric F. Wieschaus. They were awarded the Nobel Prize in 1995 for their work. The importance of this pathway in cancers has been drawing attention since it was identified as a potential therapeutic target in lethal childhood brain tumor medulloblastoma in the year 1998 by Professor Philip Beachy at the Johns Hopkins University and eventually in a wide range of cancers for “mechanism based chemotherapy”. In the year 2003 two seminal papers in Nature had substantiated the therapeutic importance of the Hh-signaling pathway in pancreatic cancer and other gastrointestinal cancers. I was investigating the role of this pathway in the process of metastasis in pancreatic cancer. Ectopic overexpression of hedgehog transcription factor Gli1 confers migratory and invasive phenotype to the immortalized normal human pancreatic ductal epithelial (HPDE) cells was my first important observation indicating the importance of this pathway in the process of cancer metastasis. In collaboration with Philip Beachy’s lab, we demonstrated complete inhibition of human prostate cancer metastasis by blocking Hh-signaling pathway with plant alkaloid cyclopamine in a mouse prostate cancer xenograft model (Nature 2004). This was the first report along this line of research. Later, we also demonstrated the role of this pathway in the process of metastasis in pancreatic cancer. Inhibiting this pathway by cyclopamine resulted in a complete abrogation of metastasis of pancreatic cancer cells to liver and to other visceral organs in a mouse orthotopic pancreatic cancer xenograft model leaving the primary tumor unaffected. We have shown 3 to 10 fold overexpression of hedgehog transcription factor Gli1 in metastatic lesions compared to the primary tumor counterpart of the same patient tumors. Moreover, a special pool of ALDH (aldehyde dehydrogenase, a “cancer stem cell” marker)-positive pancreatic cancer cells, express 7 to 10 fold more Gli1 mRNA as compared to the whole population of the same cells (Cancer Research, 2007).
Currently, I am in the Department of Radiology at the Johns Hopkins University. I am investigating inter- and intra- tumor heterogeneity of Hh- signaling pathway by directly visualizing the tumor cells which overexpress the hedgehog transmembrane receptor ‘smoothened (Smo)’ in vivo with the help of molecular and functional imaging (MFI-) techniques. I am addressing two key questions in targeting Hh-signaling pathway. First, to identify the target cells (Smo- expressing cells) more specifically in vivo and secondly, the efficient delivery of the pharmacological inhibitors, e.g., cyclopamine to the specific target cells in the tumor microenvironment. In our laboratory, we have developed a method to radiolabel cyclopamine (and other small molecule smoothened antagonists) as radioactive “tracers” to image the Hh-signaling pathway in the tumor microenvironment in vivo. (Proceedings of AACR annual meeting 2008) Since tumors consist of heterogeneous clonal subpopulations of cancer cells, I hypothesized a significant degree of heterogeneity in the activation of hh-signaling pathway among different tumors and also among the different clonal subpopulations within a tumor.
Success of my current project in imaging the hh-signaling pathway in vivo in tumors will enable us to stratify anti-cancer chemotherapy with Hh- inhibitors (such as cyclopamine). It will also yield valuable information about the delivery and retention of cyclopamine (and other Smo antagonists) in the solid tumor microenvironment in vivo.
Human tumor cells are hopelessly heterogeneous; therefore it is difficult to know how many and which cells in a complex in vivo tumor microenvironment will show dependency on a specific signaling pathway. I am interested addressing the question of tumor heterogeneity in terms of activation of hedgehog/notch- pathways more closely. It is essential to develop fast and easy methods of stratification of therapy, such as imaging the target pathways in vivo, which is the key to the success of all mechanism-based chemotherapy.
FAX: 410 614-3147
Dhara, S. (2008). Tumor Biology. Textbook of Molecular Imaging in Oncology. Pomper, M.G., Ed. New York: Taylor & Francis, (in press).
Review articles (in chronological order)
Research articles (in chronological order)
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