Browsing by Subject "hedgehog"

Now showing 1 - 3 of 3
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    Deciphering the role of hedgehog signaling in pancreatic cancer.
    (JBR, 2016-09) Gu, Dongsheng; Schlotman, Kelly E.; Xie, Jingwu; Department of Pediatrics, IU School of Medicine
    Pancreatic cancer, mostly pancreatic ductal adenocarcinoma (PDAC), is a leading cause of cancer-related death in the US, with a dismal median survival of 6 months. Thus, there is an urgent unmet need to identify ways to diagnose and to treat this deadly cancer. Although a number of genetic changes have been identified in pancreatic cancer, their mechanisms of action in tumor development, progression and metastasis are not completely understood. Hedgehog signaling, which plays a major role in embryonic development and stem cell regulation, is known to be activated in pancreatic cancer; however, specific inhibitors targeting the smoothened molecule failed to improve the condition of pancreatic cancer patients in clinical trials. Furthermore, results regarding the role of Hh signaling in pancreatic cancer are controversial with some reporting tumor promoting activities whereas others tumor suppressive actions. In this review, we will summarize what we know about hedgehog signaling in pancreatic cancer, and try to explain the contradicting roles of hedgehog signaling as well as the reason(s) behind the failed clinical trials. In addition to the canonical hedgehog signaling, we will also discuss several non-canonical hedgehog signaling mechanisms.
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    Promising molecular mechanisms responsible for gemcitabine resistance in cancer
    (Elsevier, 2015-12) Jia, Yanfei; Xie, Jingwu; Department of Pediatrics, IU School of Medicine
    Gemcitabine is the first-line treatment for pancreatic ductual adenocarcinoma (PDAC) as well as acts against a wide range of other solid tumors. Patients usually have a good initial response to gemcitabine-based chemotherapy but would eventually develop resistance. To improve survival and prognosis of cancer patients, better understanding of the mechanisms responsible for gemcitabine resistance and discovery of new therapeutic strategies are in great need. Amounting evidence indicate that the developmental pathways, such as Hedgehog (Hh), Wnt and Notch, become reactivated in gemcitabine-resistant cancer cells. Thus, the strategies for targeting these pathways may sensitize cancer cells to gemcitabine treatment. In this review, we will summarize recent development in this area of research and discuss strategies to overcome gemcitabine resistance. Given the cross-talk between these three developmental signaling pathways, designing clinical trials using a cocktail of inhibitory agents targeting all these pathways may be more effective. Ultimately, our hope is that targeting these developmental pathways may be an effective way to improve the gemcitabine treatment outcome in cancer patients.
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    Targeting the Hedgehog Pathway in Pediatric Medulloblastoma
    (MDPI, 2015) Huang, Sherri Y.; Yang, Jer-Yen; Department of Pharmacology and Toxicology, IU School of Medicine
    Medulloblastoma (MB), a primitive neuroectomal tumor of the cerebellum, is the most common malignant pediatric brain tumor. The cause of MB is largely unknown, but aberrant activation of Hedgehog (Hh) pathway is responsible for ~30% of MB. Despite aggressive treatment with surgical resection, radiation and chemotherapy, 70%-80% of pediatric medulloblastoma cases can be controlled, but most treated patients suffer devastating side effects. Therefore, developing a new effective treatment strategy is urgently needed. Hh signaling controls transcription of target genes by regulating activities of the three Glioma-associated oncogene (Gli1-3) transcription factors. In this review, we will focus on current clinical treatment options of MB and discuss mechanisms of drug resistance. In addition, we will describe current known molecular pathways which crosstalk with the Hedgehog pathway both in the context of medulloblastoma and non-medulloblastoma cancer development. Finally, we will introduce post-translational modifications that modulate Gli1 activity and summarize the positive and negative regulations of the Hh/Gli1 pathway. Towards developing novel combination therapies for medulloblastoma treatment, current information on interacting pathways and direct regulation of Hh signaling should prove critical.