Targeting MUC4 for chemosensitization of pancreatic cancer

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DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the U.S. and has a five-year survival rate of only 5%. The current standard of care for advanced PC, gemcitabine, prolongs survival by only a few weeks, and only 25% of patients respond to this treatment. Resistance to gemcitabine is a major problem in the treatment of pancreatic cancer. We have recently shown that MUC4 contributes to the resistance of PC cells to gemcitabine-induced apoptosis. MUC4 mucin is a large glycoprotein aberrantly expressed by PC cells. We have previously shown that MUC4 downregulation induces apoptosis, inhibits proliferation, blocks invasion and metastasis and sensitizes PC cells to gemcitabine. These results suggest that MUC4 could be an extremely relevant therapeutic target in PC. However, there are currently no therapeutic strategies to downregulate MUC4 expression in vivo. Fluticasone propionate (FP), a potent anti-inflammatory glucocorticoid used clinically in treating bronchial asthma, has previously been reported to repress the expression of MUC4 mRNA in cultured nasal polyp cells. However, its role in regulating MUC4 expression in PC cells and on PC cell behavior has never been examined. The central hypothesis of the proposal is that Pharmacological downregulation of MUC4 with glucocorticoids would enhance the sensitivity of PC cells to chemotherapeutic agents and a combination of GCs will synergistically enhance the therapeutic efficacy of chemotherapy. The preliminary studies have indicated that FP downregulates MUC4 expression at the transcript level via the glucocorticoid receptor (GR). To investigate further the mechanism by which FP affects MUC4 expression and to assess its potential therapeutic relevance in PC, we propose three specific aims. In aim 1 we will investigate the mechanisms underlying the observed downregulation of MUC4 by FP in PC cells using GR specific shRNAs, promoter-reporter assays and chromatin immunoprecipitation. In aim 2 we will examine the effect of FP treatment on PC cell function in vitro, compare FP with dexamethasone (a glucocorticoid currently used in co-treatment with cancer chemotherapy) in affecting the sensitivity of PC cells to gemcitabine, and examine the effect of FP treatment on PC tumor growth and chemosensitivity in vivo in an orthotopic xenograft model in nude mice. In aim 3, we will examine the effect of FP treatment on PC tumor growth and chemosensitivity in vivo in a clinically relevant spontaneous PC mouse model. Taken together, the proposed studies will investigate the therapeutic potential of this novel MUC4 repressing agent for possible application as an adjuvant to existing PC chemotherapy regimens. PUBLIC HEALTH RELEVANCE: Although gemcitabine is the standard of care for advanced pancreatic cancer, it offers limited survival benefit due to chemoresistance. MUC4 mucin has been demonstrated to contribute to chemoresistance in pancreatic cancer. The proposal aims to investigate the utility of glucocorticoids to downregulate MUC4 to augment chemosensitivity and thereby serve as adjuvants in combination with gemcitabine (and possible other chemotherapeutic drugs) for the treatment of lethal pancreatic cancer.