Targeting MUC4 for chemosensitization of pancreatic cancer

描述(申请人提供)：胰腺癌(PC)是美国癌症死亡的第四大原因，五年存活率仅为5%。目前对晚期PC的治疗标准是吉西他滨，只延长了几周的生存时间，而且只有25%的患者对这种治疗有反应。对吉西他滨的耐药性是胰腺癌治疗中的一个主要问题。我们最近发现，MUC4参与了PC细胞对吉西他滨诱导的细胞凋亡的抵抗。MUC4粘蛋白是PC细胞异常表达的一种大糖蛋白。我们以前已经证明，MUC4下调诱导细胞凋亡，抑制增殖，阻止侵袭和转移，并使PC细胞对吉西他滨敏感。这些结果表明，MUC4可能是PC的一个极其相关的治疗靶点。然而，目前还没有在体内下调MUC4表达的治疗策略。丙酸氟替卡松(FP)是一种有效的抗炎性糖皮质激素，临床上用于治疗哮喘，已有报道抑制培养的鼻息肉细胞MUC4mRNA的表达。然而，它在PC细胞中调节MUC4表达和对PC细胞行为的作用从未被研究过。该方案的中心假设是，糖皮质激素对MUC4的药理下调将增强PC细胞对化疗药物的敏感性，而联合使用GC将协同增强化疗的疗效。初步研究表明，FP通过糖皮质激素受体(GR)在转录水平下调MUC4的表达。为了进一步研究FP影响MUC4表达的机制，并评估其在PC中的潜在治疗意义，我们提出了三个特定的目标。在目标1中，我们将使用GR特异性shRNAs、启动子报告分析和染色质免疫沉淀来研究FP下调PC细胞MUC4的机制。目的2研究FP对PC细胞体外功能的影响，比较FP和地塞米松对PC细胞对吉西他滨敏感性的影响，并在裸鼠原位移植瘤模型中检测FP对PC肿瘤生长和化疗敏感性的影响。在目标3中，我们将在临床相关的自发性PC小鼠模型中检测FP治疗对PC肿瘤生长和体内化疗敏感性的影响。综上所述，拟议的研究将探讨这种新型MUC4阻滞剂作为现有PC化疗方案的辅助剂的治疗潜力。 公共卫生相关性：虽然吉西他滨是晚期胰腺癌的标准治疗方案，但由于化疗耐药，它提供的生存益处有限。MUC4粘蛋白已被证明在胰腺癌的化疗耐药中起作用。该提案旨在研究糖皮质激素下调MUC4以增强化疗敏感性的效用，从而作为佐剂与吉西他滨(以及可能的其他化疗药物)联合治疗致命的胰腺癌。

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.