MUC1 AND RESISTANCE OF CANCER CELLS TO ONCOLYTIC VIROTHERAPY

描述(由申请人提供)：本学术研究促进奖(AREA)R15提案的主要目的是评估粘蛋白家族成员MUC1蛋白在胰腺癌细胞对溶瘤病毒(OV)耐药中的作用。大约95%的胰腺癌是PDA，它具有高度侵袭性，局部生长侵袭性强，转移迅速。几种癌症疗法在其他类型的肿瘤中被证明是成功的，但对治疗PDA几乎没有效果，PDA的5年存活率为8-20%。因此，迫切需要为PDA患者开发新的治疗策略。OV疗法是一种新的抗癌方法，它利用复制能力强的病毒特异性地杀死肿瘤细胞。在大量成功的临床前研究之后，几种OV现在已经或正在进入针对各种癌症的第三阶段临床试验，因此，FIRS OV有望在不久的将来在北美获得批准。尽管取得了所有这些成功，但很明显，在开发有效的卵子疗法方面仍然存在一些重要的障碍。最近的几项研究表明，许多癌症类型对OVS的敏感性/耐药性具有高度的异质性。人们对耐药机制知之甚少。我们的初步数据表明，至少部分PDA细胞对病毒治疗的耐药性可能是由于MUC1蛋白的过度表达所致。MUC1受发育调节，在许多人类腺癌中异常过度表达，包括胰腺癌、乳腺癌和卵巢癌。我们推测，MUC1的过度表达在PDA细胞对卵子治疗的耐药性中起着重要作用。在目标1中，我们将在体外使用几种遗传和生化方法来检验这一假说，而在目标2中，我们将在裸鼠和免疫活性的PDA模型中解决这个问题。由于MUC1已经被用作PDA的预后和诊断标记物，了解MUC1在胰腺癌对OV治疗耐药中的作用不仅对于更好地了解癌细胞中病毒与宿主的相互作用非常重要，而且对于对特定OV治疗的癌症患者进行预筛选具有潜在的实际意义。 公共卫生相关性：这项学术研究促进奖(AREA)R15提案旨在了解MUC1蛋白在胰腺癌细胞对溶瘤病毒治疗的耐药性中的作用。约95%的胰腺癌是胰腺导管腺癌(PDA)，具有侵袭性局部生长和向周围组织快速转移的特点。动脉导管未闭(PDA)被认为是最致命的腹部恶性肿瘤之一，为PDA患者开发新的合理治疗策略至关重要。我们的初步数据表明，至少部分PDA细胞对病毒治疗的耐药性是由于粘蛋白家族成员MUC-1蛋白的过度表达。我们将在体外和体内使用几种遗传和生化方法来检验这一假说。由于MUC1已经被用作PDA的预后和诊断标记物，了解MUC1在溶瘤病毒治疗耐药中的作用不仅对于更好地了解癌细胞中病毒与宿主的相互作用非常重要，而且对于对癌症患者进行特定溶瘤治疗的预筛选具有潜在的实际意义。

DESCRIPTION (provided by applicant): The major objective of this Academic Research Enhancement Award (AREA) R15 proposal is to evaluate the role of MUC1 protein, a member of the mucin family, in resistance of pancreatic cancer cells to oncolytic viruses (OV). About 95% of pancreas cancers are PDAs which are highly invasive with aggressive local growth and rapid metastases. Several cancer therapies proven successful in other tumor types have had little effect in treating PDA, which has a 5 year survival rate of 8-20%. Therefore there is a grea need for developing new treatment strategies for patients suffering from PDA. OV therapy is a new anticancer approach that utilizes replication-competent viruses specifically killing tumor cells. Following numerous successful preclinical studies, several OVs have now entered or are entering phase III clinical trials against various cancers, and therefore, the approval of the firs OV in North America is expected in the near future. Despite all these successes, it has become clear that several important barriers remain in the development of effective OV therapy. Several recent studies indicated that many cancer types are highly heterogeneous in their susceptibility/resistance to OVs. Mechanisms of resistance are poorly understood. Our preliminary data suggest that the resistance to virotherapy in at least some PDA cells could be due to the over-expression of MUC1 protein. MUC1 is developmentally regulated and aberrantly over expressed in many human adenocarcinomas including those of the pancreas, breast, and ovaries. We hypothesize that over-expression of MUC1 plays an important role in the resistance of PDA cell lines to OV therapy. In Aim 1 we will examine this hypothesis using several genetic and biochemical approaches in vitro, while in Aim 2 we will address this problem in nude athymic mice and in an immunocompetent model of PDA. As MUC1 is already used as a prognostic and diagnostic marker for PDA, understanding the role of MUC1 in resistance of pancreatic cancers to OV therapy is very important not only for better understanding virus-host interactions in cancer cells, but for potential practical implications for prescreening of cancer patients for a particular OV therapy. PUBLIC HEALTH RELEVANCE: This Academic Research Enhancement Award (AREA) R15 proposal is aimed at understanding the role of MUC1 protein in resistance of pancreatic cancer cells to oncolytic virotherapy. About 95% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDA) which are highly invasive with aggressive local growth and rapid metastases to surrounding tissues. PDA is considered one of the most lethal abdominal malignancies and the development of new rational treatment strategies for patients suffering from PDA is of utmost importance. Our preliminary data suggest that the resistance to virotherapy in at least some PDA cells is due to the over-expression of MUC-1 protein, a member of the mucin family. We will examine this hypothesis using several genetic and biochemical approaches in vitro and in vivo. As MUC1 is already used as a prognostic and diagnostic marker for PDA, understanding the role of MUC1 in resistance to oncolytic virotherapy is very important not only for better understanding virus-host interactions in cancer cells, but for potential practical implications for prescreening of cancer patients for a particula oncolytic therapy.