MUC1 AND RESISTANCE OF CANCER CELLS TO ONCOLYTIC VIROTHERAPY

MUC1 和癌细胞对溶瘤病毒疗法的抵抗

• 批准号: 8290645
• 负责人: Valery Zurabovich Grdzelishvili
• 金额: $ 43.67万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8290645
• 关键词: Abdomen; Academic Research Enhancement Awards; Address; Adenocarcinoma; Adenocarcinoma Cell; Biochemical; Breast; CA-15-3 Antigen; Cancer Model; Cancer Patient; Carbohydrates; Cell Death; Cell Line; Cessation of life; Colon; Data; Development; Diagnostic; Disease; Family; Future; Genetic; Human; Immunocompetent; In Vitro; Incidence; Malignant Neoplasms; Malignant neoplasm of pancreas; Modeling; Mucin-1 Staining Method; Mucins; Mus; Neoplasm Metastasis; North America; Nude Mice; Oncolytic; Oncolytic viruses; Ovary; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phase III Clinical Trials; Play; Predisposition; Proteins; Resistance; Resistance development; Role; Survival Rate; Testing; Tissues; Vesicular stomatitis Indiana virus; Virus; base; cancer cell; cancer therapy; cancer type; conditionally replicative adenovirus; in vitro Model; in vivo; killings; member; mouse model; neoplastic cell; pancreatic cancer cells; preclinical study; prognostic; rapid growth; research study; resistance mechanism; success; treatment strategy; tumor; virus host interaction

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.

描述（由申请人提供）：本学术研究增强奖（AREA） R15提案的主要目的是评估MUC1蛋白（粘蛋白家族的一员）在胰腺癌细胞对溶瘤病毒（OV）的抗性中的作用。约95%的胰腺癌为PDAs，具有高度侵袭性，局部生长迅速，转移迅速。一些癌症疗法在其他肿瘤类型中被证明是成功的，但对PDA的治疗效果甚微，其5年生存率为8-20%。因此，迫切需要为PDA患者开发新的治疗策略。OV疗法是利用具有复制能力的病毒特异性杀伤肿瘤细胞的一种新的抗癌方法。在大量成功的临床前研究之后，一些OV现已进入或正在进入针对各种癌症的III期临床试验，因此，预计北美首个OV将在不久的将来获得批准。尽管取得了这些成功，但很明显，在发展有效的外阴疗法方面仍然存在一些重要的障碍。最近的几项研究表明，许多癌症类型在对OVs的易感性/抗性方面具有高度异质性。人们对耐药性的机制了解甚少。我们的初步数据表明，至少一些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。MUC1在许多人类腺癌（包括胰腺、乳腺和卵巢的腺癌）中受发育调控和异常过表达。我们假设MUC1的过表达在PDA细胞系对OV治疗的抗性中起重要作用。在Aim 1中，我们将使用几种体外遗传和生化方法来检验这一假设，而在Aim 2中，我们将在裸胸腺小鼠和PDA免疫功能模型中解决这一问题。由于MUC1已被用作PDA的预后和诊断标志物，因此了解MUC1在胰腺癌对OV治疗耐药中的作用不仅对更好地了解癌细胞中病毒-宿主相互作用非常重要，而且对癌症患者进行特定OV治疗的预筛选具有潜在的实际意义。

项目成果

An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells.

• DOI: 10.1016/j.virol.2015.04.017
• 发表时间: 2015-09
• 期刊: Virology
• 影响因子: 3.7
• 作者: Hastie E;Cataldi M;Steuerwald N;Grdzelishvili VZ
• 通讯作者: Grdzelishvili VZ

Induction of apoptosis in pancreatic cancer cells by vesicular stomatitis virus.

• DOI: 10.1016/j.virol.2014.10.026
• 发表时间: 2015-01-01
• 期刊: VIROLOGY
• 影响因子: 3.7
• 作者: Felt, Sebastien A.;Moerdyk-Schauwecker, Megan J.;Grdzelishvili, Valery Z.
• 通讯作者: Grdzelishvili, Valery Z.

Breaking resistance of pancreatic cancer cells to an attenuated vesicular stomatitis virus through a novel activity of IKK inhibitor TPCA-1.

• DOI: 10.1016/j.virol.2015.08.003
• 发表时间: 2015-11
• 期刊: Virology
• 影响因子: 3.7
• 作者: Cataldi M;Shah NR;Felt SA;Grdzelishvili VZ
• 通讯作者: Grdzelishvili VZ

Oncolytic vesicular stomatitis virus in an immunocompetent model of MUC1-positive or MUC1-null pancreatic ductal adenocarcinoma.

MUC1 阳性或 MUC1 缺失胰腺导管腺癌免疫活性模型中的溶瘤性水泡性口炎病毒。

• DOI: 10.1128/jvi.01412-13
• 发表时间: 2013
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Hastie,Eric;Besmer,DahliaM;Shah,NiravR;Murphy,AndreaM;Moerdyk-Schauwecker,Megan;Molestina,Carlos;Roy,LopamudraDas;Curry,JenniferM;Mukherjee,Pinku;Grdzelishvili,ValeryZ
• 通讯作者: Grdzelishvili,ValeryZ

Novel biomarkers of resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus.

• DOI: 10.18632/oncotarget.11202
• 发表时间: 2016-09-20
• 期刊: Oncotarget
• 作者: Hastie E;Cataldi M;Moerdyk-Schauwecker MJ;Felt SA;Steuerwald N;Grdzelishvili VZ
• 通讯作者: Grdzelishvili VZ