Novel Approaches for Pancreatic Cancer Therapy

胰腺癌治疗的新方法

• 批准号: 6698527
• 负责人: PAUL B FISHER
• 金额: $ 36.38万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-21 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6698527
• 关键词: Adenoviridae; BCL2 gene /protein; Bax gene /protein; antisense nucleic acid; apoptosis; athymic mouse; biological signal transduction; combination chemotherapy; gene expression; gene induction /repression; melanoma; method development; mutant; neoplasm /cancer therapy; neoplastic cell; nonhuman therapy evaluation; oncogenes; p53 gene /protein; pancreas neoplasms; pancreatic islets; protein structure function; recombinant virus; transfection /expression vector; tumor suppressor genes; tumor suppressor proteins; virus replication

DESCRIPTION (provided by applicant): Pancreatic cancer is an extremely aggressive neoplasm whose incidence equals its death rate. Despite extensive analysis, no effective therapeutic approaches for diminishing the morbidity associated with this disease are available. By appropriate pharmacological manipulation, human melanoma cells can be induced to lose tumorigenic potential, irreversibly growth arrest and terminally differentiate. Through the use of subtraction hybridization, a novel gene associated with these changes in human melanoma cells, melanoma differentiation associated gene-7 (mda-7), has been identified. Ectopic expression of mda-7 using a recombinant adenovirus, Ad.mda-7, promotes growth suppression and apoptosis in diverse cancer cell types, including tumor cells with wild-type p53 or mutant for p53, Rb or p53 + Rb. Moreover, growth and progression of human breast, lung and cervical cancer cells in vivo in nude mice are inhibited by Ad.mda-7. In contrast, no deleterious effect is apparent following Ad.mda-7 infection of normal human cells. Selective induction of apoptosis in multiple tumor cell types correlates with an elevation in the level of the pro-apoptotic protein BAX and an increase in the ratio of BAX to BCL-2. In contrast to its apoptosis-inducing effects in the majority of human cancers, pancreatic carcinomas are refractory to Ad.mda-7. However, when Ad.mda-7 is combined with approaches that specifically inhibit expression of the K-ras oncogene, which is mutated in approximately 85 to approximately 95 percent of pancreatic carcinomas, a loss of viability by induction of apoptosis results. These intriguing observations suggest that a combinatorial approach consisting of a cancer-specific apoptosis-inducing gene and an oncogene inactivation strategy may provide the basis for developing an effective molecular-target based therapy for pancreatic cancer. Experiments will expand on these observations and determine the mechanism underlying the synergy and develop potential cancer therapeutic viruses, including Ads expressing a combination of mda-7 and antisense K-ras and an Ad displaying cancer-restricted replication and cytolytic activity in the context of pancreatic carcinoma cells. The present studies will provide the obligatory preclinical support for novel approaches with significant potential for rapid translation into rational methods for treating patients' afflicted with an invariably incurable disease, pancreatic cancer.

描述（由申请人提供）：胰腺癌是一种极具侵略性的肿瘤，其发病率等于其死亡率。 尽管进行了广泛的分析，但仍未使用有效的治疗方法来减少与该疾病相关的发病率。 通过适当的药理操纵，可以诱导人类黑色素瘤细胞失去肿瘤性潜力，不可逆转的生长停滞和极端分化。 通过使用减法杂交，已经鉴定出了与人黑色素瘤细胞中这些变化相关的新基因，黑色素瘤分化相关基因-7（MDA-7）。使用重组腺病毒AD.MDA-7的MDA-7异位表达可促进各种癌细胞类型的生长抑制和凋亡，包括p53，RB或p53 + Rb的野生型p53或突变体的肿瘤细胞。 此外，AD.MDA-7抑制了裸鼠体内人乳房，肺和宫颈癌细胞的生长和进展。 相反，在正常人细胞的MDA-7感染后，没有明显的有害作用。多种肿瘤细胞类型中凋亡的选择性诱导与促凋亡蛋白Bax水平的升高以及BAX与Bcl-2的比率增加相关。 与大多数人类癌症中的凋亡诱导作用相反，胰腺癌对AD.MDA-7难治性。 但是，当AD.MDA-7与特异性抑制K-RAS癌基因表达的方法结合使用时，在大约85至85％至约95％的胰腺瘤中突变，通过诱导凋亡结果丧失了生存能力。 这些有趣的观察结果表明，由癌症特异性细胞凋亡基因和致癌基因灭活策略组成的组合方法可能为开发有效的基于分子靶向胰腺癌的治疗提供了基础。 实验将扩大这些观察结果，并确定协同效应的机制并开发潜在的癌症治疗病毒，包括表达MDA-7和反义K-RAS组合的ADS以及在胰腺癌细胞上下文中表现出癌症限制的复制和细胞溶解活性的AD。 本研究将为新方法提供强制性的临床前支持，并将快速转化为理性方法，以治疗患者遭受不变疾病，胰腺癌的治疗。