Kinetic analysis of Myc-induced carcinogenesis in vivo

Myc 诱导体内致癌作用的动力学分析

• 批准号: 7810404
• 负责人: GERARD IAN EVAN
• 金额: $ 46.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810404
• 关键词: Adverse effects; Anabolism; Animals; Antigens; Antineoplastic Agents; Apoptosis; Binding; Biological; Boxing; CDKN2A gene; Cancer Patient; Cell Proliferation; Cytostatics; DNA Binding; Data; Diagnosis; Dimerization; Dominant-Negative Mutation; Drug usage; E-Box Elements; Elements; Evolution; Funding; Gene Targeting; Generic Drugs; Genetic; Genotype; Heterodimerization; Human; Immune; Individual; Induction of Apoptosis; Inflammatory Response; Islets of Langerhans; Kinetics; Lung Neoplasms; MYC gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolism; Modality; Modeling; Molecular; Mus; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Proliferating; Protein p53; Recovery; Relative (related person); Repression; Resistance; Rest; Role; Simian virus 40; Staging; TP53 gene; Therapeutic; Therapeutic Effect; Tissues; Transactivation; Treatment Efficacy; United States National Institutes of Health; Work; angiogenesis; anti-cancer therapeutic; base; c-myc Genes; cancer therapy; carcinogenesis; chemotherapy; design; dimer; effective therapy; extracellular; gemcitabine; in vivo; inhibitor/antagonist; interest; mouse model; mutant; neoplastic cell; pancreatic neoplasm; pre-clinical; programs; promoter; public health relevance; response; restoration; senescence; standard of care; therapeutic target; transcription factor; tumor

DESCRIPTION (provided by applicant): Expression of the c-myc oncogene is deregulated in almost all cancers. c-myc encodes a transcription factor, Myc, that coordinates the many diverse intra and extracellular biological programs that underpin normal and tumor cell proliferation, including cell proliferation, metabolism, biosynthesis, invasion, de-differentiation and angiogenesis. Its pivotal role in maintaining so many disparate aspects of cell proliferation make it a superb potential target for therapeutic inhibition in cancer. Recently, we reduced this idea to practice using a genetic mouse model for Myc inhibition by showing that systemic inhibition of Myc triggers rapid and complete tumor regression in a preclinical mouse model of Non Small Cell Lung Cancer driven by mutant K-Ras, while eliciting only mild, well-tolerated and completely reversible side effects in normal proliferating tissues. Our subsequent work has now validated the therapeutic efficacy of Myc inhibition in other tumor types driven by other oncogenes in other tissues, raising the tantalizing possibility that inhibition of Myc might be the basis for a generalized anti-cancer therapeutic. In response to notice number NOT-OD-09-058 "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications", we propose to extend these initial studies by ascertaining the therapeutic impact of systemic Myc inhibition in vivo in pancreatic adenocarcinoma, one of the most intractable and deadly cancers, using a well validated preclinical mouse model. We will also ascertain the use of Myc inhibition therapy in combination with several other therapeutic modalities - restoration of the p53 tumor suppressor and standard of care chemotherapy with gemcitabine. In a second aim, we will establish how best to target Myc at the molecular level, so paving the way for the rational design of a Myc inhibitory drug. PUBLIC HEALTH RELEVANCE: Currently, there is great interest in the idea of personalized therapy for cancer, based on the notion that each patient's cancer is distinct. However, despite clear idiopathic differences in individual patients' tumors, there remains substantial evidence that cancers also share common, obligate aberrant elements that, if adroitly targeted, might offer generic therapeutic options. One of these is Myc - a pleiotropic transcription factor whose function is deregulated in almost all human cancers. We have developed unique and sophisticated, switchable genetic pre-clinical mouse model with which to ascertain the therapeutic value of inhibiting Myc in established cancers and shown it to be effective at triggering regression in several tumor types. Hence, Myc inhibition may be an effective therapy for treating many cancers, including those currently incurable. In this proposal, we will ascertain the value of Myc inhibition-based therapy for treating pancreatic adenocarcinoma, one of the most intractable and deadly of all cancers with a mean survival post diagnosis of only 5 months and for which there are no effective therapeutic options.

描述(申请人提供)：c-myc癌基因的表达在几乎所有癌症中都是非调控的。C-myc编码一种转录因子Myc，它协调许多不同的细胞内外生物学程序，包括细胞增殖、新陈代谢、生物合成、侵袭、去分化和血管生成。它在维持如此多不同的细胞增殖方面发挥着关键作用，使其成为癌症治疗抑制的极佳潜在靶点。最近，我们将这一想法简化为使用Myc抑制的遗传小鼠模型进行实践，表明在由突变K-RAS驱动的非小细胞肺癌临床前小鼠模型中，全身抑制Myc可触发快速且完全的肿瘤消退，而在正常增殖组织中仅引起轻微的、耐受性良好的且完全可逆的副作用。我们随后的工作现在已经验证了Myc抑制在其他组织中由其他癌基因驱动的其他肿瘤类型中的治疗效果，增加了Myc抑制可能是普遍抗癌治疗的基础的诱人可能性。为了回应通知NOT-OD-09-058“NIH宣布恢复法案资金可用于竞争性修订应用”，我们建议扩展这些初步研究，通过使用经过良好验证的临床前小鼠模型，确定体内系统性Myc抑制对胰腺癌的治疗影响，胰腺癌是最难治疗和最致命的癌症之一。我们还将确定Myc抑制疗法与其他几种治疗方式的联合使用--恢复p53肿瘤抑制基因和吉西他滨的标准护理化疗。在第二个目标中，我们将确定如何在分子水平上最好地靶向Myc，从而为合理设计Myc抑制药物铺平道路。 公共卫生相关性：目前，人们对癌症个性化治疗的想法非常感兴趣，这是基于每个患者的癌症是不同的这一概念。然而，尽管个别患者的肿瘤存在明显的特发性差异，但仍有大量证据表明，癌症也具有共同的、特有的异常因素，如果巧妙地进行靶向，可能会提供通用的治疗方案。其中之一是Myc，这是一种多效性转录因子，其功能在几乎所有人类癌症中都是失控的。我们已经开发了独特的、复杂的、可切换的临床前遗传学小鼠模型，用来确定抑制Myc在已建立的癌症中的治疗价值，并表明它在几种肿瘤类型中引发消退是有效的。因此，抑制Myc可能是治疗许多癌症的有效疗法，包括目前无法治愈的癌症。在这项建议中，我们将确定基于Myc抑制的治疗胰腺癌的价值，胰腺癌是所有癌症中最难治和最致命的癌症之一，确诊后平均生存时间只有5个月，而且没有有效的治疗选择。