Mediators of cancer cell homeostasis: intervention targets common to diverse types of cancer

癌细胞稳态的介质：不同类型癌症共有的干预目标

• 批准号: 10215239
• 负责人: Hartmut Land
• 金额: $ 85.39万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215239
• 关键词: Automobile Driving; Behavior; Bioinformatics; Cancer Intervention; Cancer Patient; Cellular Metabolic Process; Data; Disease; Disease Progression; Drug resistance; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Intervention; Investigation; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular Analysis; Mutate; Mutation; Oncogenes; Oncogenic; Oncoproteins; Patients; Phenotype; Process; Proteins; Recurrence; Recurrent Malignant Neoplasm; Refractory; Regulation; Regulatory Pathway; Research; Resistance; Role; Tissues; cancer cell; cancer therapy; cancer type; cell motility; cell transformation; chemotherapy; driver mutation; genetic testing; genomic RNA; in vitro Model; in vivo; malignant state; mutant; mutational status; novel; novel strategies; programs; public health relevance; response; self-renewal; side effect; trait; tumor

 DESCRIPTION (provided by applicant): Cancer treatments targeting mutated oncoproteins have proven highly effective and are often associated with fewer side effects than conventional chemotherapy. The expansion of this paradigm of mutation- specific treatments continues to impact the treatment of a large diversity of cancers. In spite of these advances many tumor types and many genetic contexts remain refractory to such "targeted approaches", chief among these are RAS mutant tumors. Furthermore, even when key mutant proteins are targeted resistance almost invariably develops. Thus, new approaches capable of delivering targeted interventions to a large fraction of cancer patients, independent of the tumors' mutational status and with lower rates of associated disease recurrence, are highly desirable. Here we propose a research program with the intent of developing a rational path towards reaching these important goals. It is well established that cancer cells of diverse tissue origin share a variety of critica features, including immortality, uncontrolled self- renewal, survival, motility, invasiveness, and cell metabolism. Notably, these features emerge in diverse cancers in response to a wide variety of oncogenic mutations. Such strong convergence in behavior suggests a critical role for mechanisms shared between diverse cancers that act downstream of mutant oncogenic drivers and mediate the malignant cell transformation process and/or maintain cancer cell homeostasis. Through analysis of the molecular mechanisms underlying oncogene cooperativity we have shown that the combined effect of multiple oncogenic mutations is mediated through synergistic regulation of so-called `cooperation response genes' (CRGs). Notably, these non-mutated genes downstream of oncogenic mutations are critical to the emergence of the cancer cell traits shared among diverse types of cancer. In depths functional analysis indicates that the majority of CRGs tested are critical to the cancer phenotype, and investigation of the processes they govern is revealing novel points of synthetic, cancer cell-specific vulnerability. Further, we are finding that many CRGs are similarly de-regulated in various cancers harboring a wide spectrum of oncogenic driver mutations. Notably, CRG expression patterns are also conserved in primary and recurrent cancers that have undergone a switch in oncogenic driver identity during disease progression. Our preliminary data are thus consistent with our central hypothesis that CRGs are critical to sustaining core features of a malignant state shared between diverse cancers. Understanding mechanisms underlying emergence and stability of cancer cell homeostasis, we believe, will hold great promise and unexpected opportunities for targeted and cancer cell-specific interventions independent of the identity of oncogenic driver mutations. We will be using genetically tractable in vivo and in vitro models in combination with genomic RNA expression and bioinformatics analyses to identify key regulatory pathways and circuits related to CRG activity in cancer cell homeostasis.

 描述（由适用提供）：靶向突变癌蛋白的癌症治疗已被证明非常有效，并且与常规化学疗法相比，副作用通常更少。这种突变特定治疗范式的扩展继续影响对大量癌症的治疗。尽管这些进展许多肿瘤类型，许多遗传环境仍然对这种“靶向方法”仍然难治性，其中主要是RAS突变肿瘤。此外，即使关键突变蛋白被靶向抗性几乎总是发展出来。这是高度可取的，这使得针对大部分癌症患者的大量癌症患者的针对性干预措施是高度可取的。在这里，我们提出了一项研究计划，目的是为实现这些重要目标开发理性的道路。众所周知，各种组织起源的癌细胞具有多种关键特征，包括永生，不受控制的自我更新，生存，运动，侵入性和细胞代谢。值得注意的是，这些特征响应多种致癌突变而出现在潜水员癌症中。这种强烈的行为收敛性表明，对突变体致癌驱动因素下游作用并介导恶性细胞转化过程和/或维持癌细胞体内平衡的潜水癌的机制至关重要。通过分析癌基因协调的分子机制，我们已经表明，多种致癌突变的综合作用是通过对所谓的“合作响应基因”（CRG）的协同调节（CRGS）介导的。值得注意的是，这些非突变突变下游的非突变基因对于在潜水员类型的癌症中共享的癌细胞特征的出现至关重要。深度功能分析表明，所测试的大多数CRG对癌症表型至关重要，并且对它们所管理的过程的研究揭示了合成，癌细胞特异性脆弱性的新颖点。此外，我们发现在具有广泛的致癌驱动器突变的各种癌症中，许多CRG被同样被脱离。值得注意的是，在疾病进展过程中经历过致癌驱动器身份的原发性和复发性癌症中，CRG表达模式也是保守的。因此，我们的初步数据与我们的核心假设一致，即CRG对于维持发散癌症共享恶性状态的核心特征至关重要。我们认为，了解癌细胞体内稳态的出现和稳定性的机制将为靶向和癌细胞特异性干预措施带来巨大的希望和意外机会，而与致癌驱动器突变的身份无关。我们将使用基因组RNA表达和生物信息学分析结合使用的普通体内和体外模型来鉴定与癌细胞稳态中与CRG活性相关的关键调节途径和电路。