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

 描述（由申请人提供）：靶向突变癌蛋白的癌症治疗已被证明非常有效，并且通常与常规化疗相比副作用较少相关。突变特异性治疗的这种范例的扩展继续影响多种癌症的治疗。尽管有这些进展，但许多肿瘤类型和许多遗传背景仍然对这种“靶向方法”难以治疗，其中主要是RAS突变型肿瘤。此外，即使靶向关键突变蛋白，抗性也几乎总是发展。因此，非常需要能够向大部分癌症患者提供靶向干预的新方法，其独立于肿瘤的突变状态并且具有较低的相关疾病复发率。在这里，我们提出了一个研究计划，旨在制定一条实现这些重要目标的合理路径。众所周知，不同组织来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、存活、运动性、侵袭性和细胞代谢。值得注意的是，这些特征出现在不同的癌症中，以响应各种各样的致癌突变。这种强烈的行为趋同表明，不同癌症之间共享的机制发挥着关键作用，这些机制作用于突变致癌驱动因子的下游，并介导恶性细胞转化过程和/或维持癌细胞稳态。通过分析致癌基因协同性的分子机制，我们已经表明，多个致癌基因突变的联合作用是通过所谓的“合作反应基因”（CRG）的协同调节介导的。值得注意的是，致癌突变下游的这些非突变基因对于不同类型癌症中共有的癌细胞特征的出现至关重要。深入的功能分析表明，大多数测试的CRG对癌症表型至关重要，对它们所控制的过程的研究揭示了合成的癌细胞特异性脆弱性的新点。此外，我们发现许多CRG在各种癌症中类似地失调，这些癌症具有广泛的致癌驱动突变。值得注意的是，CRG表达模式在原发性和复发性癌症中也是保守的，这些癌症在疾病进展期间经历了致癌驱动因子身份的转换。因此，我们的初步数据与我们的中心假设一致，即CRG对于维持不同癌症之间共享的恶性状态的核心特征至关重要。我们相信，了解癌细胞稳态的出现和稳定性的潜在机制，将为靶向和癌细胞特异性干预提供巨大的希望和意想不到的机会，而不依赖于致癌驱动突变的身份。我们将使用遗传学上易于处理的体内和体外模型，结合基因组RNA表达和生物信息学分析，以确定与癌细胞稳态中CRG活性相关的关键调控途径和回路。

 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.