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

 描述(申请人提供)：针对突变癌蛋白的癌症治疗已被证明非常有效，而且通常与传统化疗相比副作用较少。这一突变特异性治疗范例的扩展继续影响着对多种癌症的治疗。尽管取得了这些进展，但许多肿瘤类型和许多遗传背景仍然难以实现这种“靶向治疗”，其中最主要的是RAS突变肿瘤。此外，即使以关键突变蛋白为靶点，也几乎总是会产生耐药性。因此，新的方法能够为大部分癌症患者提供有针对性的干预，独立于肿瘤的突变状态，并具有较低的相关疾病复发率，是非常可取的。在这里，我们提出了一个研究计划，目的是开发一条实现这些重要目标的合理途径。众所周知，不同组织来源的癌细胞具有各种关键特征，包括永生、不受控制的自我更新、存活、运动、侵袭和细胞代谢。值得注意的是，这些特征出现在不同的癌症中，以应对各种各样的致癌突变。这种行为上的强烈趋同表明，不同癌症之间共享的机制发挥了关键作用，这些机制作用于突变的致癌驱动因素的下游，并介导了恶性细胞转化过程和/或维持癌细胞的动态平衡。通过对癌基因协同作用的分子机制的分析，我们发现多个致癌基因突变的联合作用是通过协同调节所谓的“协同反应基因”(CRGs)来实现的。值得注意的是，癌基因突变下游的这些非突变基因对于不同类型癌症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、癌细胞特异性的脆弱性的新点。此外，我们发现许多CRG在含有广泛致癌驱动基因突变的各种癌症中类似地去调节。值得注意的是，CRG的表达模式在原发和复发的癌症中也是保守的，这些癌症在疾病进展过程中经历了致癌驱动因素的转换。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，了解癌细胞稳态产生和稳定的潜在机制，将为靶向和癌症细胞特异性干预带来巨大的希望和意想不到的机会，而不依赖于致癌驱动基因突变的身份。我们将使用可遗传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，确定与癌细胞动态平衡中CRG活性相关的关键调控途径和电路。

 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.