Targeting ALT-Cancer

项目总结 拟议项目的长期目标是确定第一批化学探测器和线索，以开发 首先针对替代延长端粒(ALT)途径的临床候选药物。细胞永生是 对肿瘤的发生至关重要，在约85%的癌症和ALT中是通过端粒酶的作用实现的 约15%的癌症的发病机制。人们对ALT知之甚少，但大多数ALT细胞似乎都有一个共同的 生物标记物，染色体外的C-环，被预测参与端粒维持。在许多 在癌症中，ALT表型与高级别和不良预后有关。这表明将目标对准 ALT途径将在相当数量的疾病状态中产生重大影响。除了临床上的 ALT的相关性，在基础水平上，ALT的机制还没有被很好地理解。要解决这些问题 未满足的需求，我们将使用C环作为ALT的读数来识别针对ALT的化学探针 表型。我们方法的强大之处在于读出是特定于表型的，并且复合文库 我们将使用包括靶标的特定文库，重点放在表观遗传和激酶靶标上，以及多样化 化学图书馆。目标集中的文库将允许使用化学遗传学方法来解开ALT 机械装置。我们期待着发现类似药物的小分子作为研究的起点 发现ALT-癌细胞选择性试剂和探针。我们预测筛选以目标为重点的文库 对于ALT特定的表型，将允许高效生产化学探针，这些探针将在 解开ALT的机制并允许评估ALT特异性的抗癌方法。

PROJECT SUMMARY The long-term goal of the proposed project is to identify the first chemical probes and leads for developing the first clinical candidates targeting the alternative lengthening of telomeres (ALT) pathway. Cellular immortality is essential for tumorigenesis and is achieved by the action of telomerase in ~85% of cancers and the ALT mechanism in ~15% of cancers. ALT is poorly understood, but most ALT cells appear to share a common biomarker, extrachromosomal C-circles, that are predicted to be involved in telomere maintenance. In many cancers, the ALT phenotype is associated with high grade and poor prognosis. This suggests that targeting the ALT pathway will have significant impact in a substantial number of disease states. In addition to the clinical relevance of ALT, at a fundamental level, the mechanisms of ALT are not well understood. To address these unmet needs, we will identify chemical probes that target ALT using C-circles as a readout for the ALT phenotype. The power of our approach is that the readout is phenotype specific and the compound libraries we will use include target specific libraries, with a focus on epigenetic and kinase targets, as well as diverse chemical libraries. The target focused libraries will allow a chemical genetics approach towards unraveling ALT mechanisms. We anticipate the discovery of small, drug-like molecules to serve as starting points for the discovery of ALT-cancer cell selective agents and probes. We predict that screening target-focused libraries for an ALT-specific phenotype will allow efficient production of chemical probes that will be transformative in unraveling the mechanisms of ALT and allow the evaluation ALT-specific anticancer approaches.