Novel therapeutics for targeting checkpoint dysfunction in cancer

摘要 正常细胞使用几种基本的刹车机制来紧密协调不同细胞的执行 周期阶段。失去这些检查站控制是癌症的一个标志。我们的目标是设计一种治疗方法 针对携带突变型p53的癌症中新发现的检查点扰动机制的策略。 抑癌基因P53是G1期细胞周期检查点的关键调节因子。突变型P53介导的功能获得 促进肿瘤进展和耐药性。然而，如何在癌症中靶向突变的p53仍然是一个 这是个大挑战。我们的初步研究确定了几种新的机制，突变型p53通过这些机制与 检查点激活蛋白TopBP1在物理和功能上扰乱检查点控制，并诱导 ACTL6A促进顺铂耐药。我们认为突变型p53-TopBP1轴是一种有效的治疗方法 癌症的靶子。我们已经开发了两类新的TopBP1抑制剂，可以靶向突变的P53- TopBP1轴。在这项提案中，我们将确定它们在靶向检查点功能障碍方面的治疗潜力。 癌症。首先，我们将研究突变型P53-TopBP1轴如何扰乱复制控制。第二，我们将 确定突变型P53和ACTL6A在生长控制和顺铂耐药中的功能相互作用。 第三，我们将研究针对乳腺癌和卵巢癌的靶向治疗的新组合。这部小说 我们开发的TopBP1抑制剂将大大增强这一提议的可行性和影响。在……里面 简而言之，拟议的研究将阐明检查点扰动的新机制，并将我们的 发现治疗多种癌症的新疗法。

Abstract Normal cells employ several fundamental brake mechanisms to tightly coordinate the execution of different cell cycle phases. Loss of these checkpoint controls is a hallmark of cancer. Our goal is to devise therapeutic strategies targeting newly discovered checkpoint perturbation mechanisms in cancers harboring mutant p53. Tumor suppressor p53 is a key regulator for G1 cell cycle checkpoint. Mutant p53 mediates gain of functions to promote tumor progression and drug resistance. Nevertheless, how to target mutant p53 in cancer remains a big challenge. Our preliminary study identifies several novel mechanisms by which mutant p53 interacts with a checkpoint activator protein TopBP1 physically and functionally to perturb the checkpoint control, and induces ACTL6A to promote cisplatin resistance. We propose that the mutant p53-TopBP1 axis is a valid therapeutic target in cancer. We have developed two classes of novel TopBP1 inhibitors that can target the mutant p53- TopBP1 axis. In this proposal, we will determine their therapeutic potential in targeting checkpoint dysfunction in cancer. First, we will study how the mutant p53-TopBP1 axis perturbs replication control. Second, we will determine the functional interaction between mutant p53 and ACTL6A in growth control and cisplatin resistance. Third, we will investigate new combinations of targeted therapy against breast and ovarian cancers. The novel TopBP1 inhibitors that we have developed will greatly enhance the feasibility and impact of this proposal. In short, the proposed study will elucidate novel mechanisms of checkpoint perturbation and translate our discoveries into new therapeutics for a broad range of cancers.