Novel therapeutics for targeting checkpoint dysfunction in cancer

针对癌症检查点功能障碍的新疗法

基本信息

批准号：
10444747
负责人：
FANG-TSYR LIN
金额：
$ 38.25万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444747
关键词：
ACTL6A gene Antibodies Award Binding Biochemical Biological Assay Breast CDK4 gene Cancer cell line Cell Cycle Cell Line Cells Cisplatin Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy DNA DNA Damage DNA Repair DNA biosynthesis DNA replication fork Data Dependence Dropout Drug resistance ERCC1 gene Exhibits Fiber Functional disorder G1/S Checkpoint Pathway G1/S Transition G2 Phase Gene Silencing Genome Stability Goals Growth Immunofluorescence Immunologic In Situ Laboratories Lead Legal patent Ligation Malignant Neoplasms Malignant neoplasm of ovary Mediating Methods Molecular Normal Cell Nucleotide Excision Repair Ovarian Pathologic Phase Platinum Proteins Regulation Replication Initiation Resistance Role Site TP53 gene TREX1 gene Testing Therapeutic Translating Xenograft procedure anticancer activity cancer cell cancer therapy cisplatin-DNA adduct combination cancer therapy gain of function in vivo inhibitor malignant breast neoplasm mutant new therapeutic target novel novel therapeutics overexpression patient derived xenograft model prevent recruit repaired replication stress response targeted treatment therapeutic target tool triple-negative invasive breast carcinoma tumor progression

项目摘要

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.

抽象的正常细胞采用几种基本制动机制来紧密协调不同细胞的执行循环阶段。失去这些检查点控制是癌症的一个标志。我们的目标是设计治疗方法针对携带突变 p53 的癌症中新发现的检查点扰动机制的策略。肿瘤抑制因子 p53 是 G1 细胞周期检查点的关键调节因子。突变体 p53 介导功能获得促进肿瘤进展和耐药性。然而，如何针对癌症中的突变 p53 仍然是一个难题巨大的挑战。我们的初步研究确定了突变体 p53 与 p53 相互作用的几种新机制。检查点激活蛋白 TopBP1 在物理上和功能上扰乱检查点控制，并诱导 ACTL6A促进顺铂耐药。我们认为突变的 p53-TopBP1 轴是一种有效的治疗方法癌症的目标。我们开发了两类新型 TopBP1 抑制剂，可以靶向突变 p53- TopBP1 轴。在本提案中，我们将确定它们针对检查点功能障碍的治疗潜力癌症。首先，我们将研究突变体 p53-TopBP1 轴如何扰乱复制控制。其次，我们将确定突变体 p53 和 ACTL6A 在生长控制和顺铂耐药性中的功能相互作用。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。小说我们开发的TopBP1抑制剂将大大增强该提案的可行性和影响力。在简而言之，拟议的研究将阐明检查点扰动的新机制，并将我们的研究成果转化为针对多种癌症的新疗法的发现。