权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要