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Novel DNA damage response therapeutics targeting replication protein A

针对复制蛋白 A 的新型 DNA 损伤反应疗法

基本信息

批准号：
10653707
负责人：
JOHN J. TURCHI
金额：
$ 48.14万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653707
关键词：
Address Automobile Driving Biochemical CHEK1 gene CHEK2 gene CRISPR screen Cell Death Cells Characteristics Chemicals Chromosomal Rearrangement Chromosomes Clinical Clinical Trials Combined Modality Therapy Coupled DNA Binding DNA Damage DNA Repair Pathway DNA-dependent protein kinase Data Developmental Therapeutics Program Drug Targeting Epithelial Cells Epithelial ovarian cancer Genetic Genetic Determinism Genetic Models Genomic DNA Health Human Individual Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Measures Methodology Modeling Molecular Mutation Non-Small-Cell Lung Carcinoma Oncogenic PIK3CG gene Pathway interactions Patients Phosphotransferases Play Poly(ADP-ribose) Polymerase Inhibitor Publishing Research Role SS DNA BP Series Serous Signal Transduction Single-Stranded DNA Therapeutic Therapeutic Agents Toxic effect anticancer activity ataxia telangiectasia mutated protein cancer cell cancer type chemical genetics clinically relevant driver mutation effective therapy exhaustion genome sequencing homologous recombination in vivo inhibitor inhibitor therapy novel novel therapeutics patient derived xenograft model patient response personalized medicine pharmacologic repaired replication factor A replication stress response small molecule success synthetic lethal interaction targeted agent targeted cancer therapy targeted treatment therapeutic target treatment response treatment strategy tumor whole genome

项目摘要

Novel DNA damage response therapeutics targeting replication protein A Abstract The DNA damage response (DDR) is now considered a tractable pathway to target for cancer therapy. The DDR and DNA repair pathways are also amenable to personalized therapies by exploiting synthetic lethal interactions as evidenced by the clinical success of PARP inhibitors in homologous recombination (HR) deficient cancers. The DDR is initiated by engagement of the PI3 kinase-related kinases ATM, ATR, and DNA- PK. These kinases and the downstream checkpoint kinases CHK1 and CHK2, are clinically validated targets being actively investigated in multiple clinical trials. A novel target in the DDR pathway is the human single stranded DNA binding protein, replication protein A (RPA) which plays a critical role in the DDR to detect replication stress (RS) and signal to the ATR kinase. RS is a common feature in cancer cells and provides the therapeutic window for the anticancer activity of DDR targeted drugs. RS coupled with a DDR blockade results in replication catastrophe (RC) and eventually cell death. RPA is a critical protector from RC and depletion of RPA or “RPA exhaustion” can elicit RC and cell death when there is insufficient single-strand DNA binding capacity to protect the genomic DNA. We have identified a potent and selective small molecule RPA inhibitor (RPAi), NERx 329, which possesses biochemical RPA inhibition and cellular engagement of RPA. NERx 329 also displays no overt toxicity in vivo and possesses anticancer activity alone and in combination with DNA damaging chemotherapeutics and certain DDR targeted agents. While the anticancer activity could be the result of inhibiting RPA’s role in individual repair or replication pathways, our published and preliminary data point to a more global mechanism of action. Our overarching hypothesis is that chemical inhibition of RPA can mimic RPA exhaustion to inhibit the DDR and provide selective anticancer activity via novel genetic interactions common in lung and ovarian cancer. To address this hypothesis, we will elucidate the mechanisms and determinants of the cellular anticancer activity of our novel RPAi. We will focus on two cancers types, high grade serous epithelial ovarian cancer (EOC) and non-small cell lung cancer (NSCLC), as our analysis of clinical survival data reveals an important role for RPA in these cancers. In Aim 1 we will interrogate how chemical exhaustion of RPA impacts RS and the DDR in lung and ovarian cancer. Aim 2 will focus on elucidating the genetic determinants of sensitivity to RPAi’s. We will identify novel chemical-genetic interactions in a DDR focused CRISPR screen assessing RPAi activity. Clinically relevant genetic interactions will be identified in a unique series of PD-EOC spheroid lines we have developed. Whole genome sequencing will identify genetic alterations and chromosomal rearrangements which may correlate with response to RPAi therapy. From these studies, specific genetic alterations that impact RPAi sensitivity will be validated with in vivo PDX models of lung and ovarian cancer and DDR targeted developmental therapeutic agents. Completion of these aims will define RPAi mechanism of action and the genetic interactions that dictate RPAi sensitivity. These data are crucial towards developing novel DDR targeted cancer therapeutics and identifying the relevant genetics characteristics to maximize patient response and efficacy.

靶向复制蛋白A的新型DNA损伤反应疗法

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair.

DOI：
10.3389/fonc.2022.850883
发表时间：
2022
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
通讯作者：

Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.

DOI：
10.1016/j.molcel.2021.06.011
发表时间：
2021-08-05
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Cong, Ke;Peng, Min;Kousholt, Arne Nedergaard;Lee, Wei Ting C.;Lee, Silviana;Nayak, Sumeet;Krais, John;VanderVere-Carozza, Pamela S.;Pawelczak, Katherine S.;Calvo, Jennifer;Panzarino, Nicholas J.;Turchi, John J.;Johnson, Neil;Jonkers, Jos;Rothenberg, Eli;Cantor, Sharon B.
通讯作者：
Cantor, Sharon B.

OB-Folds and Genome Maintenance: Targeting Protein-DNA Interactions for Cancer Therapy.

DOI：
10.3390/cancers13133346
发表时间：
2021-07-03
期刊：
Cancers
影响因子：
5.2
作者：
Par S;Vaides S;VanderVere-Carozza PS;Pawelczak KS;Stewart J;Turchi JJ
通讯作者：
Turchi JJ

In Vivo Targeting Replication Protein A for Cancer Therapy.

DOI：
10.3389/fonc.2022.826655
发表时间：
2022
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
VanderVere-Carozza PS;Gavande NS;Jalal SI;Pollok KE;Ekinci E;Heyza J;Patrick SM;Masters A;Turchi JJ;Pawelczak KS
通讯作者：
Pawelczak KS