Defining and Targeting Homologous Recombination Deficiency in Breast Cancer
乳腺癌同源重组缺陷的定义和针对
基本信息
- 批准号:10478008
- 负责人:
- 金额:$ 44.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-13 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:4T1AffectAgingAllelesBRCA1 geneBRCA2 geneBackBiological ProcessBreast Cancer ModelBreast Cancer PatientBreast Cancer TreatmentBreast Epithelial CellsBreast cancer metastasisCHEK2 geneCell LineCell SurvivalCellsClinicalClinical DataClinical TrialsClinical Trials DesignComplexCorrelative StudyCytosine deaminaseCytotoxic agentDNA DamageDNA RepairDNA Repair DisorderDNA Repair PathwayDNA Sequence AlterationDefectDevelopmentDiseaseDouble Strand Break RepairEngineeringEstrogen receptor positiveEventExcisionFrequenciesGene MutationGenesGeneticGenomeGenomic InstabilityGenomicsGenotypeGoalsHumanImmune checkpoint inhibitorImmune systemInterruptionLeadLengthLinkMCF10A cellsMCF7 cellMalignant NeoplasmsMemorial Sloan-Kettering Cancer CenterMetastatic breast cancerMethodsMusMutationNew AgentsNon-MalignantNonhomologous DNA End JoiningPALB2 genePathway interactionsPatient SelectionPatientsPatternPlayProteinsRadiation therapyRecoveryRoleSequence DeletionSignal TransductionSpecimenSubgroupSystemT47DTaxonomyTestingTherapeuticTherapeutic AgentsTherapeutic Interventionbasebrca genebreast cancer genomicsbreast tumorigenesiscytotoxic radiationds-DNAgene repairgenetically modified cellsgenome sequencinggenomic signaturehomologous recombinationimprovedimproved outcomeinhibitormalignant breast neoplasmmouse modelmutantneoplastic cellpatient prognosispersonalized medicinepre-clinicalrepairedresponsestemtargeted treatmenttherapeutic targettreatment responsetumortumor DNAwhole genome
项目摘要
Abstract
Homologous recombination deficiency is prevalent in breast cancer up to a level of ~25%. Large-scale
alterations to the genome have been observed in these tumors, but if double-strand junctions are sequenced in
addition, it is possible to categorize these tumors into upstream and downstream defects in the DNA repair
pathway. We assert that there fundamentally different patterns of genome instability for double-strand break
repair. One is focused on the function of the BRCA1-BRCA2 pathway, where alterations in function are rather
frequent in breast cancers. Although traditionally perceived as equivalent, there is evidence to demonstrate
that downstream alterations that are BRCA1-like may have genomic and functional differences from those that
are BRCA2-like. Conversely, the upstream defects are focused on sensing DNA damage, which is another way
to suppress cancer formation. Our hypothesis is that different types of DNA repair defects result in the
utilization of distinct back-up DNA repair mechanisms, which themselves result in specific genomic signatures
and sensitivity to different therapeutic agents. Hence, we posit that upstream defects are best targeted by the
use of replication checkpoint inhibitors, but that BRCA defective tumors are best treated by targeting the
backup pathway, such as PARP-inhibitors or new agents beyond PARP-inhibitors. The goal of the first aim is
to apply the current genomic landscape tests of HR-deficiency and determine which method predicts most
accurately the type of homologous recombination DNA repair defect. The ultimate goal is to devise a
taxonomy based on the genomics features of homologous recombination DNA repair-deficiency, in addition to
target gene mutations, which will ultimately guide therapeutic options. The second aim is to generate
genetically engineered cell lines to understand the developmental drivers of the genomic landscape changes.
In addition, we will use these cells to test new synthetic lethal approaches to target specific subsets of breast
cancers with distinct types of homologous recombination DNA repair defects. The third aim consists of human
clinical trials either being conducted at Memorial Sloan Kettering Cancer Center or elsewhere, where we are
conducting the trial or leading the analysis of the clinical bio-specimens for correlative study analyses. We will
study the impact of the PARP-inhibitor olaparib in patients who are BRCA1/2 wild-type but harbor a germline
and/or somatic genetic alteration affecting homologous recombination DNA repair-related genes. We will
extend our studies to also consider the combined effects of radiotherapy in combination with either ATR-
inhibitors or PARP-inhibitors. The ultimate goal of this project is to personalize the treatment of breast cancer
patients whose tumors display homologous recombination DNA repair-related defects according to their
genetic and genomic features, seeking to substantially improve the outcome of these poor prognosis patients
and direct the deployment of therapeutic agents either already approved (e.g. olaparib) or already in clinical
trials (e.g. ATR-inhibitors).
摘要
同源重组缺陷在乳腺癌中普遍存在,高达25%。大规模
在这些肿瘤中观察到了基因组的变化,但如果对双链连接进行测序
此外,有可能将这些肿瘤归类为DNA修复的上游和下游缺陷
路径。我们断言,双链断裂存在根本不同的基因组不稳定模式
修理。一种是集中在BRCA1-BRCA2通路的功能上,其中功能的改变更多的是
常见于乳腺癌。尽管传统上被视为等同的,但有证据表明
下游类似BRCA1的改变可能在基因组和功能上与
与BRCA2相似。相反,上游的缺陷集中在检测DNA损伤上,这是另一种方式
以抑制癌症的形成。我们的假设是,不同类型的DNA修复缺陷会导致
利用不同的备用DNA修复机制,这本身就导致了特定的基因组签名
以及对不同的治疗药物的敏感性。因此,我们假设上游缺陷最好由
使用复制检查点抑制剂,但BRCA缺陷肿瘤最好的治疗方法是靶向
备用途径,如PARP抑制剂或超越PARP抑制剂的新药物。第一个目标的目标是
应用目前的HR缺乏症的基因组图谱测试,并确定哪种方法预测最多
准确判断同源重组DNA修复缺陷的类型。最终目标是设计一种
基于同源重组DNA修复缺陷的基因组学特征的分类学
靶基因突变,这最终将指导治疗选择。第二个目标是产生
基因工程细胞系,以了解基因组格局变化的发育驱动因素。
此外,我们将使用这些细胞来测试新的合成致命方法,以针对特定的乳房亚群
具有不同类型同源重组DNA修复缺陷的癌症。第三个目标是人类
临床试验要么在纪念斯隆·凯特琳癌症中心进行,要么在我们所在的其他地方
对临床生物标本进行试验或牵头分析,进行相关研究分析。我们会
研究PARP抑制剂olaparib对BRCA1/2野生型但有生殖系的患者的影响
和/或影响同源重组DNA修复相关基因的体细胞遗传改变。我们会
扩大我们的研究范围,以考虑放射治疗与ATR-
抑制剂或PARP抑制剂。这个项目的最终目标是使乳腺癌的治疗个性化。
肿瘤显示同源重组DNA修复相关缺陷的患者
基因和基因组特征,寻求大幅改善这些预后不良患者的预后
并指导已经批准(例如奥拉帕利)或已经在临床上使用的治疗剂的部署
试验(例如ATR抑制剂)。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Simon N. Powell其他文献
The predicted effect of HDR dose heterogeneity on local/regional control for post-surgical patients: Location matters
- DOI:
10.1016/j.brachy.2006.03.090 - 发表时间:
2006-04-01 - 期刊:
- 影响因子:
- 作者:
Joseph O. Deasy;Simon N. Powell;Imran Zoberi - 通讯作者:
Imran Zoberi
A local ATR-dependent checkpoint pathway is activated by a site-specific replication fork block in human cells
人类细胞中的位点特异性复制叉阻断激活局部 ATR 依赖性检查点通路
- DOI:
10.1101/2023.03.26.534293 - 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Sana Ahmed;Manisha Jalan;Helen E. Grimsley;Aman Sharma;Shyam Twayana;Settapong T. Kosiyatrakul;Christopher Thompson;C. Schildkraut;Simon N. Powell - 通讯作者:
Simon N. Powell
Defining the Optimal Dose for 3-Dimensional Conformal Accelerated Partial Breast Irradiation: 15-Year Follow-Up of a Dose-Escalation Trial
定义三维适形加速部分乳腺照射的最佳剂量:一项剂量递增试验的 15 年随访
- DOI:
10.1016/j.ijrobp.2024.10.029 - 发表时间:
2025-03-15 - 期刊:
- 影响因子:6.500
- 作者:
Alphonse G. Taghian;George E. Naoum;Lior Z. Braunstein;Andrzej Niemierko;Barbara L. Smith;Michele A. Gadd;Simon N. Powell;Abram Recht - 通讯作者:
Abram Recht
The biology of radioresistance: similarities, differences and interactions with drug resistance
- DOI:
10.1007/bf00744671 - 发表时间:
1993-01-01 - 期刊:
- 影响因子:1.700
- 作者:
Simon N. Powell;Edward H. Abraham - 通讯作者:
Edward H. Abraham
Ultrasound-mediated mechanical forces selectively kill tumor cells
超声介导的机械力选择性杀死肿瘤细胞
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
A. Tijore;F. Margadant;Mingxi Yao;Anushya Hariharan;C. Chew;Simon N. Powell;G. Bonney;M. Sheetz - 通讯作者:
M. Sheetz
Simon N. Powell的其他文献
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{{ truncateString('Simon N. Powell', 18)}}的其他基金
MSK SPORE in Genomic Instability in Breast Cancer
MSK SPORE 在乳腺癌基因组不稳定性中的作用
- 批准号:
10237877 - 财政年份:2020
- 资助金额:
$ 44.91万 - 项目类别:
MSK SPORE in Genomic Instability in Breast Cancer
MSK SPORE 在乳腺癌基因组不稳定性中的作用
- 批准号:
10704063 - 财政年份:2020
- 资助金额:
$ 44.91万 - 项目类别:
Defining and Targeting Homologous Recombination Deficiency in Breast Cancer
乳腺癌同源重组缺陷的定义和针对
- 批准号:
10237881 - 财政年份:2020
- 资助金额:
$ 44.91万 - 项目类别:
MSK SPORE in Genomic Instability in Breast Cancer
MSK SPORE 在乳腺癌基因组不稳定性中的作用
- 批准号:
10477981 - 财政年份:2020
- 资助金额:
$ 44.91万 - 项目类别:
Defining and Targeting Homologous Recombination Deficiency in Breast Cancer
乳腺癌同源重组缺陷的定义和针对
- 批准号:
10704096 - 财政年份:2020
- 资助金额:
$ 44.91万 - 项目类别:
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