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
项目成果
期刊论文数量(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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