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

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)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
Career Enhancement Program
职业提升计划
  • 批准号:
    10478022
  • 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:
Administrative Core
行政核心
  • 批准号:
    10704069
  • 财政年份:
    2020
  • 资助金额:
    $ 44.91万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10237878
  • 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:
Career Enhancement Program
职业提升计划
  • 批准号:
    10704117
  • 财政年份:
    2020
  • 资助金额:
    $ 44.91万
  • 项目类别:
Career Enhancement Program
职业提升计划
  • 批准号:
    10237885
  • 财政年份:
    2020
  • 资助金额:
    $ 44.91万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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