PROJECT 1: Genomic Vulnerabilities in Leiomyosarcoma (LMS)

项目 1:平滑肌肉瘤 (LMS) 的基因组漏洞

基本信息

项目摘要

Project 1: Summary/Abstract Leiomyosarcoma (LMS) is one of the most common sarcomas and is a considerable therapeutic challenge because 50% of patients develop metastases for which current chemotherapy provides clinical benefit to only a small minority. We have shown that most LMS have chromosomal instability (CIN), which results in part from defects in homologous recombination and from ubiquitous TP53 and RB1 inactivation. Our recent studies show that these CIN aberrations are associated with hyper-dependency on DNA protein kinase (DNA-PK), which – along with ATM and ATR – is a member of the PI3K-like kinase family of DNA damage response (DDR) enzymes. DNA-PK is a key repair mechanism for double-strand DNA damage, thereby maintaining CIN below genotoxic thresholds. In Project 1, we wish to develop therapies that maximize intrinsic LMS genotoxic stress, particularly be targeting DNA-PK and by discovering more selective ways to target the DNA-PK pathway. To this end, Aim 1 determines whether relevant biomarkers (biochemical DNA-PK pathway activation, DNA damage response, and genomic evidence of CIN) are found homogeneously within a metastasis and in different metastases from a given patient. Aim 1 also determines whether partially vs. completely inactivating TP53 mutations have differing impact on LMS CIN and DNA-PK activation levels and therefore differing predictive relevance with respect to therapies targeting DNA-PK and DNA integrity. By determining if assays of DNA-PK activation and DNA damage are effectively demonstrated by LMS IHC and genomic profiles, Aim 1 shows whether these assays can be used as robust and reproducible correlative science assessments for our subsequent (Aim 3b) clinical trial combining low-dose doxorubicin and DNA-PK inhibition. Aim 2 provides biologic insights needed to achieve efficacy and selectivity for DNA-PK inhibition and other DDR-targeted therapies in LMS. These in vitro studies include DDR CRISPR-i and CRISPR-a screens, which are performed with/without DNA-PKi, PARPi and doxorubicin treatment. The CRISPR screens aim to discover DNA-PK inhibitor synthetic lethals and resistance mechanisms, and the biologic insights from these screens are enhanced by performing RNAseq and phosphoproteome profiles in the same LMS conditions, and by characterizing LMS cells with acquired resistance to DNA-PKi or doxorubicin. Aim 3 is the clinical translation for Project 1, which encompasses in vitro, and murine preclinical validations and an initial clinical trial of doxorubicin coupled with DNA-PK inhibition. Here we test the hypothesis that a very low dose of doxorubicin sensitizes LMS cells to DNA-PKi, thereby converting CIN into a liability while minimizing nonneoplastic cell toxicity.
项目1:摘要/摘要

项目成果

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JONATHAN Alfred FLETCHER其他文献

JONATHAN Alfred FLETCHER的其他文献

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{{ truncateString('JONATHAN Alfred FLETCHER', 18)}}的其他基金

Career Enhancement Program
职业提升计划
  • 批准号:
    10493635
  • 财政年份:
    2022
  • 资助金额:
    $ 48.76万
  • 项目类别:
Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment
平滑肌肉瘤 (LMS) 的遗传学和基因组学:增进对癌症生物学和诊断和治疗新方法的了解
  • 批准号:
    10705677
  • 财政年份:
    2022
  • 资助金额:
    $ 48.76万
  • 项目类别:
PROJECT 1: Genomic Vulnerabilities in Leiomyosarcoma (LMS)
项目 1:平滑肌肉瘤 (LMS) 的基因组漏洞
  • 批准号:
    10493629
  • 财政年份:
    2022
  • 资助金额:
    $ 48.76万
  • 项目类别:
Overcoming Resistance to KIT/PDGFRA Inhibition in GIST
克服 GIST 中对 KIT/PDGFRA 抑制的耐药性
  • 批准号:
    8485721
  • 财政年份:
    2007
  • 资助金额:
    $ 48.76万
  • 项目类别:
Overcoming Resistance to KIT/PDGFRA Inhibition in GIST
克服 GIST 中对 KIT/PDGFRA 抑制的耐药性
  • 批准号:
    8933243
  • 财政年份:
    2007
  • 资助金额:
    $ 48.76万
  • 项目类别:
TRANSLOCATION OF 8-13 IN STEM-CELL LEUKEMIA/LYMPHOMA
干细胞白血病/淋巴瘤中 8-13 的易位
  • 批准号:
    2769908
  • 财政年份:
    1997
  • 资助金额:
    $ 48.76万
  • 项目类别:
TRANSLOCATION OF 8-13 IN STEM-CELL LEUKEMIA/LYMPHOMA
干细胞白血病/淋巴瘤中 8-13 的易位
  • 批准号:
    2388744
  • 财政年份:
    1997
  • 资助金额:
    $ 48.76万
  • 项目类别:
TRANSLOCATION OF 8-13 IN STEM-CELL LEUKEMIA/LYMPHOMA
干细胞白血病/淋巴瘤中 8-13 的易位
  • 批准号:
    2895778
  • 财政年份:
    1997
  • 资助金额:
    $ 48.76万
  • 项目类别:
TUMOR SUPPRESSOR LOCI IN MESOTHELIOMA
间皮瘤中的肿瘤抑制基因座
  • 批准号:
    2390897
  • 财政年份:
    1996
  • 资助金额:
    $ 48.76万
  • 项目类别:
TUMOR SUPPRESSOR LOCI IN MESOTHELIOMA
间皮瘤中的肿瘤抑制基因座
  • 批准号:
    2683616
  • 财政年份:
    1996
  • 资助金额:
    $ 48.76万
  • 项目类别:

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机构外的生活:1900 - 1960 年心理健康善后护理的历史
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