Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer
转移性乳腺癌 APOBEC 突变的诊断和治疗
基本信息
- 批准号:10478015
- 负责人:
- 金额:$ 42.28万
- 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:AffectAromatase InhibitorsBenchmarkingBiochemistryBioinformaticsBiological AssayBiological MarkersBiological ModelsBreast Cancer ModelBreast Cancer cell lineBreast Cancer therapyCDK4 geneCRISPR/Cas technologyCancer ModelCaringCause of DeathCell Cycle InhibitionCell LineCellsCessation of lifeCharacteristicsClinicClinicalClinical TrialsComparative Genomic AnalysisDNA RepairDNA Sequence AlterationDataData SetDependenceDetectionDevelopmentDiagnosisDiseaseDisease ResistanceDisseminated Malignant NeoplasmDrug CombinationsDrug resistanceERBB2 geneESR1 geneEndocrineEnzymesEstrogen AntagonistsEstrogen ReceptorsEstrogen receptor positiveEstrogensFAT geneFamilyGenesGeneticGenetic TranscriptionGenomic InstabilityGenomicsGlareImmune responseImmunohistochemistryImmunologicsIndividualKineticsKnock-outLarge-Scale SequencingLinkMalignant NeoplasmsMediatingMedicalMetastatic breast cancerMethodsMinorityModelingMutagenesisMutationNF1 geneNeoplasm MetastasisNewly DiagnosedPathogenesisPathogenicityPatientsPatternPhenotypePositioning AttributePrevalencePrimary NeoplasmProcessRB1 geneRecurrenceRegimenResistanceResistance developmentSamplingSeriesShapesSystemic TherapyTamoxifenTestingTherapeuticTimeTranslatingUnited StatesWomanacquired drug resistanceantagonistbasebreast cancer diagnosiscancer cellcancer genomecancer therapycell free DNAchromatin remodelingcurative treatmentsdeprivationgenomic profileshormone therapyimmune checkpoint blockadeinhibitorinnovationinsightknock-downmalignant breast neoplasmmortalitymultimodalityneoplastic cellnovel strategiesoverexpressionpatient derived xenograft modelpreventrefractory cancerresistance alleleresistance mutationtherapeutic targettranscription factortumortumor DNAtumor progression
项目摘要
Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer
Summary: Although the majority of early stage estrogen receptor (ER)-positive breast cancers are cured
through multimodality care, metastatic ER-positive breast cancer remains a lethal disease. Insights into this
discrepancy have come through comparative genomic analyses of primary and metastatic tumors. We and
others have identified several mutations affecting specific genes that are more prevalent in metastatic cancers
than in their primary counterparts, including ESR1, ERBB2, and NF1. These mutations result in resistance to
front-line endocrine treatments that are the mainstay systemic therapy in ER-positive breast cancer. Even
more striking than such individual mutations, however, has been the finding that certain `mutational signatures'
are enriched in metastatic disease as compared to primary breast cancers. These mutational signatures
represent the DNA damage and repair processes that shape the cancer genome and can give rise to such
mutations and the transformed phenotypes they convey. A glaring and consistent finding from multiple large-
scale sequencing studies has been that the APOBEC mutational signature is both enriched and highly
prevalent in ER-positive metastatic disease, comprising the dominant mutational signature for these drug-
resistant and ultimately lethal cancers. Our preliminary data confirm that APOBEC activation can promote the
development of endocrine resistance in ER-positive cancer models and is associated with characteristic
APOBEC-mutational changes in many drug resistance alleles. Together, these results point to the APOBEC
mutational process as a key driver in the development and pathogenesis of ER-positive metastatic breast
cancer and endocrine therapy resistance. In this highly collaborative and innovative project, we propose three
specific aims to advance the APOBEC mutational process as a biomarker and therapeutic target in breast
cancer. (1) We will develop and utilize robust bioinformatic methods to detect the presence and the timing of
onset of the APOBEC mutational signature from clinical NGS datasets of both tumor and cell free DNA
(cfDNA). We will further ascertain if a promising IHC assay for the A3B enzyme can identify those ER-positive
cancers likely to subsequently develop an APOBEC mutational signature. (2) We will determine the
mechanisms and kinetics of APOBEC's contribution to endocrine resistance. We will use isogenic cell line
models and patient derived xenografts to dissect the types of resistance patterns that are caused by APOBEC
as well their timing and whether the endocrine therapy itself contributes to the induction of APOBEC activity.
(3) We will assess both immunologic and synthetic lethal approaches to targeting tumors in which APOBEC
activity is induced and determine their capabilities in killing APOBEC-positive cancers. We anticipate that our
findings will uniquely position our team to launch clinical trials testing specific approaches to diagnose
APOBEC-positive tumors, to prevent the development of resistance to endocrine therapies, and to target the
largest subset of ER-positive endocrine-resistant metastatic breast cancers.
转移性乳腺癌APOBEC突变的诊断和治疗
摘要:尽管大多数早期雌激素受体(ER)阳性乳腺癌都能治愈,
通过多模式护理,转移性ER阳性乳腺癌仍然是一种致命疾病。对此的见解
通过对原发性和转移性肿瘤的比较基因组分析,已经发现了差异。我们和
其他人已经确定了几个影响特定基因的突变,这些基因在转移性癌症中更普遍
包括ESR 1、ERBB 2和NF 1。这些突变导致对
一线内分泌治疗是ER阳性乳腺癌的主要全身治疗。甚至
然而,比这些个体突变更引人注目的是,
与原发性乳腺癌相比,在转移性疾病中富集。这些变异的特征
代表了DNA损伤和修复过程,这些过程塑造了癌症基因组,
突变和它们传递的转化表型。从多个大的-
大规模测序研究表明,APOBEC突变特征是富集的,并且高度依赖于DNA序列。
在ER阳性转移性疾病中普遍存在,包括这些药物的显性突变特征,
耐药并最终致命的癌症。我们的初步数据证实,APOBEC激活可以促进
ER阳性癌症模型中内分泌抵抗的发展,并与特征性
APOBEC-许多耐药等位基因的突变变化。总之,这些结果指向APOBEC
突变过程作为ER阳性转移性乳腺癌发生和发病机制的关键驱动因素
癌症和内分泌治疗抗性。在这个高度合作和创新的项目中,我们提出三个
具体目标是推进APOBEC突变过程作为乳腺癌的生物标志物和治疗靶点。
癌(1)我们将开发和利用强大的生物信息学方法来检测的存在和时间,
来自肿瘤和无细胞DNA的临床NGS数据集的APOBEC突变特征的出现
(cfDNA)。我们将进一步确定一种有前途的A3 B酶免疫组化检测方法是否能鉴别出ER阳性的细胞。
癌症可能随后产生APOBEC突变标签。(2)康贝特人将以
APOBEC对内分泌抗性的作用机制和动力学。我们将使用同基因细胞系
模型和患者来源的异种移植物,以剖析由APOBEC引起的耐药模式的类型
以及它们的时机和内分泌治疗本身是否有助于诱导APOBEC活性。
(3)我们将评估针对肿瘤的免疫和合成致死方法,其中APOBEC
活性被诱导,并决定其杀死APOBEC阳性癌症的能力。我们预计,
研究结果将使我们的团队能够启动临床试验,测试特定的诊断方法,
APOBEC阳性肿瘤,以防止对内分泌治疗产生耐药性,并靶向
ER阳性内分泌耐药转移性乳腺癌的最大子集。
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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Sarat Chandarlapaty其他文献
Sarat Chandarlapaty的其他文献
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{{ truncateString('Sarat Chandarlapaty', 18)}}的其他基金
HER2-mediated delivery of cytotoxic agents in solid tumors
实体瘤中 HER2 介导的细胞毒药物递送
- 批准号:
10381517 - 财政年份:2021
- 资助金额:
$ 42.28万 - 项目类别:
HER2-mediated delivery of cytotoxic agents in solid tumors
实体瘤中 HER2 介导的细胞毒药物递送
- 批准号:
10608129 - 财政年份:2021
- 资助金额:
$ 42.28万 - 项目类别:
Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer
转移性乳腺癌 APOBEC 突变的诊断和治疗
- 批准号:
10237883 - 财政年份:2020
- 资助金额:
$ 42.28万 - 项目类别:
Defining the impact of mutant oncogene zygosity
定义突变癌基因接合性的影响
- 批准号:
10582527 - 财政年份:2020
- 资助金额:
$ 42.28万 - 项目类别:
Defining the impact of mutant oncogene zygosity
定义突变癌基因接合性的影响
- 批准号:
10362576 - 财政年份:2020
- 资助金额:
$ 42.28万 - 项目类别:
Diagnosis and Treatment of APOBEC Mutagenesis in Metastatic Breast Cancer
转移性乳腺癌 APOBEC 突变的诊断和治疗
- 批准号:
10704108 - 财政年份:2020
- 资助金额:
$ 42.28万 - 项目类别:
Defining mechanisms of resistance to hormonal therapy in breast cancer
乳腺癌激素治疗耐药机制的定义
- 批准号:
10533264 - 财政年份:2018
- 资助金额:
$ 42.28万 - 项目类别:
Defining mechanisms of resistance to hormonal therapy in breast cancer
乳腺癌激素治疗耐药机制的定义
- 批准号:
10304866 - 财政年份:2018
- 资助金额:
$ 42.28万 - 项目类别:
Defining mechanisms of resistance to hormonal therapy in breast cancer
乳腺癌激素治疗耐药机制的定义
- 批准号:
10054178 - 财政年份:2018
- 资助金额:
$ 42.28万 - 项目类别:
Therapeutic approaches to ER mutant breast cancer
ER突变乳腺癌的治疗方法
- 批准号:
9238168 - 财政年份:2017
- 资助金额:
$ 42.28万 - 项目类别:
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