FGFR4: A druggable mediator of endocrine resistance in breast cancer
FGFR4: A druggable mediator of endocrine resistance in breast cancer
批准号:
10054975
负责人:
Steffi Oesterreich
金额:
$35.45万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-12-15 至 2022-11-30
关键词:
Automobile DrivingBioinformaticsBiological MarkersBiometryBreast Cancer CellBreast Cancer cell lineBreast Cancer therapyBreast cancer metastasisCell LineCellsClinicalCombined Modality TherapyDatabasesDiseaseDuct (organ) structureE-CadherinERBB2 geneERBB3 geneEndocrineEnvironmentEstrogen AntagonistsEstrogen ReceptorsEstrogen receptor negativeEstrogen receptor positiveEstrogensFGFR1 geneGenesGeneticGenomicsGoalsGrowthHistologicIn VitroKnowledgeLaboratoriesLeadLobularMalignant NeoplasmsMediatingMediator of activation proteinMedical OncologyMetastatic breast cancerModelingMolecularMolecular BiologyMutationN-CadherinNeoplasm MetastasisPathologyPatient-Focused OutcomesPatientsPatternPharmaceutical PreparationsPrognostic MarkerRecurrenceResistanceResistance developmentRoleSamplingSignal PathwaySignal TransductionTestingThe Cancer Genome AtlasTissuesTreatment EfficacyTumor BiologyWomanWorkXenograft Modelbasebreast cancer diagnosiscancer invasivenesscancer subtypescohortdruggable targetfibroblast growth factor receptor 4genome-wide analysishormone therapyimproved outcomein vivoin vivo Modelinnovationliquid biopsymalignant breast neoplasmmalignant endocrine gland neoplasmnoveloverexpressionpredicting responsepredictive markerpredictive testtargeted treatmenttherapy resistanttooltranscriptomicstreatment strategytumorworking group
中文摘要
每年诊断出约 30,000 例新诊断的浸润性小叶乳腺癌 (ILC) 病例,使 ILC 成为第六大常见病例
女性癌症。 ILC 的治疗方法与更常见的浸润性导管癌 (IDC) 几乎相同,尽管
临床表现和肿瘤生物学的差异,包括 E-钙粘蛋白几乎普遍缺失。虽然
ILC 显示出比 IDC 更好的预后标志物,例如雌激素受体 (ER) 阳性率高和雌激素受体 (ER) 阳性率低
增殖,ILC 患者常常对内分泌治疗产生耐药性,从长远来看,会遭受更多的痛苦
复发率高于 IDC。我们的长期目标是改善 ILC(一种与 ILC 相关的疾病)患者的治疗结果
理解有限,代表着巨大的未满足的临床需求。
为了了解驱动 ILC 内分泌抵抗的机制,我们开发了内分泌抵抗 ILC 细胞系
模型,并收集内分泌抵抗性转移性乳腺癌样本,并进行无偏转录组学分析
分析发现成纤维细胞生长因子受体 4 (FGFR4) 是最过度表达的
基因。对公开数据库的分析可识别 FGFR4 热点突变。缺乏
FGFR1-3 在内分泌抵抗模型和转移组织中一致过度表达强烈表明
FGFR4 具有独特且之前未被重视的作用,值得进一步研究。而 FGFR4
在 IDC 和 ILC 中均观察到过表达和突变,并且它们在 ILC 中显着富集。这个
表明 ILC 的独特遗传背景,包括众所周知的 E-钙粘蛋白丢失,但也包括
最近发现的 ERBB2/ERBB3 激活可能为 FGFR4 提供宽松的环境
发信号。从功能上来说,FGFR4 缺失或抑制会导致 ER 靶基因的表达改变,
生长和集落形成减少。最后,FGFR4和ER联合靶向的初步研究
具有协同生长抑制作用。因此,我们假设 ILC 的独特遗传背景
为 FGFR4 信号传导介导内分泌抵抗创造了一个宽松的环境,并且
FGFR4 抑制和内分泌治疗的结合代表了一种新的治疗策略。
在当前的研究中,我们将 i) 确定 FGFR4 如何导致乳腺癌内分泌抵抗,以及 ii)
检查原发性和转移性乳腺癌的关键基因组特征是否相互影响并增强
FGFR4 信号传导和活性,以及 iii) 证明 FGFR4 作为乳腺癌治疗中的药物靶标
定义生物标志物。
我们的协作团队拥有分子生物学、生物统计学/生物信息学、病理学和医学方面的专业知识
肿瘤学将利用独特的模型、有价值的临床样本、已经在试验中的有前途的药物,以及
创新方法和工具来测试我们对 FGFR4 在内分泌中的新作用的集中假设
阻力。我们期望获得关于易于药物化的 ER-FGFR4 轴如何在体内发出信号的基础知识
ILC 并评估 FGFR4 抑制作为内分泌抵抗性乳腺癌的新型治疗策略。
!
英文摘要
~30,000 new cases of invasive lobular breast cancer (ILC) diagnosed per year make ILC the 6th most common
cancer in women. ILC is treated almost identically to the more common invasive ductal cancer (IDC), despite
differences in clinical presentation and tumor biology, including the near universal loss of E-cadherin. Although
ILCs show better prognostic markers than IDC, such as high rates of estrogen receptor (ER) positivity and low
proliferation, patients with ILC often develop resistance to endocrine therapy and in the long term suffer more
recurrences than IDC. Our long-term goal is to improve outcome for patients with ILC, a disease associated
with limited understanding and representing a great unmet clinical need.
To understand mechanisms driving ILC endocrine resistance, we developed endocrine-resistant ILC cell line
models, and collected endocrine resistant metastatic breast cancer samples, and unbiased transcriptomic
profiling led to the identification of fibroblast growth factor receptor 4 (FGFR4) as the most overexpressed
gene. Analysis of publicly available databases lead to identification of hotspot FGFR4 mutations. Lack of
consistent overexpression of FGFR1-3 in endocrine resistant models and metastatic tissues strongly suggests
a unique and previously unappreciated role for FGFR4 that warrants further study. While FGFR4
overexpression and mutations are observed in both IDC and ILC, they are significantly enriched in ILC. This
suggests that the unique genetic background of ILC, including the well-known loss of E-cadherin but also the
more recently identified activation of ERBB2/ERBB3, may provide a permissive environment for FGFR4
signaling. Functionally, FGFR4 loss or inhibition results in altered expression of ER target genes and
decreased growth and colony formation. Finally, preliminary studies of combined FGFR4 and ER targeting
confer synergistic growth inhibition. We therefore hypothesize that the unique genetic background of ILC
creates a permissive environment for FGFR4 signaling to mediate endocrine resistance, and that the
combination of FGFR4 inhibition and endocrine therapy represents a novel treatment strategy.
In the current study, we will i) determine how FGFR4 causes endocrine resistance in breast cancer, and ii)
examine whether key genomic features of primary and metastatic breast cancer cross-talk and enhance
FGFR4 signaling and activity, and iii) credential FGFR4 as a druggable target in breast cancer therapy by
defining biomarkers.
Our collaborative team with expertise in molecular biology, biostatistics/bioinformatics, pathology and medical
oncology will utilize unique models, valuable clinical samples, promising drugs that are already in trials, and
innovative approaches and tools to test our focused hypotheses on a novel role of FGFR4 in endocrine
resistance. We expect to gain fundamental knowledge of how the readily druggable ER-FGFR4 axis signals in
ILC and!to assess FGFR4 inhibition as a novel treatment strategy in endocrine resistant breast cancers.
!
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会议论文
2019 Hormone-Dependent Cancers Gordon Research Conference and Gordon Research Seminar
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