Project 1: Co-Targeting ER and Kinome Deregulation in Breast Cancers with Neurofibromin Deficiency

项目 1:联合靶向 ER 和激酶组失调治疗神经纤维蛋白缺乏的乳腺癌

基本信息

  • 批准号:
    10460212
  • 负责人:
  • 金额:
    $ 33.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-19 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Over 250,000 cases of breast cancer are diagnosed annually in the US alone, and about 80% of these will be estrogen receptor-α positive (ER+). Despite great progress in treating this ER+ disease by endocrine therapy, resistanceto this treatment remains a major problem, causing the majority of deaths from breast cancer. Our clinical studies on resistance have found that inactivation of the NF1 (for neurofibromatosis type 1) gene, which may occur in as much as 20% of primary ER+ breast cancer patients, correlates with a poor outcome in tamoxifen-treated patients. NF1 encodes neurofibromin, best known as a Ras repressor (a GTPase Activating Protein, or GAP), but the scie ntific premise of this project stems from our discovery that besides activating Ras, loss of NF1 also globally enhances estradiol (E2)-dependent gene expression, thus permitting the cells to grow in lower levels of E2 or even in tamoxifen, because NF1 also directly interacts with ER as a transcriptional co- repressor. In contrast to their lack of response to E2-deprivation or tamoxifen treatment, NF1-depleted cells still respond to fulvestrant, a SERD (Selective ER Degrader), and although the reduced repression of Ras-Raf signaling in NF1-depleted cells still allows promotion of cell survival/growth, this in turn could be blocked pharmacologically by FDA-approved kinase inhibitors. This project will therefore investigate the hypothesis that NF1-deficient ER+ breast tumors should be treated by a SERD together with inhibitors bloc king the Ras-Raf pathway. To assess whether NF1-status in patient tumors can differentiate treatment responses to various endocrine agents, Aim 1 will first establish an effective diagnosis for NF1-deficiency and then analyze how NF1- status impacts long-term treatment responses in two large randomized neoadjuvant clinical trials, ALTERNATE and P024. The former compares fulvestrant vs. AI (anastrozole), while the latter compares tamoxifen vs. another AI (letrozole). In addition, we propose that NF1-deficient ER+ breast cancer should be treated by a SERD combined with kinase inhibitors targeting the Ras-Raf pathway, so that Aim 2 will conduct preclinical modeling to examine new generation oral SERDs and Ras effector kinase inhibitors to find the best combination to drive clinical trial design and encourage pharma interest in trial support. A Phase -2 clinical trial to further this treatment concept has been planned, for which we already have pharma interest and commitment. We will support this trial here by developing technologies to assess how NF1-heterogeneity impacts treatment response. Finally, Aim 3 will analyze kinome reprograming after SERD treatment in primary NF1-deficient patients (Aim 1) and in preclinical models (Aim 2) by a mass spectrometry-based micro-scaled platform called KiP (Kinome Profiling). While our primary objective is to assess whether the use of a SERD in NF1 -depleted tumors can lead to compensatory Ras-Raf activation, the KiP platform is intrinsically unbiased and may also discover additional kinases driving SERD resistance. The successful execution of this project may stop the progression of the NF1- deficient subset of ER+ aggressive breast cancer early in its tracks.
项目总结 仅在美国,每年就有超过25万例乳腺癌被诊断出来,其中约80% 将雌激素受体α阳性(ER+)。尽管内分泌治疗ER+病取得了很大进展 尽管对这种疗法的抵抗力仍然是一个主要问题,导致大多数乳腺癌死亡。 我们对耐药的临床研究发现,NF1(针对1型神经纤维瘤病)基因的失活, 这可能发生在多达20%的ER+乳腺癌患者中,与 他莫昔芬治疗的患者。NF1编码神经纤维素,最为人所知的是RAS抑制因子(一种激活GTP酶 蛋白质,或GAP),但这个项目的科学前提源于我们的发现,除了激活RAS, NF1的缺失也会全面增强依赖雌二醇(E2)的基因表达,从而允许细胞生长 在较低水平的E2中,甚至在他莫昔芬中,因为NF1也作为转录共刺激因子直接与ER相互作用 抑制者。与剥夺E2或他莫昔芬治疗缺乏反应相反,NF1耗尽的细胞仍然 对SERD(选择性内质网降解物)fulvestrant的反应,尽管RAS-Raf的抑制减少 NF1缺失的细胞中的信号仍然可以促进细胞的存活/生长,这反过来可能被阻止 药理上由FDA批准的激酶抑制剂。因此,该项目将调查以下假设 NF1缺陷型ER+乳腺肿瘤应联合应用SERD和阻断RAS-Raf的抑制剂 路径。评估患者肿瘤中NF1状态是否可以区分对不同疾病的治疗反应 内分泌药物,目标1将首先建立NF1缺乏症的有效诊断,然后分析NF1如何- 两个大型随机新辅助临床试验的状态对长期治疗反应的影响 和P024。前者将fulvestrant与AI(阿那曲唑)进行比较,后者将他莫昔芬与另一种药物进行比较 AI(来曲唑)。此外,我们建议NF1缺失的ER+乳腺癌应该接受SERD治疗 与靶向Ras-Raf通路的激酶抑制剂结合,使Aim 2将进行临床前建模 检查新一代口服SERDS和RAS效应蛋白激酶抑制剂以寻找最佳组合 设计临床试验并鼓励制药商对试验支持感兴趣。进一步推广这种疗法的二期临床试验 概念已经计划好了,我们已经有了制药兴趣和承诺。我们将支持这一点 通过开发技术来评估NF1的异质性如何影响治疗反应,在这里进行试验。最后, AIM 3将分析SERD治疗后NF1缺乏患者的动态组重新编程(AIM 1)和 临床前模型(AIM 2)由一个名为KIP(Kinome Profiling)的基于质谱学的微尺度平台实现。 虽然我们的主要目标是评估在NF1缺失的肿瘤中使用SERD是否会导致 补偿性RAS-RAF激活,KIP平台本质上是不偏不倚的,还可能发现其他 驱动SERD抵抗的蛋白激酶。该项目的成功实施可能会阻止NF1的进展- 早期ER+侵袭性乳腺癌的缺陷亚群。

项目成果

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MATTHEW J ELLIS其他文献

MATTHEW J ELLIS的其他文献

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{{ truncateString('MATTHEW J ELLIS', 18)}}的其他基金

Translational Breast Cancer Research Training Program
转化乳腺癌研究培训计划
  • 批准号:
    9977965
  • 财政年份:
    2018
  • 资助金额:
    $ 33.98万
  • 项目类别:
Administration and Advocacy
行政及宣传
  • 批准号:
    10704511
  • 财政年份:
    2014
  • 资助金额:
    $ 33.98万
  • 项目类别:
Administration and Advocacy
行政及宣传
  • 批准号:
    10460206
  • 财政年份:
    2014
  • 资助金额:
    $ 33.98万
  • 项目类别:
Project 1: Co-Targeting ER and Kinome Deregulation in Breast Cancers with Neurofibromin Deficiency
项目 1:联合靶向 ER 和激酶组失调治疗神经纤维蛋白缺乏的乳腺癌
  • 批准号:
    10704529
  • 财政年份:
    2014
  • 资助金额:
    $ 33.98万
  • 项目类别:
PROTEOGENOMIC ANALYSIS OF HUMAN-IN-MOUSE BREAST CANCER XENOGRAFTS
人鼠乳腺癌异种移植物的蛋白质组学分析
  • 批准号:
    8361435
  • 财政年份:
    2011
  • 资助金额:
    $ 33.98万
  • 项目类别:
Breast Cancer Research
乳腺癌研究
  • 批准号:
    8181188
  • 财政年份:
    2010
  • 资助金额:
    $ 33.98万
  • 项目类别:
Biological Breast Cancer Classification by qRT-PCR
通过 qRT-PCR 进行乳腺癌生物学分类
  • 批准号:
    7913963
  • 财政年份:
    2009
  • 资助金额:
    $ 33.98万
  • 项目类别:
NOVEL BIOMARKERS FOR AROMATASE INHIBITOR THERAPY
用于芳香酶抑制剂治疗的新型生物标志物
  • 批准号:
    7953937
  • 财政年份:
    2009
  • 资助金额:
    $ 33.98万
  • 项目类别:
NOVEL BIOMARKERS FOR AROMATASE INHIBITOR THERAPY
用于芳香酶抑制剂治疗的新型生物标志物
  • 批准号:
    7721520
  • 财政年份:
    2008
  • 资助金额:
    $ 33.98万
  • 项目类别:
Biological Breast Cancer Classification by qRT-PCR
通过 qRT-PCR 进行乳腺癌生物学分类
  • 批准号:
    7127620
  • 财政年份:
    2005
  • 资助金额:
    $ 33.98万
  • 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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