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:10704529
- 负责人:
- 金额:$ 33.05万
- 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
- 来源:
- 关键词:
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, resistance to 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 scientific 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 corepressor. 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 blocking 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
项目成果
期刊论文数量(0)
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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:
$ 33.05万 - 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:
10460212 - 财政年份:2014
- 资助金额:
$ 33.05万 - 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:
$ 33.05万 - 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:
$ 33.05万 - 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:
$ 33.05万 - 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:
$ 33.05万 - 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:
$ 33.05万 - 项目类别: