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
• 负责人: MATTHEW J ELLIS
• 金额: $ 33.05万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10704529
• 关键词: Cause of Death; Cessation of life; Estrogen receptor positive; NF1 gene; Patients; Resistance; Role; Translational Research; Treatment Efficacy; improved; malignant breast neoplasm

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.

项目摘要 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%的人患有乳腺癌。 雌激素受体-α阳性（ER+）。尽管通过内分泌治疗这种ER+疾病取得了很大进展， 尽管目前的治疗方法不多，但对这种治疗的耐药性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，NF 1（1型神经纤维瘤病）基因的失活， 这可能发生在多达20%的原发性ER+乳腺癌患者中， 他莫昔芬治疗的患者。NF 1编码神经纤维蛋白，最为人所知的是Ras阻遏物（一种GT3激活蛋白）。 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， NF 1的缺失也全面增强了雌二醇（E2）依赖性基因的表达，从而允许细胞生长 在较低水平的E2或甚至在他莫昔芬中，由于NF 1也作为转录因子直接与ER相互作用，阻遏物与它们对E2剥夺或他莫昔芬治疗缺乏反应相反，NF 1耗尽的细胞仍然 对氟维司群（一种SERD（选择性ER降解剂））有反应，尽管Ras-Raf的抑制减少， 在NF 1耗尽的细胞中的信号传导仍然允许促进细胞存活/生长，这反过来可以被阻断， FDA批准的激酶抑制剂。因此，本项目将调查以下假设： NF 1缺乏的ER+乳腺肿瘤应通过SERD与阻断Ras-Raf的抑制剂一起治疗 通路为了评估患者肿瘤中的NF 1状态是否可以区分对各种肿瘤的治疗反应， 内分泌药物，目标1将首先建立有效的诊断NF 1缺乏症，然后分析如何NF 1- 在两项大型随机新辅助治疗临床试验ALTERNATE中，状态影响长期治疗反应 P024前者比较了氟维司群与AI（阿那曲唑），而后者比较了他莫昔芬与另一种 AI（来曲唑）。此外，我们建议NF 1缺陷型ER+乳腺癌应采用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 研究新一代口服SERD和Ras效应激酶抑制剂，以找到最佳组合， 临床试验设计和鼓励制药公司对试验支持的兴趣。一项旨在进一步促进这种治疗的2期临床试验 概念已经规划，我们已经有制药的兴趣和承诺。我们将支持这一点 通过开发技术来评估NF 1异质性如何影响治疗反应。最后， 目的3将分析原发性NF 1缺陷患者（目的1）和原发性NF 1缺陷患者（目的2）SERD治疗后的激酶组重编程。 临床前模型（Aim 2）通过基于质谱的微型平台KiP（Kinome Profiling）。 虽然我们的主要目的是评估在NF 1缺失的肿瘤中使用SERD是否会导致 补偿Ras-Raf激活，KiP平台本质上是无偏的，也可能发现额外的 驱动SERD抗性的激酶。该项目的成功执行可能会阻止NF 1的进展， ER+侵袭性乳腺癌的早期缺陷亚群。