Mechanisms of resistance to endocrine therapy in ER positive breast cancer

ER阳性乳腺癌内分泌治疗耐药机制

• 批准号: 10704051
• 负责人: BRENT N REXER
• 金额: $ 32.48万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-07 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704051
• 关键词: Acceleration; Accounting; Aromatase Inhibitors; Breast; Breast Cancer Patient; CCND1 gene; CDK4 gene; CRKL gene; Cell Cycle Progression; Cell Survival; Cells; Cessation of life; Clinic; Clinical Trials; Cytotoxic Chemotherapy; Data; Development; Disease; Drug resistance; E2F transcription factors; ERBB2 gene; Endocrine; Estrogen Antagonists; Estrogen Receptors; Estrogen Therapy; Estrogen receptor positive; Exhibits; FGFR1 gene; FGFR2 gene; Fibroblast Growth Factor Receptors; Fulvestrant; Future; Gene Amplification; Genetic Transcription; Growth; Human; Knowledge; Letrozole; Libraries; Ligand Binding Domain; MCF7 cell; Malignant Neoplasms; Mammary Neoplasms; Metastatic breast cancer; Molecular; Molecular Analysis; Molecular Target; Mutation; Open Reading Frames; Organoids; Outcome; Pathway interactions; Patient Care; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Plasma Cell Neoplasm; Progression-Free Survivals; Quality of life; Randomized; Recurrence; Recurrent Malignant Neoplasm; Recurrent tumor; Resistance; Selective Estrogen Receptor Modulators; Signal Transduction; Specimen; Tamoxifen; Testing; Time; Toxic effect; Tyrosine Kinase Inhibitor; Woman; acquired drug resistance; adjuvant endocrine therapy; anastrozole; biomarker identification; cancer recurrence; cancer subtypes; cell free DNA; clinical investigation; comparison control; disorder subtype; drug discovery; genetic signature; hormone therapy; improved; inhibitor; malignant breast neoplasm; mortality; next generation sequencing; novel; participant enrollment; patient derived xenograft model; phase II trial; predicting response; predictive marker; prevent; programs; resistance mechanism; response; standard of care; targeted cancer therapy; transcriptome sequencing; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT: MECHANISMS OF RESISTANCE TO ENDOCRINE THERAPY IN ER+ BREAST CANCER Estrogen receptor positive (ER+) breast cancer is the most common subtype of breast cancer, but ~20% of ER+ tumors recur during or following adjuvant endocrine therapy, accounting for ~50% of breast cancer deaths in the US each year. The CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have been recently approved in combination with endocrine therapy for the treatment of metastatic ER+ breast cancer. However, as for other cancer targeted therapies, all patients with metastatic disease on CDK4/6 inhibitors eventually progress, suggesting the development of mechanisms of acquired drug resistance that remain to be discovered. We propose a continuation project where we will investigate the effect of aberrant FGFR signaling on resistance to endocrine therapy in combination with CDK4/6 inhibitors in patients with ER+ breast cancer with the following aims:  Aim 1: To elucidate the mechanisms by which FGFR1 amplification confers resistance to the combination of fulvestrant and CDK4/6 inhibitors in ER+/FGFR amplified breast cancers  Aim 2: To conduct a phase Ib and a randomized phase II trial of the ER downregulator fulvestrant plus palbociclib ± the pan-FGFR inhibitor erdafitinib in patients with ER+/FGFR-amplified metastatic breast cancer  Aim 3: To discover mechanisms of drug resistance in organoids derived from tumors progressing on CDK4/6 inhibitors. These will include: 1) tumors from patients progressing on treatment with fulvestrant/palbociclib ± erdafitinib in Aim 2, and 2) tumors from breast cancer patients on standard-of-care therapy with CDK4/6 inhibitors To our knowledge, this is the first time an FGFR inhibitor will be tested in combination with ER and CDK4/6 inhibitors in patients with breast cancer harboring FGFR amplification. A positive outcome of this clinical trial may provide women with FGFR-amplified/ ER+ breast cancer with a novel treatment option that does not include cytotoxic chemotherapy. Increased efficacy of the combination of fulvestrant, palbociclib and erdafitinib will also accelerate the development of FGFR inhibitors. We seek to identify biomarkers predictive of response to the combination that can be used in trials in appropriately selected patients with ER+ metastatic breast cancer. In addition, the comprehensive molecular analysis of organoids from cancers progressing on treatment provides an opportunity for the unbiased discovery of novel molecular mechanisms of drug resistance. These mechanisms, in turn, may represent actionable molecular targets that can be the focus of future drug discovery efforts and/or translational/clinical investigation in breast and other FGFR-dependent cancers. As such, the aims proposed herein may contribute to progress in the eradication of ER+ breast cancers.

项目摘要/摘要：内分泌治疗抵抗的机制 在ER+乳腺癌中 雌激素受体阳性(ER+)乳腺癌是乳腺癌中最常见的亚型，但约20%的ER+ 肿瘤在辅助内分泌治疗期间或之后复发，约占乳腺癌死亡人数的50%。 我们每年都会这样。CDK4/6抑制剂Palbociclib、riociclib和abemaciclib最近已在 内分泌联合治疗转移性ER阳性乳腺癌然而，至于其他 癌症靶向治疗，所有使用CDK4/6抑制剂的转移性疾病患者最终都取得进展， 提示获得性耐药机制的发展尚待发现。我们 提出一个继续项目，我们将研究异常的FGFR信号在抗药性中的作用 内分泌治疗联合CDK4/6抑制剂治疗ER阳性乳腺癌患者 目标： 目标1：阐明FGFR1DNA扩增导致对这种结合产生抗性的机制 富维司琼和CDK4/6抑制剂在ER+/FGFR扩增乳腺癌中的作用 目标2：进行ER下调调节剂fulvestrant plus的Ib期和随机II期试验 帕波西利±泛FGFR抑制剂Erdafitinib治疗ER+/FGFR扩增的转移性乳腺癌 目标3：发现肿瘤中有机类药物耐药的机制 抑制剂。这些措施将包括：1)使用弗维斯特/帕波西利治疗进展中的患者的肿瘤。 2)乳腺癌患者使用CDK4/6进行标准治疗的肿瘤 抑制剂 据我们所知，这是FGFR抑制剂首次与ER和CDK4/6联合测试 乳腺癌患者中存在FGFR扩增的抑制剂。这项临床试验的积极结果 可能为患有FGFR扩增/ER+乳腺癌的女性提供一种新的治疗方案，该方案不包括 细胞毒性化疗。富维斯特朗、帕波西利和厄达菲替尼的联合应用也将提高疗效 加快FGFR抑制剂的开发。我们试图找出生物标志物来预测对 可用于在适当选择的ER+转移性乳腺癌患者中进行试验的组合。在……里面 此外，对癌症治疗进展中的有机化合物进行的全面分子分析提供了 不偏不倚地发现新的耐药分子机制的机会。这些 反过来，机制可能代表了可操作的分子靶点，可能成为未来药物发现的重点。 乳腺癌和其他依赖于FGFR的癌症的努力和/或翻译/临床研究。因此，目标是 本文提出的建议可能有助于在根除ER+乳腺癌方面取得进展。