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Targeting STAT3 for the Treatment of CDK4/6 Inhibitor Resistant Advanced Estrogen Receptor Positive Breast Cancer Patients

靶向 STAT3 治疗 CDK4/6 抑制剂耐药的晚期雌激素受体阳性乳腺癌患者

基本信息

批准号：
10316167
负责人：
KHANDAN KEYOMARSI
金额：
$ 58.17万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-09 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316167
关键词：
Ablation Address Adjuvant Affect Aromatase Inhibitors Binding Biological Markers Breast Cancer Model Breast Cancer Patient Breast Cancer cell line CDK4 gene Cell Cycle Cell Line Cell Survival Cell secretion Cells Clinical Disease Dose Down-Regulation ERBB2 gene Early treatment Endocrine Enrollment Estrogen receptor positive Evaluable Disease Gene Expression Profile Genetic Genomics Goals Growth Growth Factor Homodimerization IL-6 inhibitor Immune checkpoint inhibitor Inflammatory Interleukin-6 Interleukins Knockout Mice MCF7 cell Mammospheres Mediating Modeling Molecular Analysis Mus Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Oral Organoids Pathway interactions Patient Care Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase Ib Trial Phase Ib/II Clinical Trial Phenotype Phosphorylation Population Primary carcinoma of the liver cells Proteomics Qualifying Recurrence Resistance Resistance development Retinoblastoma Protein Risk Role STAT3 gene Safety Serious Adverse Event Serum Solid Neoplasm T47D Testing Time Transgenic Mice Transgenic Model Transgenic Organisms Treatment Protocols Tumor Promotion Tumor Volume Tyrosine Phosphorylation Up-Regulation adjuvant endocrine therapy advanced breast cancer autocrine biomarker identification breast cancer progression checkpoint therapy chemotherapy cytokine efficacy testing epithelial to mesenchymal transition estrophilin experience high-throughput drug screening hormone therapy improved in vivo inhibitor inhibitor therapy malignant breast neoplasm mortality mouse model novel novel therapeutic intervention paracrine patient derived xenograft model pharmacologic phase II trial pre-clinical preclinical trial predictive marker programs research clinical testing resistance mechanism response senescence small molecule inhibitor src Homology Region 2 Domain standard of care stem targeted treatment transcriptomics translational study treatment strategy tumor tumor growth tumor xenograft tumor-immune system interactions tumorigenesis virtual

项目摘要

ABSTRACT Estrogen receptor-positive (ER+)/HER2-negative breast cancer represents 70% of all breast cancer cases. Surgery and adjuvant/neo-adjuvant endocrine therapy (ET) are mainstays of treatment in early stage disease. However, some patients receiving ET for early stage ER-positive breast cancer only have a partial reduction in their risk of recurrence and mortality, and those with advanced breast cancer (ABC) either progress shortly after initiating therapy (intrinsic resistance), or ultimately experience progression over time (acquired resistance). CDK4/6 inhibitors (CDK4/6is) with ET are currently considered standard of care for patients with advanced ER +/HER2 negative breast cancer. A key feature of CDK4/6 inhibition is the cell cycle inhibitory response it elicits through induction of senescence, which can be escaped resulting in cells readily re-entering the cell cycle as soon as drug is withdrawn. Senescent cells secrete interleukins, inflammatory cytokines, and growth factors, which comprise the senescence-associated secretory phenotype (SASP) that affects surrounding cells and promotes tumor growth. The most prominent SASP cytokine is interleukin-6 (IL-6), which is associated with metastasis, tumor aggressiveness and decreased survival. IL-6 activates STAT3, which is associated with a more aggressive phenotype and resistance to many therapies [chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy]. We developed CDK4/6i (i.e. palbociclib) resistant breast tumor cell line models and their molecular analysis showed that resistant cells adapt to palbociclib treatment by upregulation of IL-6 and activation of STAT3 (phosphorylation of STAT3 on Y705, pY-STAT3). Treatment of the resistant cells with an oral, small-molecule inhibitor of STAT3 (TTI-101) decreased cell viability by >25-fold and resulted in decreased levels of pY-STAT3 with concomitant decreases in (i) stem-like (CD44high/CD24low) population, (ii) primary and secondary mammosphere formation, (iii) the EMT pathway. Furthermore, TTI-101 treatment of mice bearing patient derived xenografts (PDX) that express a similar gene expression signature as palbociclib-resistant cell lines resulted in a marked decrease in tumor volume, prolonged tumor-free survival and downregulation of serum IL-6 levels. We hypothesize that inhibition of IL-6 and/or STAT3 can reverse acquired CDK4/6i resistance in vivo transgenic and PDX models and in patients who have progressed on CDK4/6i based therapy. We propose a coordinated mechanistic, preclinical and early phase clinical testing strategy to develop biomarker-qualified therapy for the clinical need to overcome CDK4/6i resistance. To address these goals we will 1): Determine the mechanism of IL-6 induction by long term CDK4/6 inhibition in vivo and the impact of IL-6 on tumorigenesis in transgenic mouse models; 2) Conduct pre-clinical trials in palbociclib resistant PDX and transgenic mouse models to determine if inhibition of STAT3 and IL-6 can improve the survival of mice with CDK4/6i resistant tumors; and 3) Perform a Phase IB/II clinical trial of adding TTI-101 to standard of care palbociclib and aromatase inhibitor upon progression.

摘要雌激素受体阳性（ER+）/HER 2阴性乳腺癌占所有乳腺癌病例的70%。手术和辅助/新辅助内分泌治疗（ET）是早期疾病的主要治疗手段。然而，一些接受ET治疗早期ER阳性乳腺癌的患者仅部分降低了ER水平。他们的复发和死亡风险，以及那些患有晚期乳腺癌（ABC）的人，开始治疗（内在抗性），或最终经历随时间的进展（获得性抗性）。 CDK 4/6抑制剂（CDK 4/6 is）与ET目前被认为是晚期ER患者的标准治疗 +/HER 2阴性乳腺癌。CDK 4/6抑制的一个关键特征是它引起的细胞周期抑制反应通过诱导衰老，衰老可以逃逸，导致细胞容易地重新进入细胞周期，一旦停药。衰老细胞分泌白细胞介素、炎性细胞因子和生长因子，其包含影响周围细胞的衰老相关分泌表型（SASP），促进肿瘤生长。SASP中最主要的细胞因子是白细胞介素-6（IL-6），它与SASP相关。转移、肿瘤侵袭性和存活率降低。IL-6激活STAT 3，STAT 3与IL-10相关。更具侵袭性的表型和对许多治疗[化疗，靶向治疗和免疫治疗]的抗性检查点抑制剂疗法]。我们开发了CDK 4/6 i（即palbociclib）耐药乳腺肿瘤细胞系模型，他们的分子分析表明，耐药细胞通过上调IL-6和IL-10来适应palbociclib治疗， STAT 3的活化（STAT 3在Y 705上的磷酸化，pY-STAT 3）。用抗肿瘤药物处理抗性细胞口服小分子STAT 3抑制剂（TTI-101）使细胞活力降低>25倍， pY-STAT 3水平与伴随的降低在（i）干细胞样（CD 44高/CD 24低）群体，（ii）原发性和次级乳腺球形成，（iii）EMT途径。此外，TTI-101治疗荷瘤小鼠，表达与Palbociclib耐药细胞相似的基因表达特征的患者源性异种移植物（PDX）细胞系的表达导致肿瘤体积显著减小，无瘤生存期延长，血清 IL-6水平。我们假设抑制IL-6和/或STAT 3可以逆转体内获得性CDK 4/6 i抗性，在转基因和PDX模型中以及在基于CDK 4/6 i的治疗中进展的患者中。我们提出了一个协调的机制，临床前和早期临床试验策略，以开发生物标志物合格的临床上需要克服CDK 4/6 i耐药。为了实现这些目标，我们将1）：确定长期抑制CDK 4/6诱导IL-6的体内机制以及IL-6对肿瘤发生的影响转基因小鼠模型; 2）在palbociclib耐药PDX和转基因小鼠中进行临床前试验模型以确定STAT 3和IL-6的抑制是否可以改善具有CDK 4/6 i抗性的小鼠的存活肿瘤;和3）进行IB/II期临床试验，将TTI-101添加到palbociclib和芳香酶的标准治疗中抑制剂。