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.

抽象的雌激素受体阳性 (ER+)/HER2 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方法。然而，一些接受 ET 治疗早期 ER 阳性乳腺癌的患者仅部分减少他们有复发和死亡的风险，而患有晚期乳腺癌 (ABC) 的人要么在术后不久就出现进展开始治疗（内在耐药），或最终随着时间的推移而进展（获得性耐药）。 CDK4/6 抑制剂 (CDK4/6is) 联合 ET 目前被认为是晚期 ER 患者的标准治疗方法 +/HER2 阴性乳腺癌。 CDK4/6 抑制的一个关键特征是它引发的细胞周期抑制反应通过诱导衰老，可以逃避衰老，导致细胞很容易重新进入细胞周期一旦停药。衰老细胞分泌白细胞介素、炎症细胞因子和生长因子，其中包括影响周围细胞的衰老相关分泌表型（SASP）促进肿瘤生长。最重要的 SASP 细胞因子是白细胞介素 6 (IL-6)，它与转移、肿瘤侵袭性和生存率下降。 IL-6 激活 STAT3，STAT3 与更具侵略性的表型和对许多疗法的抵抗性[化疗、靶向治疗和免疫治疗] 检查点抑制剂疗法]。我们开发了CDK4/6i（即palbociclib）耐药性乳腺肿瘤细胞系模型并他们的分子分析表明，耐药细胞通过上调 IL-6 和 IL-6 来适应 palbociclib 治疗。 STAT3 的激活（Y705 上 STAT3 的磷酸化，pY-STAT3）。耐药细胞的处理口服小分子 STAT3 抑制剂 (TTI-101) 使细胞活力降低 25 倍以上，并导致细胞活力下降 pY-STAT3 水平伴随 (i) 干状 (CD44high/CD24low) 群体、(ii) 初级和次级乳腺球形成，(iii) EMT 途径。此外，TTI-101 治疗小鼠患者来源的异种移植物 (PDX) 表达与 Palbociclib 耐药细胞相似的基因表达特征细胞系导致肿瘤体积显着减小、无瘤生存期延长以及血清水平下调 IL-6 水平。我们假设抑制 IL-6 和/或 STAT3 可以逆转体内获得性 CDK4/6i 耐药性转基因和 PDX 模型以及在基于 CDK4/6i 的治疗中取得进展的患者。我们提出一个协调机械、临床前和早期临床测试策略，以开发合格的生物标志物临床治疗需要克服CDK4/6i耐药性。为了实现这些目标，我们将 1)：确定体内长期抑制CDK4/6诱导IL-6的机制以及IL-6对肿瘤发生的影响转基因小鼠模型； 2）在palbociclib耐药的PDX和转基因小鼠中进行临床前试验确定抑制 STAT3 和 IL-6 是否可以提高 CDK4/6i 耐药小鼠的存活率的模型肿瘤； 3) 进行 IB/II 期临床试验，将 TTI-101 添加到护理标准 palbociclib 和芳香酶中进展时的抑制剂。