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：
10097489
负责人：
KHANDAN KEYOMARSI
金额：
$ 58.75万
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/10097489
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 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 Lead MCF7 cell Mammospheres Mediating Modeling Molecular Analysis Mus Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Oral Organoids Pathway interactions Patient Care Patients Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Phase Ib Trial Phase Ib/II Clinical Trial Phenotype Phosphorylation Population Primary carcinoma of the liver cells Proteins Proteomics 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 Volume Tyrosine Phosphorylation Up-Regulation advanced breast cancer autocrine base biomarker identification checkpoint therapy chemotherapy cytokine efficacy testing epithelial to mesenchymal transition experience high-throughput drug screening hormone therapy improved in vivo inhibitor/antagonist malignant breast neoplasm mortality mouse model novel novel therapeutic intervention paracrine patient derived xenograft model phase II trial pre-clinical preclinical trial predictive marker 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/新辅助内分泌疗法（ET）是早期疾病的主要治疗方法。但是，一些接受ET的ET早期ER阳性乳腺癌的患者仅部分降低他们复发和死亡的风险，以及患有晚期乳腺癌（ABC）的风险在不久之后进展启动治疗（固有抗药性），或者最终会随着时间的推移（获得的抗药性）体验。目前，具有晚期ER患者的CDK4/6抑制剂（CDK4/6IS）被认为是护理标准 +/HER2阴性乳腺癌。 CDK4/6抑制的关键特征是细胞周期抑制反应IT引起通过诱导衰老，可以逃脱，从而导致细胞容易将细胞周期重新输入，因为一旦毒品撤回。衰老细胞分泌白细胞室，炎性细胞因子和生长因子，其中包括影响周围细胞和的衰老相关分泌表型（SASP）促进肿瘤生长。最突出的SASP细胞因子是白介素-6（IL-6），与转移，肿瘤侵袭性和生存降低。 IL-6激活了与对许多疗法[化学疗法，靶向疗法和免疫检查点抑制剂治疗]。我们开发了CDK4/6i（即palbociclib）耐药性乳腺肿瘤细胞系模型和他们的分子分析表明，抗性细胞通过上调IL-6和 STAT3的激活（Y705上STAT3的磷酸化，PY-STAT3）。用 STAT3（TTI-101）的口服，小分子抑制剂可降低细胞活力> 25倍，导致降低（I）茎样（CD44高/CD24LOW）种群的PY-STAT3水平降低（I）次生乳球的形成，（iii）EMT途径。此外，TTI-101治疗轴承的小鼠患者衍生的异种移植物（PDX），表达与耐Palbociclib细胞相似的基因表达签名线导致肿瘤体积显着减少，无肿瘤生存率延长和血清下调 IL-6水平。我们假设抑制IL-6和/或STAT3可以在体内逆转CDK4/6I的抗性转基因和PDX模型以及在基于CDK4/6i治疗的患者中。我们提出了一个协调的机械，临床前和早期临床测试策略，以发展生物标志物质量克服CDK4/6I耐药性的临床需要的治疗。要解决这些目标，我们将1）：确定长期CDK4/6抑制体内IL-6诱导的机理以及IL-6对肿瘤发生的影响转基因小鼠模型； 2）在抗Palbociclib抗性PDX和转基因小鼠中进行临床前试验确定抑制STAT3和IL-6的模型是否可以改善CDK4/6I抗性的小鼠的存活率肿瘤； 3）对将TTI-101添加到护理标准palbociclib和芳香酶进行IB/II期临床试验进展后抑制剂。