Re-purposing beta-blockers to improve chemotherapy response

重新调整β受体阻滞剂的用途以改善化疗反应

基本信息

批准号：
10112734
负责人：
Amy C Rowat
金额：
$ 21.88万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112734
关键词：
3-Dimensional Address Adrenergic beta-Agonists Adrenergic beta-Antagonists Affect Anxiety Architecture Biological Biological Assay Biophysics Breast Cancer Patient Cardiac Cell Death Cells Cellular biology Chemoresistance Clinical Clinical Management Clinical Research Clinical Trials Collagen Cues Data Disease Disseminated Malignant Neoplasm Doxorubicin Ensure Epinephrine Extracellular Matrix FBN1 Fibroblasts Gel Gene Expression Genomics Goals Growth Heart Diseases Hormones Immunohistochemistry Improve Access Knowledge Malignant Neoplasms Mechanics Mediating Mental Depression Molecular Mus Myosin Type II Neoplasm Metastasis Outcome Paclitaxel Patients Penetration Pharmaceutical Preparations Pharmacology Phase III Clinical Trials Phenotype Public Health Quality of life Receptor Signaling Research Project Grants Resistance Role Sampling Social isolation Stress Testing Translations Treatment Protocols Tumor Biology Vision Work beta-adrenergic receptor biomarker selection cancer cell cancer therapy chemotherapy clinical practice clinically relevant density effective therapy epithelial to mesenchymal transition fibrillin genetic manipulation high risk hypertension control improved in vivo insight mouse model multidisciplinary neoplastic cell non-muscle myosin novel overexpression physical property prospective resistance mechanism response treatment strategy tsk mouse tumor tumor progression

项目摘要

ABSTRACT Metastatic tumors often develop chemoresistance, which makes chemotherapy ineffective. We have exciting evidence that beta-blockers, which are widely used cardiac drugs, can be repurposed to improve the effects of chemotherapy. If we could understand how beta-blockers enhance the effects of chemotherapy, this would expedite the translation of beta-blockers for treatment of patients with metastatic cancer, who are at high risk for anxiety and depression and tend to have elevated levels of endogenous stress hormones including epinephrine. Here we will test the hypothesis that beta-blockers can improve access of chemotherapy drugs to the tumor by decreasing tumor density or stiffness to improve chemotherapy response. Our recent work shows that beta- blockers modulate the physical tension of tumor cells. Building on these findings, we will test if beta-blockers can be used to make tumors more porous to increase the delivery of chemotherapy drugs to tumor cells and enhance the response of tumor cells to chemotherapy agents, paclitaxel and doxorubicin. We will also determine how the effects of ?-blockers on tumor cell chemosensitivity are modulated by matrix stiffness through RhoA and ROCK. Beta-blockers are already well established for clinical use for heart disease, and are showing promising effects on tumor biology in prospective clinical trials, which provides strong rationale for continued biological analysis of the basic mechanisms involved to guide biomarker selection as this field advances toward Phase III clinical trials. Repurposing beta-blockers to enhance chemotherapy response could thus have patient-related outcomes on a short timescale of 5 years.

抽象的转移性肿瘤通常会产生化疗耐药性，这使得化疗无效。我们有令人兴奋的有证据表明，β-受体阻滞剂是广泛使用的心脏药物，可以重新利用以改善心脏功能的效果化疗。如果我们能够理解β受体阻滞剂如何增强化疗的效果，这将是加快β受体阻滞剂用于治疗转移性癌症患者的转化，这些患者具有高风险焦虑和抑郁，并且内源性应激激素（包括肾上腺素）水平往往升高。在这里，我们将检验以下假设：β-受体阻滞剂可以通过以下方式改善化疗药物进入肿瘤的机会：降低肿瘤密度或硬度以改善化疗反应。我们最近的工作表明 beta- 阻滞剂调节肿瘤细胞的物理张力。基于这些发现，我们将测试β受体阻滞剂是否可以用于使肿瘤变得更加多孔，以增加化疗药物向肿瘤细胞的输送并增强肿瘤细胞对化疗药物紫杉醇和阿霉素的反应。我们还将确定如何 β-受体阻滞剂对肿瘤细胞化疗敏感性的影响通过 RhoA 和 ROCK 受基质硬度的调节。 β-受体阻滞剂已在心脏病的临床应用中得到广泛应用，并显示出良好的效果前瞻性临床试验中的肿瘤生物学，这为继续进行生物学分析提供了强有力的理由随着该领域向 III 期临床试验的进展，指导生物标志物选择所涉及的基本机制。因此，重新利用β受体阻滞剂来增强化疗反应可能会产生与患者相关的结果 5年的短时间尺度。