Re-purposing beta-blockers to improve chemotherapy response

摘要 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，被广泛使用的心脏药物β-受体阻滞剂可以被改变用途，以改善 化疗。如果我们能够了解β-受体阻滞剂是如何增强化疗效果的，这将是 加快β-受体阻滞剂的翻译，用于治疗转移性癌症患者，这些患者是 焦虑和抑郁，并倾向于内源性应激激素水平升高，包括肾上腺素。 在这里，我们将检验这一假设，即β-受体阻滞剂可以通过以下方式改善化疗药物对肿瘤的可及性 降低肿瘤密度或硬度以提高化疗效果。我们最近的研究表明，贝塔- 阻滞剂调节肿瘤细胞的物理张力。在这些发现的基础上，我们将测试β受体阻滞剂是否可以 用于使肿瘤更具渗透性，增加化疗药物对肿瘤细胞的输送，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 ？-受体阻滞剂对肿瘤细胞化疗敏感性的影响是通过RhoA和ROCK的基质刚性调节的。 β-受体阻滞剂已经很好地用于心脏病的临床应用，并显示出良好的效果。 关于未来临床试验中的肿瘤生物学，这为继续进行肿瘤生物学分析提供了强有力的理论基础 随着该领域进入第三阶段临床试验，指导生物标记物选择的基本机制。 因此，改变β-受体阻滞剂的用途以增强化疗反应可能会产生与患者相关的结果 短短5年的时间尺度。

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.