Re-purposing beta-blockers to improve chemotherapy response

摘要 转移性肿瘤通常会产生耐药性，这使得化疗无效。我们有令人兴奋 有证据表明，广泛使用的心脏药物β受体阻滞剂可以重新用于改善 化疗如果我们能了解β受体阻滞剂如何增强化疗的效果， 加快β受体阻滞剂的转化，用于治疗转移性癌症患者，这些患者具有高风险， 焦虑和抑郁，并且倾向于具有升高水平的内源性应激激素，包括肾上腺素。 在这里，我们将测试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假设： 降低肿瘤密度或硬度以改善化疗反应。我们最近的研究表明，β- 阻断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 可用于使肿瘤更多孔，以增加化疗药物向肿瘤细胞的输送， 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 影响？阻断剂对肿瘤细胞化学敏感性的调节通过RhoA和ROCK的基质硬度。 β-受体阻滞剂已经在心脏病的临床应用中得到了很好的确立，并显示出有希望的效果 在前瞻性临床试验中的肿瘤生物学，这为持续的生物学分析提供了强有力的理由， 随着该领域向III期临床试验的发展，指导生物标志物选择的基本机制。 因此，重新使用β受体阻滞剂以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。

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.