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Landscape of Combination Therapy Trials in Breast Cancer Brain Metastasis.

乳腺癌脑转移联合治疗试验的景观。

  • 影响因子:6.93
  • DOI:10.1002/ijc.32937
  • 作者列表:"Fares J","Kanojia D","Rashidi A","Ulasov I","Lesniak MS
  • 发表时间:2020-02-22
Abstract

:Combination therapy has become a cornerstone in cancer treatment to potentiate therapeutic effectiveness and overcome drug resistance and metastasis. In this work, we explore combination trials in breast cancer brain metastasis (BCBM), highlighting deficiencies in trial design and underlining promising combination strategies. On October 31, 2019, we examined ClinicalTrials.gov for interventional and therapeutic clinical trials involving combination therapy for BCBM, without limiting for date or location. Information on trial characteristics was collected. Combination therapies used in trials were analyzed and explored in line with evidence from the medical literature. Sixty-five combination therapy trials were selected (n=65), constituting less than 0.7% of all breast cancer trials. Most trials (62%) combined ≥2 chemotherapeutic agents. Chemotherapy with radiation was main-stay in 23% of trials. Trastuzumab was mostly used in combination (31%), followed by lapatinib (20%), and capecitabine (15%). Common strategies involved combining tyrosine kinase inhibitors with thymidylate synthase inhibitors (6 trials), dual HER-dimerization inhibitors (3 trials), and microtubule inhibitors and tyrosine kinase inhibitors (3 trials), and HER-dimerization inhibitors and tyrosine kinase inhibitors (3 trials). The combination of tucatinib and capecitabine yielded the highest objective response rate (83%) in early phase trials. The triple combination of trastuzumab, tucatinib, and capecitabine lowered the risk of disease progression or death by 52% in patients with HER2-positive BCBM. Combining therapeutic agents based on biological mechanisms is necessary to increase the effectiveness of available anti-cancer regimens. Significant survival benefit has yet to be achieved in future combination therapy trials. Enhancing drug delivery through blood-brain barrier permeable agents may potentiate the overall therapeutic outcomes. This article is protected by copyright. All rights reserved.

摘要

: 联合治疗已成为癌症治疗的基石,以增强治疗效果,克服耐药性和转移。在这项工作中,我们探讨了乳腺癌脑转移 (BCBM) 的组合试验,强调了试验设计中的不足,强调了有希望的组合策略。2019年10月31日,我们检查了 ClinicalTrials.gov 涉及 BCBM 联合治疗的介入和治疗临床试验,但不限于日期或地点。收集试验特征信息。根据医学文献的证据,对试验中使用的联合疗法进行了分析和探讨。选择了 65 项联合治疗试验 (n = 65),占所有乳腺癌试验的不到 0.7%。大多数试验 (62%) 联合 ≥ 2 种化疗药物。放疗化疗是主要的-在 23% 的试验中停留。曲妥珠单抗主要联合使用 (31%),其次是拉帕替尼 (20%) 和卡培他滨 (15%)。常见策略包括将酪氨酸激酶抑制剂与胸苷酸合成酶抑制剂 (6 项试验) 、双 HER-二聚化抑制剂 (3 项试验) 以及微管抑制剂和酪氨酸激酶抑制剂 (3 项试验) 相结合, 和 HER-二聚化抑制剂和酪氨酸激酶抑制剂 (3 项试验)。在早期临床试验中,tuctinib 和卡培他滨联合治疗的客观缓解率最高 (83%)。曲妥珠单抗、图卡替尼和卡培他滨的三联疗法使 HER2-positive BCBM 患者的疾病进展或死亡风险降低了 52%。结合基于生物机制的治疗药物是必要的,以增加可用的抗癌方案的有效性。在未来的联合治疗试验中尚未达到显著的生存获益。通过血脑屏障渗透性药物增强药物递送可能增强整体治疗结果。本文受版权保护。保留所有权利。

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DOI:10.1002/ijc.32847
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影响因子:4.88
发表时间:2020-03-01
DOI:10.1016/j.ecoenv.2019.110098
作者列表:["Suvina V","Kokulnathan T","Wang TJ","Balakrishna RG"]

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影响因子:6.50
发表时间:2020-03-31
来源期刊:Cancer letters
DOI:10.1016/j.canlet.2019.12.039
作者列表:["Zhou Z","Zhou Q","Wu X","Xu S","Hu X","Tao X","Li B","Peng J","Li D","Shen L","Cao Y","Yang L"]

METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.

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