Preclinical test of dacomitinib, an irreversible EGFR inhibitor, confirms it...

Preclinical test of dacomitinib, an irreversible EGFR inhibitor, confirms its effectiveness for glioblastoma
Glioblastomas (GBMs) are devastating tumors in which there has been little clinical improvement in the last decades. New molecularly-directed therapies are under development. EGFR is one of the most promising targets, as this receptor is mutated and/or overexpressed in nearly half of the GBMs. However, the results obtained with first generation tyrosine-kinase inhibitors have been disappointing with no clear predictive markers of tumor response. Here we have tested the antitumoral efficacy of a second-generation inhibitor: dacomitinib (PF299804, Pfizer) that binds in an irreversible way to the receptor. Our results confirm that dacomitinib has an effect on cell viability, self-renewal and proliferation in EGFR amplified +/- EGFRvIII GBM cells. Moreover, systemic administration of dacomitinib strongly impaired the in vivo tumor growth rate of these EGFR amplified cell lines, with a decrease in the expression of stem-cell-related markers. However, continuous administration of the compound was required to maintain the antitumor effect. The data presented here confirms that dacomitinib clearly affects receptor signaling in vivo and that its strong antitumoral effect is independent of the presence of mutant receptor isoforms although it could be affected by the PTEN status (as it is less effective in a PTEN deleted GBM line). Dacomitinib is being tested in second line for EGFR amplified GBMs. We hope that our results could help to select retrospectively molecular determinants of this response and to implement future trials with dacomitinib (alone or in combination with other inhibitors) in newly diagnosed GBMs.

达可替尼，一种不可逆的EGFR抑制剂，在临床试验中证实其对胶质母细胞瘤的作用
胶质母细胞瘤是一种极具危害性的肿瘤，在过去的几十年中，临床上对于它治疗方法未取得实质性进展。目前，新的分子靶向治疗正在研发当中。EGFR是一种最有前途的靶点，因为这种受体在近半数胶质母细胞瘤患者中存在突变或过表达。但是，由于不具备明确的可预测的肿瘤反应标记物，第一代酪氨酸激酶抑制剂得到的结果让人失望。现在，我们已经测试了一种第二代抑制剂的抗肿瘤疗效：达可替尼（PF299804，辉瑞），它以不可逆的方式与受体结合。我们的研究结果证实，达可替尼能影响细胞活性，影响EGFR扩增+ / - EGFRvIII 的胶质母细胞瘤细胞自我更新和增殖。此外，伴随着干细胞相关标志物表达减少，达可替尼全身性用药强烈破坏人体组织中肿瘤内部EGFR扩增细胞群生长速度，尽管需要持续用药以维持抗肿瘤效果。现有数据表明，达可替尼明确作用于人体组织内受体信号通路，而且其抗肿瘤效果与是否存在突变受体亚型无关，尽管它受PTEN状态影响（它在PTEN缺失的胶质母细胞瘤细胞群中效果变差）。达可替尼目前正在EGRF突变的胶质母细胞瘤患者二线治疗中进行测试。我们希望，我们的结论能够帮助筛选相关相应的决定性因素，并在新诊断的胶质母细胞瘤患者中使用达可替尼进行后续试验（单独用药或者与其他抑制剂联用）。
该文证实了论坛病友的用药经验，804对脑转有效果。不知道能不能让妹妹服用。求主带领……

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