晚期NSCLC靶向和化疗方案选择的几个问题

老马 · 发表于 2013-11-24 13:26:52

老马 · 发表于 2013-11-25 03:07:38

http://www.nature.com/nm/journal ... ?WT.ec_id=NM-201311

The quest to overcome resistance to EGFR-targeted therapies in cancer.PDF (1.27 MB, 下载次数: 123)
The quest to overcome resistance to EGFR-targeted therapies in cancer
Curtis R Chong1, 2 & Pasi A Jänne1, 2, 3

论文附表.PDF (857.48 KB, 下载次数: 127)

老马 · 发表于 2013-11-26 00:29:29

上皮间质细胞转化的分子机制及其在肿瘤转移中的作用.pdf (419.86 KB, 下载次数: 161)

老马 · 发表于 2013-11-28 19:51:18

GALAXY-1 Trial: Investigation of Hsp90 Inhibition in NSCLC
http://www.onclive.com/peer-exch ... Inhibitors-in-NSCLC
The Hsp90 inhibitor ganetespib stirred excitement at the 2013 ASCO Annual Meeting when results of the GALAXY-1 trial were presented, notes moderator Corey J. Langer, MD. In this study, ganetespib plus docetaxel demonstrated some promise as a treatment for patients with non-small cell lung cancer (NSCLC), in the second-line setting.

There was excitement for this class of agents, even before these results were presented, believes Anne S. Tsao, MD. Initially, the GALAXY-1 trial enrolled patients with all histologies. However, following the accrual of 72 patients with squamous NSCLC, the enrollment was halted. Overall, there was a high-rate of hemoptysis and a lack of efficacy in the squamous population, Tsao notes. After this point, only patients with adenocarcinoma were enrolled.

In the results presented at ASCO, the combination of ganetespib and docetaxel showed a nonstatistically significant improvement in overall survival and progression-free survival for patients with adenocarcinoma. However, Tsao suggests that several problems existed in the design of the trial. In total, patients in the ganetespib plus docetaxel arm received a median of 6 cycles of treatment compared to only 4 in the docetaxel alone arm. Moreover, patient characteristics were not well balanced in each arm, in regard to gender and location. Additionally, more patients received salvage pemetrexed in the investigational arm compared to the control, Tsao states.

A single biomarker of response was not identified in the phase II trial, notes Tsao. However, patients who received treatment greater than 6 months following diagnosis experienced a statistically significant prolongation in survival. As a result, a phase III trial was formed investigating ganetespib plus docetaxel for patients with adenocarcinoma after at least 6 months from the time of diagnosis, which is an unusual eligibility criterion for a clinical trial in NSCLC, Langer notes.

水冰山山 · 发表于 2013-12-11 19:49:37

“而相对ALK突变阴性的患者，ALK突变阳性的患者培美曲塞化疗方案有效率较高。”
马哥，我妈妈起初检查确诊为间皮瘤，肺没有病灶，后经免疫组化确诊为肺腺癌，医生断定病灶在肺叶之间，经培美化疗后肺上几个小病灶消失，医生说效果一般。后空窗两个月进展，结果肺上原条索状的东西变大。医生又说不属于典型肺腺癌。请问马哥：1.怎么评估培美对我妈妈的疗效？2.如果我妈妈培美疗效一般的话是不是可以判断ALK基因不突变？3.经过化疗后不突变的的ALK基因会发生突变？

老马 · 发表于 2013-12-15 00:02:03

IGF-1R/epithelial-to-mesenchymal transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR exon 19 deletion mutations
http://www.nature.com/srep/2013/ ... full/srep02560.html

An epithelial-mesenchymal transition (EMT) gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance
http://clincancerres.aacrjournal ... 78-0432.CCR-12-1558
Purpose: EMT has been associated with metastatic spread and EGFR inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using NSCLC cell lines and patients treated in the BATTLE study. Methods: We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from NSCLC patients. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) study, and potential therapeutic targets associated with EMT were identified. Results: Compared with epithelial cells, mesenchymal cells demonstrated significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend towards greater sensitivity to the Axl inhibitor SGI-7079. Furthermore, the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In NSCLC patients, the EMT signature predicted 8-week disease control in patients receiving erlotinib, but not other therapies. Conclusion: We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype.

老马 · 发表于 2013-12-15 00:51:03

上皮 - 间质转化（EMT）与播散转移的表皮生长因子受体（EGFR）抑制剂的耐药性相关。来自美国德州大学生物癌症系的Byers LA等人对患者应用肺癌清除靶向治疗的生物标记整合方法（BATTLE），并通过测定4个平台的基因表达谱，发现并验证了非小细胞肺癌（NSCLC）细胞系76号基因的EMT标志谱，其结果发布在最新一期的Clinical Cancer Research杂志上。研究者应用NSCLC患者的细胞株和肿瘤组织进行了整合型基因表达、蛋白质组学，以及药物反应性的分析。他们通过来自4个基因芯片平台的基因谱对NSCLC患者的细胞系进行BATTLE试验，从而发现并验证了 76号基因的EMT标志谱，并对与EMT相关的潜在治疗靶点进行了鉴定。

与上皮细胞相比，在不依赖EGFR的突变的状态下，间充质细胞对EGFR和PI3K/Akt信号通路抑制剂表现出了更显著的耐药性，但其对某些化疗药物的敏感性更高。亦发现，间充质细胞酪氨酸激酶受体Axl的表达升高，且趋于对AXL抑制剂SGI -7079表现出更高的灵敏度；然而，在对间充质非小细胞肺癌应用异种移植物模型研究时，联合应用SGI-7079与厄洛替尼，可发现表达Axl的间充质细胞系中厄洛替尼的耐药性被逆转。接受厄洛替尼NSCLC患者的EMT标志谱可预测其未来8周的疾病控制期，而其他治疗不可。综上，研究者发现了可用于EGRF和PI3k/Akt抑制剂耐药性预测的EMT基因标志谱，并强调上皮细胞和间质细胞对药物的不同反应。此外，他们还将Axl作为克服与间充质型相关的EGFR抑制剂耐药的一个潜在的治疗靶点。

老马 · 发表于 2013-12-15 01:13:40

胰岛素样生长因子1(insulin-like growth factor1，IGF1) 可促进细胞增殖并抑制凋亡，IGF-1 受体介导的信号传导通路被认为与肿瘤发生有关，因此IGF-1R 目前已成为靶向治疗研究的一个靶点。本届会议上公布了一项关于口服IGF-1R 抑制剂AXL1717 的Ⅰ期研究结果。该研究入组42 例晚期实体恶性肿瘤患者，结果显示，AXL1717 每日2次的方案可用至很高剂量而耐受性良好，无剂量限制性毒性反应发生。42 例患者中，12 例为晚期NSCLC，中位生存期为45 周，至研究终止，7 例患者出现疾病进展，中位TTP 为37 周。虽然该研究仅为Ⅰ期临床研究，入组例数很少，仍能看到AXL1717 在NSCLC 治疗中显示的一定治疗优势，期待进一步的Ⅱ、Ⅲ期临床研究。