我父亲肺鳞癌的治疗贴(2014年3月1日驾鹤西去）

老马 · 发表于 2013-1-11 08:35:40

Altered Dosing of Vemurafenib Could Delay or Prevent Resistance
http://www.cancernetwork.com/mel ... ticle/10165/2122328
n a new study published today in Nature, researchers using a mouse model of melanoma were able to prevent resistance to vemurafenib by altering the dosing schedule from a continuous daily dose to an intermittent dose, suggesting a possible way to prolong the onset of resistance for melanoma patients.
Micrograph of pigmented malignant melanoma; source: Nephron, Wikimedia Commons

Vemurafenib (Zelboraf), a small-molecule kinase inhibitor, is the first targeted therapy approved by the US Food and Drug Administration for metastatic melanoma, approved for tumors that express the BRAF V600E gene mutation. Resistance to the drug, however, is problematic, with the vast majority of patients experiencing tumor regrowth several months into treatment.

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Martin McMahon, PhD, of the Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco (UCSF), and colleagues at the Novartis Institutes for Biomedical Research in Emeryville, California found mouse models that become resistant to vemurafenib with chronic exposure have a continued dependency on the BRAF-MEK-ERK signaling pathway. The vemurafenib-resistant tumor growth that develops is actually dependent on the drug. When the drug administration was stopped, tumor regression was observed within 10 days, followed by tumor regrowth. “These data support the hypothesis that vemurafenib-resistant tumors suffer a fitness deficit in the absence of vemurafenib,” the authors conclude.

“Intermittent dosing alternates the selective pressure applied by drug treatment and prevents the evolution of a drug-resistant state,” said Darrin Stuart, PhD, a senior investigator at the Novartis Institutes for Biomedical Research and one of the lead authors of the publication.

The resistance mechanism detected was upregulation of BRAF rather than mutations within BRAF or other genes in the signaling pathway.

“Even cancer cells are sensitive to the level of oncogenic pathway activation such that too little or too much of a pathway to which a cancer cell is addicted can be deleterious to the cell. This phenomenon is known as the ‘Goldilocks effect’,” explained McMahon.

The results may have major implications for the way targeted therapies against active protein kinases are administered. “The current paradigm for oncoprotein kinase directed therapy is continuous administration—this data hints that continuous therapy may not always be the best approach,” said McMahon.

The problem is not an easy fix—physicians need to balance maximal tumor regression, typically achieved by continuous treatment, and delaying the onset of resistance, which this study suggests might best achieved with an intermittent drug dose.

Mice given vemurafenib continuously on a daily basis developed resistance within 100 days of treatment initiation. In contrast, those mice treated for their melanoma intermittently with a 4 weeks on, 2 weeks off regimen did not develop resistance by day 200 of treatment.

It is not yet possible to identify patients whose tumors are dependent on chronic vemurafenib exposure, said McMahon, but “devising such a test is feasible and ongoing.”

“There is evidence that patients with drug-resistant disease experience tumor regression when dosing is suspended, however, the therapeutic approach to test would be to use intermittent dosing from the beginning and not wait until resistance emerges,” said Stuart.

McMahon noted that there is considerable interest at the UCSF Melanoma Clinic to test whether an intermittent dose schedule of vemurafenib and other BRAF V600E inhibitors may increase the duration of responses. “The idea is now out in the clinical community and so fair game for anyone to design an appropriate clinical trial,” said McMahon. Still, more laboratory research is warranted to understand how frequently this type of phenomenon occurs and how too much BRAF V600E activity inhibits the proliferation of melanoma cells addicted to BRAF V600E signaling, said McMahon.

It is possible that changing the dosing schedule of other oral kinase inhibitors could also delay drug resistance in many other tumor types but much more research, both clinical and laboratory, is necessary.

Multiple clinical trials to test alternative dosing regimens of BRAF and likely other targeted, oral inhibitors are expected over the next few years according to Stuart. Exploring rational drug combinations is another approach that Novartis is taking.

The current study is a public–private sector collaboration between UCSF and the Novartis Institute for Biomedical Research with “a free-flow of information between the two groups as well as open sharing of materials and reagent,” said McMahon. McMahon added that testing the effects of intermittent doses of BRAF inhibitors would likely also be part of such a public–private sector partnership.

戴云草 · 发表于 2013-1-11 18:19:18

老马你好麻烦你了，请问一下吃易时每月除检查CEA以外是否还的检查肝功和血常规呢？。

dongjh952 · 发表于 2013-1-11 20:27:19

本帖最后由 dongjh952 于 2013-1-11 20:43 编辑

老马发表于 2013-1-9 22:20
( \& _( H+ F7 _8 b

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" y. v# C8 V9 O* P% bCA153对肺癌来说，不太好用，特异性不强。! u$ N: @! C' W( Y' \$ X+ u
吃2992看看吧。

谢谢老马回复，经过分析一下，我妈三次赛珍+顺铂后休息20天左右就上易，只吃四个月，是不是EGFR不突变，也就是说易根本没用，前两个月易是每个月拍一次的，稳定，也许是培美有效期内，后面两个月是拍一次。大5mm,2992我想放在后面试，
请问老马老师用什么方案好，1.试单药健泽怎样，尽管老妈不喜欢化疗，目前身体状态还好，化疗的话对她心理打击大，培美有用想放在后面用？2.继续吃易一个月看看有没有继续增大？3.还是用别的方案？谢谢

dongjh952 · 发表于 2013-1-11 22:52:27

谢谢老马，有没必要再吃一个月易看看，因为老妈对化疗心理打击大

老马 · 发表于 2013-1-11 23:53:18

老爸这几天吃了大量甘蔗，咳嗽居然没有了。

棒海狸 · 发表于 2013-1-13 20:35:02

本帖最后由棒海狸于 2013-1-13 20:38 编辑

马老师你对这段文章是怎么看的？“中山大学曾益新院士研究结果：化疗易造成癌症复发”的报告。曾益新院士研究发现：在肿瘤化疗中，DNA损伤剂一方面可能消灭肿瘤细胞，另一方面也可能加剧基因组不稳定性诱导了普通肿瘤细胞演变成干细胞样肿瘤细胞。

曾益新院士指出，“如果这一学说最终得到更多的实验室证实，那么肿瘤的治疗策略也要相应发生改变，比如在肿瘤治疗中，要注意维护基因组的稳定性，尽可能的预防普通肿瘤细胞向干细胞样肿瘤细胞演变。”