Alternative Dosing Schedule Could Delay Resistance to Targeted Melanoma Therapy
http://wwwtest.cancercommons.org ... d-melanoma-therapy/
Treatment with vemurafenib, a drug in the BRAF inhibitor family, results in rapid tumor shrinkage in metastatic melanoma patients with the V600E BRAF mutation. The response lasts for months, but unfortunately, tumors ultimately become resistant to the treatment. Currently, vemurafenib is given as an oral dose on a daily basis. But a new study published in Nature (doi:10.1038/nature11814) suggests that a 4-weeks-on, 2-weeks-off dosing schedule may help to stave off resistance.
The study was performed in a mouse model of metastatic melanoma by Darrin Stuart, a senior investigator at the Novartis Institutes for Biomedical Research in California and Martin McMahon, a professor of cancer biology at the Helen Diller Family Comprehensive Cancer Center at the University of California in San Francisco. These investigators and colleagues used mice that had received xenografts (transplants of human tissue) of BRAF-mutated melanoma. The researchers created vemurafenib-resistant tumors in these mice by giving them a daily, continuous dose of vemurafenib.
Culturing of vemurafenib-resistant tumor cells taken from the mouse models led to an interesting observation. The resistant cells had difficulty growing unless the media was spiked with vemurafenib. “The fitness benefit given to resistant cells by elevated BRAF (V600E) in the presence of vemurafenib becomes a fitness deficit when the drug is removed,” state the authors in the paper.
McMahon and colleagues then compared a continuous vemurafenib treatment schedule with a 4-weeks-on, 2-weeks-off schedule in the BRAF-mutant mouse model. While the mice that were continuously dosed developed vemurafenib-resistant melanoma within 100 days of starting the treatment, mice given vemurafenib on an on-off schedule did not have drug-resistant melanoma as many as 200 days after their initial therapy.
These results suggest that constant exposure to vemurafenib leads to resistance and that an intermittent dosing schedule could delay—if not prevent—resistance. Whether the same results will be observed in patients needs to be tested. The perfect dosing schedule would balance between allowing tumors to regress and stalling resistance
More basic research in mouse models is needed, but the concept could be tested in a metastatic melanoma clinical trial soon. This study also has implications for other targeted therapies. Hopefully, testing various dosing schedules of targeted agents to find an optimal balance between response and rate of resistance will now be a high priority for not just melanoma researchers, but for all cancer researchers. For example, it is possible that continuous dosing contributes to the rate of resistance to other targeted agents, such as imatinib (Gleevec) prescribed for chronic myeloid leukemia. This could be relatively easily tested in experimental models and then in clinical trials.
|
既要，又要，还要，什么药品可以治疗
作者：seacat
EGFR突变可以分为常见突变和罕见突变。常见突变就是EGFR外显子19del突变
小细胞肺癌新希望？标准治疗耐药后OR
作者：Keenman
如果以药物规模化获批进入临床的时间来划分的话，进入21世纪以来，肺癌
母亲的基因检测和PD-L1报告出来了，
看了基因检测报告，似乎没有合适的靶向药，母亲确诊肺腺癌晚期，求助大家帮忙分析一下
异常凝血酶升高是复发吗？
23年12月底确诊。24年1和2月做了介入，3月份切除，5月和6月做了预防性介入。7月到11月
晚期肺癌经过4次换药，如今母亲已经4
作者：pears
“万事开头难”这句话在母亲的抗癌路上体现得淋漓尽致，最初确诊肺癌后半
显身卡
