聆听每一次呼吸——母亲晚期肺腺癌治疗记录 (克罗佐替尼)

jomn111

LZ也不说一下伯母情况如何了。。。。

虫虫301

现在克罗佐替尼的试验已经慢慢在中国上海展开，离我们最近的是上海中山医院，他们那里联系的医生是呼吸内科：胡洁医生和叶医生，叶医生的电话我有13512115068。

爱的力量

*Choi et al, who describe mutations in EML4-ALK that confer resistance to crizotinib. Their data support the independant appearance of mutations leading to C1156Y and L1196M coding changes in the NSCLC patients who had initial strong clinical reponse to crizobinib.

On the basis of structural considerations of the crystal structure of the ALK kinase domain. L1196M represents a mutation of the gatekeeper residue,similar to the T790M gefitinib-resistance mutations observed in EGFR and T315I mutations in ABL, and it would be predicted to prevent crizobinib binding to ALK. The effect of the C1156Y mutation is unclear, since it appears unlikely to have a direct effect on crizotinib binding. Futher studies will be required. He also found that these EML4-ALK mutants are less sensitive to crizotinib than is wild-type EML4-ALK when expressed in Ba/F3 cells,in agreement with the loss of clinical response in the patient. The resistance of the C1156Y variant to crizotinib was not as great in vitro as in vivo,suggesting that this mutation may require interaction with additional factors in the cell to have strong drug sensitivity.

The appearance of crizotinib-resistance mutations in this patient indicates that additional ALK inhibitors will be required to target EML4-ALK mutants that are insensitive to crizotinib in a clinical setting. This brings clinical reality to the predictions from a recent prospective mutagenesis study on NPM-ALK in which strong resistance to ALK inhibitors in mouse tumor models was observed with the NPM-ALK mutant L256M, which is in the same residue as L1196M of EML4-ALK. Thus, a familiar story line emerges, highlighting the need for basic scientists and clinicians to work together to plan a step ahead of the evolving tumor. It is encouraging that some progress in this area has already been made, and a number of such drugs are in the pipeline, including a new ALK inhibitor.

*Another case:Young Lim Choi and colleagues reported on the experience of a 28-year-old man who, upon failing chemotherapy treatment for his lung cancer, was tested for the presence of the EML4-ALK-fusion oncogene and found to be positive. He was enrolled in a clinical trial studying crizotinib and given the drug. The patient experienced marked improvement in his symptoms but lung tumors began to grow again after five months of treatment. At this point the patient was withdrawn from the trial.

In order to gauge resistance mutations, researchers performed molecular analysis on a sample from the patient's right lung. Deep sequencing using Illumina's Genome Analyzer and subsequent confirmation by Sanger Sequencing revealed "two new alterations, G→A and C→A changes at positions corresponding to nucleotides 4374 and 4493 of wild-type ALK cDNA." According to the study authors, these alterations were detected at high frequencies in the patient’s pleural effusion cDNA.

*Lilly,Novartis Cephalon and Ariad are producing additional kinase inhibiors hope to act as backup therapies for resistance occured.( Still not in clinical trial)

*Potential upgrade ALK inhibitor: Ariad pharmaceutical’s website and click on their investor tab (see http://phx.corporate-ir.net/phoe ... 2&p=irol-IRhome ) they have two links to posters they presented at ASCO about their ALK inhibitor ( ap26113). I found the link about AlK mutations particularly interesting. It suggests that if their early findings hold up, then their drug would be even more effective than Crizotinib (especially in terms of mutations that could create resistance for the cancer).

爱的力量

*crizotinib, an inhibitor of the Met oncogene, also has anti-ALK activity.

*2 professors working in other ALK experiment.

William Pao, M.D., Ph.D., assistant director of personalized medicine at the Vanderbilt – Ingram Cancer Center in Nashville

Ross Camidge, M.D., Ph.D., a medical oncologist at the University of Colorado in Denver.


*Drug Company  Clinical  stage
PF-2341066 Pfizer Phase III and II for NSCLC;
GSK2141795 GlaxoSmithKline Phase I, solid tumors or lymphomas
CEP-28122 Cephalon Preclinical; IND expected 2010
AP-26113 Ariad Pharmaceuticals Preclinical; IND expected 2011 -- Earlier this year at the American Association for Cancer Research annual meeting, it was reported that AP26113 overcomes mutations in EML4-ALK that confer resistance to crizotinib (abstract LB-298).
Xcovery X-276 Preclinical

*As Pfizer’s inadvertent ALK inhibitor moves through phase III, competition is emerging. New compounds may avoid or overcome the drug resistance that is causing Pfizer’s patients to eventually relapse. A compound from Ariad Pharmaceuticals, for example, has shown 10-fold greater potency and specificity for ALK in cell lines than the Pfizer compound. Potency should, in theory, overcome resistance because a single mutation is less likely to block the drug’s effects. “With a very potent compound, then it’s much harder for [ALK] to wriggle out of inhibition by mutating itself,” said Ariad chief scientific officer Tim Clackson, Ph.D., “as opposed to a rather modestly effective compound, where one mutation can blow away the benefit.”

Preclinical studies support this idea. In cell line experiments reported at the 2010 annual meeting of the American Association for Cancer Research, Ariad scientists identified six different ALK mutations that conferred resistance to crizotinib. In mousemodels, crizotinib had no effect on these mutation-bearing xenografts, whereas the Ariad compound shrank the tumors.

The biotech company Cephalon is also targeting ALK drug resistance. In preclinical models, its lead compound avoids multidrug resistance (the cell’s ability to pump out the drug) that hinders crizotinib in these models, said Cephalon chief scientific officer Jeffry Vaught, Ph.D. Cephalon used its compound in cell lines to identify a “gatekeeper mutation” — the same mutation in the active site of ALK that causes drug resistance in other kinases. The company’s second-generation compound will target such resistant tumor clones, if they exist in humans. Cephalon plans to test the first compound by early next year in lung cancer patients who can’t tolerate crizotinib. Several other companies are also targeting ALK .But whether ALK is the beginning or the end of a trend is not yet clear. Despite the EGFR, KRAS, and ALK success stories in lung cancer, widespread personalized therapy still seems a long way off. Mutation combinations for any given tumor type vary widely by individual, and which are drivers and which are passengers is not always apparent.