慧质兰馨 发表于 2011-10-30 10:06 static/image/common/back.gif
终于结束二十天的快乐自驾游，往返行程3500公里，真是很开心，身心得到极大的放松，对疾病的认知度 ...
九十六的老爸和八十四的老妈-------你太幸福了！
英雄武松 发表于 2011-10-30 11:29 static/image/common/back.gif
九十六的老爸和八十四的老妈-------你太幸福了！
哈哈:lol是的呀！
慧质兰馨 发表于 2011-10-30 10:06 static/image/common/back.gif
终于结束二十天的快乐自驾游，往返行程3500公里，真是很开心，身心得到极大的放松，对疾病的认知度 ...
你好幸福啊！有九十六岁的老爸与八十四岁的老妈，而且他们还如此健康。
枫叶红了 发表于 2011-10-30 19:06 static/image/common/back.gif
你好幸福啊！有九十六岁的老爸与八十四岁的老妈，而且他们还如此健康。
老歌生病第一年，为了不让二老知道病情，不想让他们这么大年纪还为儿女操心，近一年时间没有回家，编排各种理由，一直到吃特罗凯后，病情稳定，才回家。
最爱看你的帖子，你和你家老哥那种快乐的生活状态感人着每一个人。
慧质兰馨 发表于 2011-8-17 21:44 static/image/common/back.gif
讲点伤感的话，前几天老歌化疗后反映很重，半夜因难受睡不着，说不舒服，我知道是化疗反映，但没有办法 ...
:'(:hug:
小提琴 发表于 2011-11-1 16:52 static/image/common/back.gif
最爱看你的帖子，你和你家老哥那种快乐的生活状态感人着每一个人。
;P高高兴兴是一天，愁眉苦脸还是一天，就看如何选择。生命会随着时间的流失而慢慢远去的，珍惜现在的每一天，过好每一天是最重要的，别给自己吃后悔药。
本帖最后由 慧质兰馨 于 2011-11-1 22:58 编辑
朋友将老歌的病历发给美国的二位癌症专家会诊，他们给出如下用药的建议，与各位病友分享，看看对大家有没有帮助。
这个病人不抽烟， 特罗凯使用效果奇好， 就说明他有 EGFR 基因变异。 特罗凯的有效期限是 8 - 12 个月， 他也符合。 我们以前的判断都对。
现在是是否有办法给病人续命。 下面的内容提到一些还没有成药的抑制剂。主要是 IGF1-R (Insulin like growth factor 1 receptor) 抑制剂。 不知中国能否找到。
另外， Pan-inhibitors (泛 - 抑制剂 = 多靶位抑制剂）有点用。 目前， 有效的抵抗特罗凯抗药性的方法是同时用两个药， 泛抑制剂加上Erbitux (爱必妥)。
“Resistance to treatmentA key issue with EGFR-directed treatments is that after a period of time, frequently 8–12 months, the cancer cells become resistant to the treatment. The primary source of resistance is a second mutation called T790M. A second source of resistance is the MET mutation.
Chemically resistance appears to occur by recruiting a mutated IGF-1 receptor to act as one of the EGFR partners in the homodimer, so forming a heterodimer. This allows the signal to be transmitted even in the presence of an EGFR inhibitor. Some IGR-1R inhibitors are in various stages of development (based either around tyrphostins such as AG1024 or AG538 or pyrrolo-pyrimidine derivatives such as NVP-AEW541).
Pan-inhibitors show some promise in combating resistance, at least in cell studies. Today (3/10) the most promising approach to combating resistance appears to be a dual approach, combining pan-inhibitors like HKI 272 with Erbitux. "Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab (Erbitux) and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance." Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.”
另一篇 专门讲 怎样战胜特罗凯抗药性的文章。 不知中国能否找到 泛抑制剂HKI-272 和 爱必妥 （后者应当好找）。
ADDRESSING TARCEVA RESISTANCE
I. Overview and Background
A. EGFR and lung cancer
The human body has a complex system of signaling between cells with gene duplication a normal part of this process.Duplication is necessary for growth, repair of damaged cells and other functions, and genes signal other cells to initiate replication.Malfunctions in signaling are a critical part of cancer and the tyrosine kinases have been an important target:
Uncontrolled proliferation of tumor cells is a hallmark of cancer. In many types of cancer, mutations in genes that activate cellular signal transduction pathways contribute to enhanced proliferation and survival of cancer cells. One well-characterized example is mutation in tyrosine kinases, enzymes that regulate the growth and survival of cells. Tyrosine kinase activity is tightly regulated in normal cells, but is dysregulated due to mutation in some cancers, including lung cancer, resulting in enhanced proliferation and survival of cancer cells. The tyrosine kinases are attractive candidates for molecularly targeted therapy in cancer, because cancers become dependent on growth signals from the mutant tyrosine kinases. Tyrosine kinases require ATP for their enzymic activity, and thus small molecules that mimic ATP can bind to mutant kinases and inactivate them inveas growth factors prompt excessive carcinogenic cell duplication.Clark (6),
A subgroup of lung cancer patients has a mutation in the epidermal growth factor receptor (EGFR) which is associated with various forms of cancer, particularly lung. Vikis (2). "Recent work has identified a series of somatic mutations in exons 18 to 21 of epidermal growth factor (EGF) receptor (EGFR) that render lung tumors responsive to the gefitinib and erlotinib therapeutics." Vikis (2). These people are EGFR positive, as measured by a sensitive EGFR mutation test. See Harvard EGFR test.
The response rate to Tarceva for EGFR positive patients is approximately 60%, with response rates further varying upon the particular exon(s) on which the mutation is located. EGFR positive patients are principally but not exclusively non-smokers with adenocarcinoma.Some light former smokers and a few squamous cell patients are EGFR positive.EGFR positive patients appear to have tumors driven by aberrant EGFR signaling. with oncogene addiction, a plausible theory.
The EGFR is a part of the Erb family of receptors. Cross-signaling among the other receptors including Erb2 occurs, though the precise role of the other receptors in lung cancer is unclear.
While the initial response rate to Tarceva is impressive with partial and even complete responses, (total elimination of any visible tumor on Ct to the drug) many patients develop resistance and Tarceva becomes effective. Why do patients develop resistance and what can we do about it are the questions.
II. The Development of the T790M Mutation
A. T790 Mutation
However, many patients who initially respond to Tarceva find the drug is no longer effective. One cause appears is the development of a Tarceva-resistant EGFR mutation at T790M. "The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme." Vikis (2)."In patients that progress after drug treatment, it has been observed that a secondary "resistance" mutation is often acquired in exon 20 (4–6). This mutation, T790M, arises somatically in 50% of these cases." Vikis (2).The change involves threonine-to-methionine substitution at amino acid position 790 (T790M) of the epidermal growth factor receptor (EGFR) gene." Inukai (3)."About half of the acquired resistance to EGFR-TKIs that almost always occurs during the course of treatment is caused by a secondary mutation at codon 790 (T790M)."Fukui (8).
B. Rationale for Testing and Characteristics of the T790 Mutation
The T790m mutation plays an important but not exclusive role in generating resistance to Tarceva.It makes sense to determine its impact upon a particularly patient. See gxsgenetyping.com<http://gxsgenetyping.com/> outlining its T790 test.It may make sense to test patients taking Tarceva yearly for the mutation, or at least when it appears Tarceva is no longer effective.
"The T790M test uses a combination of Scorpions® and ARMS® (allele specific PCR) technology. This approach allows the development of very sensitive tests that can detect mutations in a background of normal cells. The real-time PCR based test enables rapid identification and quantification of the mutations. Mutations can be detected at a ratio of 1:100 mutant: normal DNA and this allows the kit to detect genetic variation that could not be detected using DNA sequencing methods." dxsgenotyping.com<http://dxsgenotyping.com/>
III. Pan-Inhibitors
A. Overall Approach
Pan-inhibitors have shown some success in cell studies in suprresing T790 resistance. Sharma explains:
"one of the main challenges in the treatment of NSCLC is to design inhibitors that can overcome the steric interference to drug binding conferred by the T790M mutation. Irreversible inhibitors seem to show some promise in this regard. In most cases, irreversible inhibitors form a covalent bond with crucial cysteine residues — Cys797 within EGFR or Cys805 within ERBB2 — in the active site of the respective enzymes. Given the fact that only EGFR and ERBB2 (as opposed to ERBB4) have cysteines at these corresponding positions, irreversible ErbB inhibitors show very high specificity for EGFR and ERBB2. Previous studies from our laboratory have shown that the irreversible dual EGFR and ERBB2 inhibitors, HKI-272 (Ref. 136) and HKI-357 (Ref. 37), as well as the irreversible EGFR inhibitor EKB-569 (Ref. 137) were all able to overcome gefitinib resistance owing to T790M in cis with an L858R mutation in EGFR. Sharma (5)
"Paninhibitors permanently and irreversibly stop certain functioning of EGFR. Initial cell studies have indicated these stronger inhibitors can work against the resistant cells with the mutation.To determine whether the T790M mutation leads to resistance to EGFR inhibitors that have different molecular structures and mechanisms, we screened four commercially available EGFR inhibitors (AG1478, cetuximab, erlotinib, and CL-387,785) using cells that were transiently transfected with the delL747–S752 construct and the delL747–S752+ T790M construct. We consistently found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, strongly inhibited EGF-induced phosphorylationWhile this may not be a valid alternative for many patients, it may make sense for patients whose cancers have been shown to be associated with EGFR."
"Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells.... Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation."Kubayashi
Its success in human studies has been debatable.There have been several trials but none sufficient impressive to move towards FDA approval.Many of these studies did not deal solely with T790M but a variety of patients.Part of the problem may be the company's desire to secure aa drug that is effective overall, and reports testing for the T790M mutation and detailing the drug's impact are strangely difficult to find.
B. HKI 272
One cell study found pan-inhibitor HKI 272 effective with tumor cells in a laboratory setting. "HKI 272 is effective in inhibiting various lung cancer mutations- "HKI-272 is effective in growth inhibition of Ba/F3 cells transformed with EGFRvIII, EGFR-L858R, and EGFR-L858R-T790M." Ji (1)
C. Lapanatib
A recent study showed promise for a combination of Cetuximab (Erbitux) and Lapatanib (Tykerp),
"In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. We observed that T790M lung cancer cells were resistant to gefitinib, and Stat3 was persistently activated in the resistant cells. A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC."
Both Erbitux and Lapatanib are FDA approved drugs, though not specifically approved for this purpose.They can be prescribed off label if a physician chooses.
D. Zactima (ZD-6474)
E. BMS 690514
Only cell studies are available."BMS-690514, a novel panHER/vascular endothelial growth factor receptor (VEGFR) inhibitor described here, exerted antiproliferative and proapoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation."