与一位非小细胞肺癌患者家属讨论治疗方案

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与一位非小细胞肺癌患者家属讨论治疗方案，患者基因突变情况如下:

EGFR基因第19号外显子缺失插入突变(c.2251_2276>TC, p.T751_I759>S)(丰度：11.8%)

TP53基因第6号外显子突变(p.Y220C)(丰度：25.4%)

RB1 基因第23号外显子突变(p.R787*)(丰度：20.0%)

TSC2 第14号外显子突变(p.R458*)(丰度：14.7%)

蛋白免疫组化如下：

EGFR(3+)，C-MET(2+)，HER2(1+)，PD-L1(SP263)(TC=2%+)

她有p53、rb1等小细胞肺癌的标志性突变，不过医生认为还没有转化成小细胞肺癌。（从根本上说，我向来是无所谓非小还是小，左右肠之类的，我主要看基因突变、蛋白表达情况）

患者有胸膜转移，这意味将来有可能要用胸腔灌注的给药方式。

患者在用伏美替尼+培美曲塞，SD

一、可用hsp90抑制剂 Pimitespib

1、患者的egfr、met、her2、gof型p53（y220c突变点位双重属性，既是gof型又失活失去抑癌作用）、aurka（rb1突变需要抑制aurka）、mtor（tsc2要抑制mtor）都是hsp90的客户蛋白，可以通过抑制hsp90加速这些蛋白的降解。

治疗策略上可以采用egfr抑制剂+hsp90抑制剂的方案。

2、Pimitespib (TAS-116) 是一种新型的HSP90小分子抑制剂，HSP90α和HSP90β的Ki值分别为34.7 nmol/L和21.3 nmol/L。TAS-11并不抑制其他ATP酶，如HSP70(IC50 >200 μmol/L)。

（1）CAS号：1260533-36-5

（2）分子量：454.53

（3）用法用量：每天160毫克，每周连续吃五天停两天；周而复始。

（4）常见副作用：腹泻、恶心、夜盲症、血肌酐增加、味觉障碍、食欲下降、眼部异常

3、Pimitespib现在还比较贵（国内也有原料药但不知道价格任何），可以先记住这个药，放到后面等价格便宜了再用。

二、p53的y220c

p53的y220c点突变具有双重属性，既是GOF型促进肿瘤发展，又失活失去抑癌作用。因此治疗策略上既可以降解也可以重新激活。

1、克唑替尼可以降解y220c点突变的p53；克唑替尼同时抑制met（患者 met 2+），一举两得。

《Crizotinib Nanomicelles Synergize with Chemotherapy through Inducing Proteasomal Degradation of Mutp53 Proteins》

Herein, we discovered a small molecule compound crizotinib, an FDA-approved antitumor drug, exhibited outstanding mutp53-degrading capability. Crizotinib induced ubiquitination-mediated proteasomal degradation of wide-spectrum mutp53 but not the wild-type p53 protein. Degradation of mutp53 by crizotinib eliminated mutp53-conferred gain-of-function (GOF), leading to reduced cell proliferation, migration, demise, and cell cycle arrest, as well as enhanced sensitivity to doxorubicin-elicited killing in mutp53 cancer. To alleviate the side effects and improve the therapeutic effect, we adopted poly(ethylene glycol)-polylactide-co-glycolide (PEG-PLGA) nanomicelles to deliver the hydrophobic drugs doxorubicin and crizotinib, demonstrating that crizotinib nanomicelles effectively enhanced doxorubicin-elicited anticancer efficacy in a p53Y220C pancreatic cancer in vitro and in vivo via mutp53 degradation induced by crizotinib, manifesting its promising application in clinical practice.

2、Caffeic acid phenethyl ester 对p53 y220c 这个突变点有重新激活的治疗作用

（1）《Caffeic acid phenethyl ester (CAPE) confers wild type p53 function in p53Y220C mutant: bioinformatics and experimental evidence》

Mutations in the tumor suppressor protein p53 is a prevalent feature in majority of cancers resulting in inactivation of its activities related to control of cell cycle progression and proliferation. p53Y220C is one of the common hotspot mutations that causes decrease in its thermodynamic stability. Some small molecules have been shown to bind to the mutated site and restore its wild type thermodynamics and tumor suppressor function. In this study, we have explored the potential of caffeic acid phenethyl ester (CAPE-a bioactive compound from propolis) to interact with p53Y220C and restore its wild type p53 (p53wt) transcription activation and tumor suppressor activities. We recruited computational methods, viz. molecular docking, molecular dynamics simulations and free energy calculations to study the interaction of CAPE at the mutation crevice and found that it has potential to restore p53wt function of the p53Y220C mutant similar to a previously described restoration molecule PK7242. We provide cell-based experimental evidence to these predictions and suggest CAPE as a potential natural drug for treatment of p53Y220C mutant harboring cancers.

（2）Caffeic acid phenethyl ester 的CAS号：104594-70-9，分子量284.31.它是从蜂胶中提取出来的，有抗菌消炎的作用，副作用很小。不难买，也不贵。

Caffeic acid phenethyl ester 没有抗癌的人体剂量，有一些抗癌动物试验剂量：

《Caffeic acid phenethyl ester induced cell cycle arrest and growth inhibition in androgen-independent prostate cancer cells via regulation of Skp2, p53, p21Cip1 and p27Kip1》

“Administration of CAPE by gavage (10 mg/kg body weight per day) for eight weeks resulted in 50% reduction of tumor volume”

可以参考这个动物剂量，换算成人体剂量是1.1毫克每公斤每天。

（3）Caffeic acid phenethyl ester是抗氧化剂，从一些动物试验结果来看，它与egfr靶向药、化疗药等抗癌药联用，并没有削弱抗癌药的药效，而是有协同作用：

①《Combination treatment of docetaxel with caffeic acid phenethyl ester suppresses the survival and the proliferation of docetaxel-resistant prostate cancer cells via induction of apoptosis and metabolism interference》

②《Caffeic acid phenethyl ester targets ubiquitin-specific protease 8 and synergizes with cisplatin in endometrioid ovarian carcinoma cells》

③《Caffeic acid phenethyl ester surmounts acquired resistance of AZD9291 in non-small cell lung cancer cells》

现在就可以把Caffeic acid phenethyl ester 加到目前的方案里去。用伽马环糊精和Caffeic acid phenethyl ester做成纳米脂质体乳化剂吃。

3、有PC14586、JAB-30300等p53 y220c 激活剂在做临床试验，可持续关注。PC14586也能买到原料药：

三、RB1突变

1、p53和RB1的双失活会提高Exportin 1表达，从而造成肿瘤向神经内分泌型转化。用Exportin 1抑制剂 selinexor 在动物模型里有治疗作用，阻止了这种转化，而且延缓了egfr抑制剂的耐药

《Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers》

In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here, we explored the role of exportin 1 in NE transformation. We observed up-regulated exportin 1 in lung and prostate pretransformation adenocarcinomas. Exportin 1 was up-regulated after genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation in different TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the aromatase inhibitor enzalutamide and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs to standard cytotoxics. Together, these data nominate exportin 1 inhibition as a potential therapeutic target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.

2、RB1突变可以用极光激酶a抑制剂

Alisertib (MLN8237)是一种选择性Aurora A抑制剂，无细胞试验中IC50为1.2 nM，作用于Aurora A比作用于Aurora B选择性强200倍以上。Alisertib 可诱导细胞周期阻滞、细胞凋亡与自噬。

（1）CAS号：1028486-01-2

（2）分子量：518.92

（3）用法用量：28天周期里，第1-3天、8-10天、15-17天每天两次，每次40毫克。（“oral alisertib 40 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 on a 28-day cycle. ”《Efficacy and Safety of Weekly Paclitaxel With or Without Oral Alisertib in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial》）胃酸对Alisertib代谢影响大，要用肠溶胶囊灌注Alisertib原料药粉。

（4）常见副作用：血液毒性

其他一些极光激酶a抑制剂见我微信公众号上的文章《一些未上市但实际可用的靶向药（一）》

极光激酶a抑制剂的替代药物有genistein金雀异黄素、蟾酥（可用含有蟾酥的六神丸等中成药）等。

现在可以把金雀异黄素加到方案里去先用起来。

四、tsc2突变

Tsc2突变可以用mtor抑制剂，mtor抑制剂有依维莫司、西罗莫司、白蛋白型西罗莫司等。

如果要胸腔灌注给药，可以考虑白蛋白型西罗莫司。

carvacrol香芹酚是一种mtor抑制剂的替代药物，现在就可以加到方案里去先用起来。具体我微信公众号上的文章《carvacrol香芹酚是一种mtor抑制剂替代药物》。

五、EGFR/MET双阳性

患者EGFR 3+，MET 2+，可以考虑埃万妥单抗等EGFR/MET 双特异性单克隆抗体药物。

六、免疫治疗

患者EGFR 3+，MET 2+，目前国内有西妥昔单抗诱导的异体脐带血NK细胞回输治疗和包含 EGFR、MET靶点多肽诱导的DC疫苗和CTL细胞回输。

西妥昔单抗诱导的异体脐带血NK细胞可以做胸腔灌注给药

现在可以把Caffeic acid phenethyl ester、金雀异黄素、carvacrol香芹酚加到伏美替尼+培美曲塞的方案里去延缓耐药。等这个方案耐药后，重新做基因检测，根据那时的基因突变情况（egfr突变型肺癌耐药后基因突变经常发生改变，要么egfr突变点位变化，要么旁路激活）再定精准治疗方案。