夜读札记（三）
一、伊立替康抑制thymidylate synthase，可考虑与培美曲塞序贯治疗1、《Finding alternatives to 5-fluorouracil: application of ensemble-based virtual screening for drug repositioning against human thymidylate synthase》
“Repurposing FDA drugs against human thymidylate synthase revealed a number of FDA drugs that have a potential to be further developed for the treatment of various cancers for which 5-fluorouracil and analogs have been used for chemotherapy. Four FDA drugs prioritized for further validation included Erismodegib, Irinotecan, Conivaptan and Ergotamine. ”
2、《Molecular Mechanisms and Tumor Biological Aspects of 5-Fluorouracil Resistance in HCT116 Human Colorectal Cancer Cells》
“In contrast, HCT116RF10 cells did not exhibit cross-resistance to the anticancer drugs, SN-38 and CDDP”
HCT116RF10 cells 是5fu耐药的高表达TS的肠癌细胞，SN-38是伊立替康在体内的代谢物
3、《Irinotecan overcomes the resistance to 5-fluorouracil in human colon cancer xenografts by down-regulation of intratumoral thymidylate synthase》、
“CPT-11, but not l-OHP, induced a decrease in activities and protein levels of TS and an increase in those of RNR in KM12C/5-FU tumors only, which was likely related to decreased expressions of several proteins in G1/S phase of the cells including CDK4, pRB, and E2F1 in these tumors. These findings suggest that CPT-11, but not l-OHP, would overcome the resistance to 5-FU in combination with 5-FU pro-drugs on 5-FU-resistant colon tumors.”
结合培美曲塞、伊立替康与TS的关系，top1、top2的跷跷板的关系，可以考虑这样贯序用药的方案：
1、在现行有效的方案的基础上，可以联用鸦胆子油；鸦胆子油是top2抑制剂，可以增加top1表达和阳性分布率；鸦胆子油靶点众多，用了不会白用；鸦胆子油比较温和，耐受比较好。
2、鸦胆子油用过一段时间比如半年以上，可以考虑用top1抑制剂伊立替康。当然用伊立替康还要看UGT1A1基因的多样性，考虑毒副作用大小。
3、包含伊立替康在内的治疗方案耐药后，测一测外周血中TS的表达情况，考虑用包含培美曲塞在内的治疗方案。
二、预测紫杉烷类化疗药疗效的生物标志物
1、III类β-微管蛋白(βIII-tubulin)
一般情况下，βIII-tubulin 表达高，紫杉醇、多烯紫杉醇的疗效就差。
例外情况有两个，一是ER阴性的乳腺癌，βIII-tubulin表达高，紫杉醇、多烯紫杉醇的疗效似乎更好一点 。二是由于 卡巴他赛对βIII-微管蛋白(- 23.0千卡/摩尔)的作用与对βI-微管蛋白(- 24.0千卡/摩尔)和βIIa-微管蛋白(- 25.9千卡/摩尔)的作用相当，所以 βIII-微管蛋白表达高低对卡巴他赛的疗效影响不是很大。
2、STMN1
STMN1表达高，紫杉烷类化疗药疗效差。
3、TEKT4基因突变
TEKT4的 A541G、A547G点位发生突变，紫杉烷类化疗药疗效差
三、索拉非尼+azd1775
BATTLE试验是安德森中心在2006-2009年针对非小细胞肺癌患者进行的一项临床试验。试验本身不成功，但是亚组分析的时候发现，kras突变的非小患者用索拉非尼似乎可以获益。
但是同期的《Evaluation of KRAS mutations, angiogenic biomarkers and DCE-MRI in patients with advanced non-small cell lung cancer receiving sorafenib》 和 MISSION 这两项临床试验的结果与BATTLE试验亚组分析结果不同，认为kras突变非小用索拉非尼益处不大。
2011年的《Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer》这篇论文分析了这三个试验结果不同的原因，认为不能笼统的认定kras突变就完事，还要细分到具体的突变的点位。kras g12d突变的非小患者用索拉非尼能获益，而 kras g 12v突变的非小患者没有获益。
2011年这篇论文的作者2018年又发表了《Wee1 inhibitor MK1775 sensitizes KRAS mutated NSCLC cells to sorafenib》的论文，提出了解决 kras g 12v突变对索拉非尼不敏感的办法：
作者对719种人体内激酶进行高通量筛选，筛选出wee1这个激酶 是索拉非尼的反应调节剂，抑制wee1可以敏化kras g 12v突变从而使其对索拉非尼敏感。
wee1抑制剂常用的就是azd1775，我们在讲p53失活突变的时候经常提到这个药，azd1775+parp抑制剂。
这个研究流程经典的反映了我们提倡的精准治疗的精髓：一是要细分再细分，从癌种到分型到突变的基因再到具体的点位，分的越细，治疗方案越精准。只根据癌种或者分型之类的就定的粗放型的方案，对于个体来说都是盲试。二是发现问题就要解决问题，而解决问题的办法，越来越倚重高通量筛选、靶点蛋白形状与药物分子结构对接这些办法。
四、pik3ca扩增一样是用阿佩利斯，而不是只有pik3ca突变才能用。
1、《PIK3CA copy number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer》
“In the present paper we describe two clinical cases in which patients harboring PIK3CA-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG Positron-emission tomography (PET) imaging. ”
2、《Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials》
“In addition to PIK3CAmutation, we also found PIK3CA amplification to be positively associated with NVP-BYL719 sensitivity in the overall and interestingly also in the PIK3CA WT cell line population”
“Considering that PIK3CA mutation or amplification might be the key molecular determinants for NVP-BYL719 patient stratification in the clinic, we next performed a molecularly defined prospective trial in PIK3CA mutant and/or amplified PDX models in mice with the aim to test our patient selection strategy in a setting that best mimics disease response in patients. Tumor-bearing animals were treated with NVP-BYL719 at 50 mg/kg/day for 14 to 16 days. Strikingly, 8 of 9 PDX models that carry a mutation and/or amplification in PIK3CA responded to NVP-BYL719, leading to a response rate of 88% (Fig. 5B and Supplementary Table S7). The PDX response to NVP-BYL719 can be observed in different lineages (breast, lung, gastric, colorectal cancer), suggesting that PIK3CA genetic status should represent a reliable patient enrollment criterion across indications.”
五、apc、kras、p53三巨头共突变的肠癌的治疗模式
肠癌突变三巨头，apc、kras、p53；三个突变目前基本上都没有专门的上市的靶向药。
《Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon cancer》这篇论文，讲了一个治疗思路：
用了同时有apc、kras、p53三巨头突变的肠癌细胞，测试了各种药物，疗效最好的方案是 泛her抑制剂+mek抑制剂+化疗药长春瑞滨。
泛her抑制剂有阿法替尼、来那替尼、拉帕替尼这些药；mek抑制剂有司美替尼、比美替尼、曲美替尼这些药。泛her抑制剂+mek抑制剂主要的还是针对的kras。
因为apc和p53还没有专门靶向药，所以就测试了各种化疗药，看哪种化疗药对泛her抑制剂+mek抑制剂这个组合的协同作用最大，测试出来长春瑞滨协同作用最大。因为泛her抑制剂和mek抑制剂都不止一个药，所以实际上这个模式可以用几次。
长春瑞滨耐药后，可以考虑一是看p53的点位，是否是三氧化二砷的敏感点位，如果是，那联用三氧化二砷；二是考虑联用用阿西替尼这些治疗apc突变的替代药物。
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