GOF突变型p53的yap降解治疗策略

GOF突变型p53会跟yap、nf-y形成一个大的蛋白复合物，这个大的蛋白复合物促进肿瘤的产生发展。
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因此GOF突变型p53的治疗策略除了直接降解GOF突变型p53外，还可以结合、降解yap，从而拆散这个mtP53-yap-nfy复合物，减少肿瘤发展的驱动力。
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有一些临床试验结果表明，对于抗血管生成药物帕唑帕尼，有p53突变的患者疗效相对无p53突变的患者更好，反映的正是这一作用机制--帕唑帕尼是一种yap降解的促进剂。
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+ m6 i- {) U4 s& i# P4 E0 K# r0 i目前没有专门的yap抑制剂、降解剂上市；有些已上市药物，有抑制、降解yap的作用。

现介绍两个有实际可行性的yap抑制剂、降解剂（维替泊芬之类的并无实际可行性就不述及了）：

& i5 H' q+ a' v5 a% R一、帕唑帕尼

% W/ \3 |7 q( ^: J1、《CD31 Expression Determines Redox Status and Chemoresistance in Human Angiosarcomas》
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Addition of pazopanib, a known enhancer of proteasomal YAP degradation resensitized CD31low cells for doxorubicin resulting in growth suppression and induction of apoptosis
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3 Y4 x6 m2 r1 z7 |! D2、《Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers》
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Dasatinib, statins and pazopanib inhibited the nuclear localization and target gene expression of YAP and TAZ. All three drugs induced phosphorylation of YAP and TAZ, and pazopanib induced proteasomal degradation of YAP/TAZ.
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# R; J) [+ h% @' A  H+ b: P二、Chlorpromazine 氯丙嗪
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: |: O, o8 E+ t( o7 W1、《The antipsychotic chlorpromazine suppresses YAP signaling, stemness properties, and drug resistance in breast cancer cells》
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' L  Q* v+ c+ e- B. q( CMechanistically, we identified that CPZ suppressed yes-associated protein (YAP) through modulating Hippo signaling and promoting proteasomal degradation of YAP.
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* e# B4 T5 F# ?% h( A2、《Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1》
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$ P% D* O" m% o* J  N* mWe conducted another experiment in which the mice were administered 10 mg/kg CPZ every 2 days for 2 weeks; compared with tumor growth in the control group, that in the CPZ-treated group was significantly suppressed (P < 0.01; Figure 6A lower panel). 

氯丙嗪静脉注射治疗p53突变型肠癌异种移植瘤的小鼠试验中，剂量是每两天一次每次每公斤10毫克；换算成人体剂量就是每公斤1.1毫克。

一个100公斤的肿瘤患者（这个体重对于中国肿瘤患者来说实属万里挑一了）按照这个剂量来用就是要用110毫克。

7 Q# r4 Z/ T* O* d2 c而氯丙嗪静脉注射治疗精神病的说明书剂量是“2、静脉滴注：从小剂量开始，25-50mg稀释于500ml葡萄糖氯化钠注射液中缓慢静脉滴注，一日1次，每隔1-2日缓慢增加25-50mg，治疗剂量一日100-200mg。不宜静脉推注。”
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在说明书剂量内，完全具有可行性，只要按照说明书剂量的高值使用 即可。
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3、氯丙嗪剂型多样，有口服药有注射药；氯丙嗪还有止吐、止痛等多重作用，相应的临床试验做过很多。

& ^3 m2 ]( d# G' T因此氯丙嗪除了正常使用全身治疗GOF型突变外，还能在很多特殊场景下使用：
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有GOF型p53突变的肿瘤患者在化疗要用止吐药时；在止癌痛要用止痛药时；在做腔体灌注要用灌注药时；都应把氯丙嗪纳入选择范围，一举多得。

# K1 y  P/ X' t' @" W4、《A clinical study to assess chlorpromazine as hypoxic cell sensitizer in head & neck cancer treated with conventional radiation》

A randomized prospective study was conducted to evaluate the effectiveness of chlorpromazine as a sensitizer of radiation in advanced head and neck cancers. Patients with unresectable laryngopharyngeal cancers except glottic cancers, with histologically proven squamous cell carcinoma staged III and IV were accrued for the study. Patients received radiation to a total dose of 6000 cGy in six weeks in both the groups except that patients in the study group received 50 mgs Chlorpromazine (CPZ) in divided doses. Fourteen of 20 patients showed complete response in the control group whereas 34 of 38 patients in chlorpromazine treated group had complete regression of the tumour (p = 0.016). The survival was (p = 0.08) better in patients receiving CPZ. This preliminary study shows beneficial effects of chlorpromazine. No adverse effects due to chlorpromazine in conjunction with radiation were documented.