Rovalpituzumab Tesirine Safe, Active in Previously Treated SCLC
吴洪波-小细胞肺癌治疗进展
疗效评估
三线治疗
目前小细胞肺癌无标准的三线治疗，ROVA-T在DLL3≥50%SCLC 临床疗效是鼓舞人心。
Overall Survival
SCLC Kaplan-Meier Overall Survival
Presented By Charles Rudin at 2016 ASCO Annual Meeting
13.7 74.1 18.5 2.0 1
18.1 65.4 19.2 2.4 2
.03 .85 .70
结论
该研究是一个阴性的结果。局限期小细胞肺癌，两种放疗方式联合化疗 都是可选的；治疗相关毒副反应相当。超分割放疗（45Gy/30f/19D, 每 日两次），常规放疗（66Gy/33f/45D,每日一次） 未来方向
摘要8504 CONVERT:III期随机对照多中心临床试验 局限期小细胞肺癌同步放化疗 超分割：常规分割
背景
SCLC占肺癌的10~ 15%; ~ 30%的患者初诊时为局限期或者（TNM分期 I-III 期）[1] 局限期小细胞肺癌伴PS评分较好，同步放化疗为标准治疗 – 相对常规放疗（每天一次），超分割放疗（每天两次）具有生存优势 (23 vs 19 mos; P = .004)[2] – Grade 3/4 esophagitis: 32% with twice daily vs 16% with once daily
Small cell lung cancer : on the move(again?)
2016年ASCO小细胞肺癌治疗探索研究
免疫治疗（CheckMate 032 和 CheckMate 451)
研究结果：ORR&DCR
Conclusions: Rovalpituzumab tesirine in SCLC
营养对比图
Multivitamin 10000OIU 150mg 1000IU 66IU 2.6mg 3mg 40mg 4mg 400mcg 75mcg 300mcg 20mg 53.8mg 150mcg 25mg 7.5mg 55mcg 100mcg 2mg 120mcg 108mg
B族维生素
钙
58mg 1000IU 2mg 3mg 20mg 6mg 800mcg 120mcg 300mcg 20mg
450mg 450mg 25mg 25mg 2mg 1mg
镁 800IU 500mg
C族
D族 消化酶
ORAC
complete green
99mg
353mg
100mg 93mg
200mg
45mcg 90mg 40mg 40mg 40mg 30mg 20mg 56mcg 20mg 549mg 98mg 78mg 314mg 110mg 78mg 78mg 39mg 24mg
美国倍力健 OPC-3 年价格 VA VC VD3 VE B1 核黄素B2 烟酸B3 B6 叶酸 B12 biotin B7 泛酸(pantothenic)B5 钙 碘 镁 锌 硒 铜 锰 铬 钼 钾 alpha lipoic acid 纤维醇,纤维糖,肌糖 番茄红素 叶黄素(lutein esters) citrus bioflavonoid dehydrate 干甘蓝(dried kale) VE 苹果皮提取物 芦笋粉 holy basil extract blend 蓝梅粉 葡萄提取物 牛至叶粉 西梅干提取物 迷迭香提取物 脱水花椰菜 越橘提取物 西洋菜浓缩物 脱水西芹 石榴提取物 sage powder extract 脱水山葵 EGCG(epigallocatechin gallate) 栎精 鞣花酸 橘皮苷 叶黄素 番茄红素 不饱和脂肪 10000IU 500mg 400IU 150IU 11.25mg 12.75mg 40mg 15mg 800mcg 45mcg 300mcg 50mg 750mg 150mcg 300mg 15mg 100mcg 2mg 5mg 120mcg 50mcg 80mg 10mg 25mg 2mg 2mg 100mg 75mg 50mg 50mg 50mg 50mg 50mg 50mg 50mg 50mg 50mg 48mg 50mg 48mg 25mg 25mg 25mg 2mg 90mg 150mg 40mg 60mg 6mg 3mg 1.5g
VivapureProtA_MiniSpin
®Vivapure Protein A Mini spin columnsfor antibody purification2Effective antibody purification using Protein AAntibody purification with Vivapure Protein A Mini spin columns200 kDa 116 kDa 97 kDa 45 kDa 31 kDa22 kDa14 kDa++++= Strong affinity += Slight affinity +++= Moderate affinity +/-= Some serum IgGs bind weakly,some not at all++= Weak affinity-= No affinity®of various immunoglobulins (Ig).RapidThe antibodies to be bound are loaded onto the membrane at neutral to high pH and eluted upon a shift to low pH.This is done very rapidly in subsequent centrifugation steps within less than 30 minutes.User friendlyThe Vivapure Protein A Mini spin devices are supplied with an easy 1-2-3 protocol and detailed instructions including optimized buffer recommendations.The Vivapure spin devices lend themselves to working with multiple samples and parallel processing.High purityProtein A is inherently known to purify antibodies from complex samplesRelated ProductsVivapure family:•Ion Exchange spin columns •Acidic Protein Purification Kit •Basic Protein Purification Kit •DNA Removal Kit •Albumin Removal Kit Production of monoclonalantibodies:•miniPERMbioreactorUltrafiltration of antibodysolutions:•Vivaspin 15R& Vivaspin 2with Hydrosart®membrane3 Antibody purification made simpleOriginalsampleAntibody isbound to membraneWash Elute Pure antibody(See ordering information on the back and at )Ordering InformationVivascience AGFeodor-Lynen-Strasse 2130625 Hannover,GermanyPhone:+49 511 524875-0Fax:+49 511 524875-19E-mail:********************Web:S p e c i f i c a t i o n s s u b j e c t t o c h a n g e w i t h o u t n o t i c e .P u b l i c a t i o n N o .S L -1510-e 02091,O r d e r N o .85030-516-60Vivascience is a member of the Sartorius Groupplease refer to the:quadriPERM (see front cover )• Vivapure ®Catalog for kits and devices for protein purificationFor current information and application notes,please visit us at 。
2018年上市十大重磅新药
2018年上市十大重磅新药2018年上市十大重磅新药作者: 李敏华生物制药公司的研究开发人员在审视他们的后期开发项目时，都会津津乐道、滔滔不绝地谈论医疗领域尚未满足的需求。
然而，市场是严酷的，潜在的希望会激起投资者的兴趣，有的创新他们也可能冷淡以对。
著名的市场调查机构Evaluate公司日前公布了一份2018年上市的预期销售峰值Top10药品。
一些成熟的公司正在鼎力为2018年上市新的重磅药品鼓足干劲。
在艾滋病和糖尿病方面有了新的进展，10个预期的重磅药品中有6个是新的癌症治疗药物或罕见病治疗药物。
NO.1 Bictegravir/F/TAF企业：吉利德销售峰值：50.5亿美元类别：艾滋病毒感染这是吉利德最大的“明星”项目，将实验性整合酶链转移抑制剂Bictegravir（50mg）（BIC）与恩曲他滨/替诺福韦甲酰胺（FTC/TAF）固定剂量组合，用于艾滋病患者治疗。
吉利德公司已于今年6月12日向美国FDA提交了新药批准申请，并计划迅速在欧洲提交上市申请。
该组合新药可以简化艾滋病治疗，给患者带来方便。
该产品一直被寄予厚望，2017年1月，EvaluatePharma 预测其2022年销售额可达25.02亿美元。
现在，吉利德公司正等待2018年2月12日（PDUFA，即美国FDA新药审批规定日期）的审批结果，并为该药上市作准备。
该药将显示出吉利德公司在艾滋病治疗市场的地位，不少分析师给予高度评价，对其期望值明显提高。
吉利德多年来一直是抗艾滋病毒药物市场的主角，无意将市场拱手让给葛兰素史克刚刚（11月21日）获准的两种药物组合Juluca（Dolutegravir-Rilpivirine）。
葛兰素史克的这个产品也是这个领域的标志性成就，鸡尾酒疗法依从性比以往更好；而吉利德的优势在于其更加了解艾滋病市场。
届时，吉利德科学和葛兰素史克将在市场上直接竞争。
NO.2 Semaglutide企业：诺和诺德销售峰值：27亿美元类别：糖尿病12月5日，美国FDA为诺和诺德（Novo Nordisk）的semaglutide（司美鲁肽）开了绿灯，这是一种每周一次的GLP-1（胰高血糖素样肽-1）糖尿病药物。
依达拉奉右莰醇联合阿替普酶治疗急性缺血性脑卒中的疗效观察
J Apoplexy and Nervous Diseases, October 2023, Vol 40，No. 10依达拉奉右莰醇联合阿替普酶治疗急性缺血性脑卒中的疗效观察李春颖1， 鞠东升1， 潘澍潇1， 朱辉2， 靳颖1摘要： 目的 观察依达拉奉右莰醇联合阿替普酶治疗急性缺血性脑卒中（AIS ）的疗效性和安全性。
方法 收集2020年11月―2022年4月松原吉林油田医院收治的AIS 患者共计124例，随机分为实验组（阿替普酶静脉溶栓+依达拉奉右莰醇组）和对照组（阿替普酶静脉溶栓组），对比治疗效果。
结果 实验组治疗总有效率为82.3%，高于对照组的64.5%，差异有统计学意义（P < 0.05）。
其溶栓后不同阶段NIHSS 评分结果（5.40 ± 3.82）分、（4.14 ± 3.44）分、（0.57 ± 0.99）分均低于对照组，差异有统计学意义（P < 0.05）。
两组患者治疗期间均未发生药物不良反应。
结论 依达拉奉右莰醇联合阿替普酶治疗AIS 患者临床疗效确切。
关键词： 依达拉奉右莰醇； 阿替普酶； 急性缺血性脑卒中； 疗效中图分类号：R743.3 文献标识码：AEfficacy of edaravone dexborneol combined with alteplase in treatment of acute ischemic stroke LI Chunying ，JU Dongsheng ， PAN Shuxiao ， et al. （Songyuan Jilin Oilfield Hospital ， Songyuan 138000， China ）Abstract ： Objective To investigate the efficacy and safety of edaravone dexborneol combined with alteplase in the treatment of acute ischemic stroke （AIS ）.Methods The data were collected from 124 patients with AIS who were admitted to our hospital from November 2020 to April 2022. The patients were randomly divided into experimental group （intravenous thrombolysis with alteplase + treatment with edaravone dexborneol ） and control group （intravenous thrombolysis with al‑teplase ）， and the two groups were compared for efficacy.Results The overall response rate in the experimental group was sig‑nificantly higher than that in the control group （82.3% vs 64.5%， P < 0.05）. The National Institutes of Health Stroke Scale scores at different stages after thrombolysis were significantly lower in the experimental group （5.40 ± 3.82， 4.14 ± 3.44， and 0.57 ± 0.99） than in the control group （P < 0.05）. No adverse drug reactions were observed in the two groups during the treat‑ment.Conclusion Edaravone dexborneol combined with alteplase has definite clinical efficacy in the treatment of AIS.Key words ： Edaravone dexborneol ； Alteplase ； Acute ischemic stroke ； Efficacy 脑卒中是全球致残的主要原因和第二大死亡原因［1］，至少50%幸存者将遗留残疾［2］。
美国联合保健公司产品说明书：测试生成产品
UnitedHealthcare PharmacyClinical Pharmacy ProgramsProgram Number 2023 P 2018-16Program Prior Authorization/Medical Necessity – TestosteroneMedication Androderm, Androgel*, Fortesta*, Jatenzo*, Natesto*, Kyzatrex*,Testim, testosterone topical solution (generic Axiron)*, testosteronetransdermal gel (generic Testim)*, Tlando*, Vogelxo*, Xyosted*P&T Approval Date 2/2014, 4/2014, 5/2014, 7/2014, 10/2014, 10/2015, 5/2016, 6/2017,6/2018, 2/2019, 6/2019, 7/2020, 8/2021, 9/2022, 1/2023Effective Date 4/1/2023;Oxford only: 4/1/20231.Background:Testosterone products are approved by the Food and Drug Administration (FDA) for testosterone replacement therapy in males with primary hypogonadism (congenital or acquired) orhypogonadotropic hypogonadism (congenital or acquired). Primary hypogonadism originatesfrom a deficiency or disorder in the testicles. Secondary hypogonadism indicates a problem in the hypothalamus or the pituitary gland. Testosterone use has been strongly linked to improvements in muscle mass, bone density, and libido.The purpose of this program is to provide coverage for androgens and anabolic steroid therapy for the treatment of conditions for which they have shown to be effective and are within the scope of the plan’s pharmacy benefit. Coverage for the enhancement of athletic performance or bodybuilding will not be provided.a3.Additional Clinical Rules:•Notwithstanding Coverage Criteria, UnitedHealthcare may approve initial and re-authorization based solely on previous claim/medication history, diagnosis codes (ICD-10)and/or claim logic. Use of automated approval and re-approval processes varies by programand/or therapeutic class.•Supply limits may be in place.•* May be excluded from coverage•+ Coverage for patient population may be dependent upon benefit design4.References:1.AACE Hypogonadism Task Force. American Association of Clinical EndocrinologistsMedical Guidelines for Clinical Practice for the Evaluation and Treatment ofHypogonadism in Adult Male Patients – 2002 Update. Endocr Pract. 2002; 8(No. 6): 439-456.2.The World Professional Association for Transgender Health (WPATH), Standards of Carefor the Health of Transsexual, Transgender, and Gender Nonconforming People, 7thVersion.3.Cook, David M, et al. "American Association of Clinical Endocrinologists medicalguidelines for clinical practice for growth hormone use in growth hormone-deficient adultsand transition patients - 2009 update: executive summary of recommendations." Endocrinepractice 15.6 (2009):580-586.4.Gibney, James, et al. "Growth hormone and testosterone interact positively to enhanceprotein and energy metabolism in hypopituitary men." American journal of physiology:endocrinology and metabolism 289.2 (2005):E266-E2715.Bhasin, S, et al. "Testosterone replacement and resistance exercise in HIV-infected menwith weight loss and low testosterone levels." JAMA. 2000. 283.(6) 763-770.6.Isidori, Andrea M, et al. Effects of testosterone on sexual function in men: results of ameta-analysis. Clinical endocrinology. 2005 63(4):381-394.7.Kenny, A M, et al. Effects of transdermal testosterone on bone and muscle in older menwith low bioavailable testosterone levels. The journals of gerontology. 2001. 56(5) M266-M272.8.Tracz, Michal J, et al. Testosterone use in men and its effects on bone health. A systematicreview and meta-analysis of randomized placebo-controlled trials. The Journal of clinicalendocrinology and metabolism. 2006. 91(6):2011-2016.9.Bolona, Enrique R, et al. Testosterone use in men with sexual dysfunction: a systematicreview and meta-analysis of randomized placebo-controlled trials. Mayo Clinicproceedings.2007. 82(1):20-28.10.Androderm [package insert]. Madison, NJ: Allergan, Inc; May 2020.11.Androgel [package insert]. North Chicago, IL: AbbVie Inc; May 2020.12.Fortesta [package insert]. Malvern, PA: Endo Pharmaceuticals Inc; January 2022.13.Testim [package insert]. Malvern, PA: Endo Pharmaceuticals Inc; August 2021.14.Natesto [package insert]. Mississauga, ON: Acerus Pharmaceuticals Corporation;December 2021.15.Vogelxo [package insert]. Maple Grove, MN: Upsher-Smith Laboratories, LLC; April2020.16.Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline.J Clin Endocrinol Metab 2017; 102:3869.17.The Endocrine Society. Testosterone therapy in Adult Men with Androgen DeficiencySyndromes. J Clin Endocrinol Metab, May 2018, 103(5):1–30.18.Mulhall JP, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline.American Urological Association Education and Research, Inc 2018.19.Xyosted [package insert]. Ewing, NJ: Antares Pharma, Inc; November 2019.20.Jatenzo [package insert]. Northbrook, IL: Clarus Therapeutics, Inc; March 2019.21.Tlando [package insert]. Ewing, NJ: Antares Pharma, Inc; March 2022.22.Kyzatrex [package insert]. Raleigh, NC: Marius Pharmaceuticals LLC; September 2022.Program Prior Authorization/Medical Necessity - TestosteroneChange ControlDate Change2/2014 Create Prior Authorization Criteria4/2014 Revised Reauthorization Criteria; formatting corrections, referencesupdated.5/2014 Revised the initial authorization criteria to include subsections for themale population and the female to male transsexual population, updatedto include language from the gender identity disorder/ gender dysphoriatreatment medical coverage determination guideline, referencesupdated7/2014 Added Natesto and Vogelxo to criteria. Changed coverage criteria fromspecific product names to topical testosterone products.10/2014 Modified criteria for total testosterone to consider reference range of thelaboratory. Added criteria for when Free Testosterone level may beutilized. Added criteria for conditions that do not require testosteronelevels. Extended initial authorization period for patients already ontherapy.12/2014 Testosterone free level units corrected.10/2015 Clarified initial authorization periods. Clarified that levels forreauthorization should be within the past 6 months for patients new totestosterone and within the past 12 months for continuing users.Updated references.5/2016 Removed age requirement from female to male transsexual coveragerequirements. Updated gender identity disorder to gender dysphoria.6/2017 Updated criteria for Gender Dysphoria. Updated reauthorizationcriteria to clarify that new to therapy refers to use of less than one yearand continuing therapy refers to use of one year or longer.6/2018 Updated required testosterone level to less than 300 ng/dL based on2018 American Urological Society treatment guidelines.2/2019 Program name change from Topical Androgens to Testosterone.Xyosted added to program.6/2019 Jatenzo added to program.7/2020 Updated initial authorization to 6 months for both new and existingusers. Added state mandate language. Updated references.8/2021 Annual review. Updated references. Removed Striant as it is no longeron the market.9/2022 Tlando added to program. Removed brand Axiron from program sinceit is no longer available. Updated to note generic Testim is typicallyexcluded. Updated references.1/2023 Kyzatrex added to program. Increased initial authorization to 12months and changed reauthorization to require a lab value within thepast 12 months.。
小细胞肺癌中Notch1信号通路、ASCL1与EMT关系研究进展
小细胞肺癌中Notch1信号通路、ASCL1与EMT关系研究进展周怡然;辛宇;陈骏【摘要】小细胞肺癌(SCLC)是人类常见恶性肿瘤之一,其具有转移率和复发率高、对初始化疗敏感、易获得化学耐药等特征.上皮-间质转化(epithelial-mesenchymal transition,EMT)是肿瘤细胞发生侵袭、转移前重要的细胞表象,EMT的发生与多种细胞因子、信号传导通路及转录因子有关.尽管Notch途径激活在非小细胞肺癌(NSCLC)中起着致癌的作用,但在神经内分泌肿瘤(neuroendocrine tumors,NET)中,Notch通路激活抑制肿瘤生长.在SCLC中,Notch1通路激活可以诱导产生E-钙黏蛋白(E-Cadherin),增强细胞的粘附,诱导间质-上皮转化,从而抑制EMT过程.ASCL1(achaete-scute complex homologue 1)是SCLC一种系特异性基因,其编码的转录因子同样具有促进神经内分泌分化、EMT的功能.Notch1信号通路可以抑制ASCL1的转录,同时也可对ASCL1进行转录后调节.因此,可通过激活Notch1信号通路、抑制ASCL1表达从而抑制SCLC的发生、侵袭和转移.【期刊名称】《大连医科大学学报》【年(卷),期】2018(040)003【总页数】5页(P270-273,277)【关键词】SCLC;Notch1信号通路;ASCL1;EMT【作者】周怡然;辛宇;陈骏【作者单位】大连医科大学附属第二医院肿瘤科,辽宁大连116027;大连医科大学附属第二医院肿瘤科,辽宁大连116027;大连医科大学附属第二医院肿瘤科,辽宁大连116027【正文语种】中文【中图分类】R734小细胞肺癌(SCLC)是各种类型肺癌中恶性程度最高的肿瘤，约占所有肺癌的15%～20%，其5年生存率<6%[1-2]。
过去几十年中，SCLC的一线化疗方案仍以顺铂或卡铂加依托泊苷为主，尽管其暂时对放化疗敏感，但很快出现复发和转移[3-5]。
仑伐替尼在肝细胞癌中的耐药机制和对策研究进展
收稿日期:２０２３Ｇ０８Ｇ２１基金项目:国家自然科学基金项目(８２０６０４３５)作者简介:徐永康(１９９６ ),男,博士研究生,主要从事肝癌的临床和基础研究.通信作者:吴建兵,主任医师,E Ｇm a i l :h h g w jb ＠１６３．c o m .仑伐替尼在肝细胞癌中的耐药机制和对策研究进展徐永康,吴建兵(南昌大学第二附属医院肿瘤科,南昌３３０００６)摘要:仑伐替尼是晚期肝癌有效的一线治疗药物.然而,许多患者在仑伐替尼治疗后出现疾病进展,耐药问题在治疗实践中普遍存在,临床急需逆转耐药策略.众多研究表明表观遗传学㊁细胞转运过程㊁肿瘤微环境㊁肿瘤干性以及细胞自噬㊁铁死亡等与仑伐替尼的耐药机制密切相关.文章对肝癌仑伐替尼耐药的机制研究进展进行归纳,并初步探讨耐药后临床治疗策略,旨在为改善仑伐替尼耐药患者预后提供理论基础.关键词:肝细胞癌;仑伐替尼;耐药性;临床策略中图分类号:R ７３５．７㊀㊀㊀文献标志码:A㊀㊀㊀文章编号:２０９５Ｇ４７２７(２０２４)０２－００８１－０７D O I :１０．１３７６４/j．c n k i ．n c d m．２０２４．０２．０１４R e s i s t a n c e o fL e n v a t i n i b a n d I t sU s e i n t h eT r e a t m e n to fH e pa t o c e l l u l a rC a r c i n o m a :aR e v i e w X UY o n g Ｇk a n g ,W UJ i a n Ｇb i n g(D e p a r t m e n t o f O n c o l o g y ,t h eS e c o n dA f f i l i a t e d H o s p i t a l o f N a n c h a n gU n i v e r s i t y ,N a n c h a n g ３３０００６,C h i n a )A B S T R A C T :L e n v a t i n i b i s a n e f f e c t i v e f i r s t Ｇl i n e t h e r a p e u t i c a g e n t f o r a d v a n c e d h e pa t o c e l l u l a r c a r Ｇc i n o m a ．H o w e v e r ,m a n y p a t i e n t s e x p e r i e n c e d i s e a s e p r o g r e s s i o n a f t e r l e n v a t i n ib t r e a t m e n t ,a n d t h e p r o b l e mo f d r u g r e s i s t a nc e i s p r e v a l e n t i n t h e r a p e u t i c p r a c t i c e ,u r g e n t l y r e q u i r i n g s t r a t e gi e s t o r e Ｇv e r s ed r u g r e s i s t a n c e ．N u m e r o u ss t u d i e sh a v es h o w nt h a te p i g e n e t i c s ,c e l l t r a n s po r t p r o c e s s e s ,t u m o rm i c r o e n v i r o n m e n t ,t u m o r d r y n e s s ,a sw e l l a s a u t o p h a g y a n d f e r r o p t o s i s ,a r e c l o s e l y re l a t e d t o t h e r e s i s t a n c e m e c h a n i s m of l e n v a t i n i b ．T h i sa r t i c l es u mm a r i z e s t h er e s e a r c h p r o gr e s so nt h e m e c h a n i s mo f l e n v a t i n i b r e s i s t a n c e i nh e p a t o c e l l u l a r c a r c i n o m a ,a n d p r e l i m i n a r i l y e x p l o r e s c l i n i c a l t r e a t m e n t s t r a t e g i e s t o p r o v i d e a t h e o r e t i c a l b a s i s f o r i m p r o v i n g t h e p r o g n o s i s o f l e n v a t i n i b Ｇr e s i s t Ｇa n t p a t i e n t s ．K E Y W O R D S :h e p a t o c e l l u l a r c a r c i n o m a ;l e n v a t i n i b ;d r u g r e s i s t a n c e ;c l i n i c a l s t r a t e g y㊀㊀据国际癌症研究机构的估算,到２０４０年,全球新发肝癌病例预计将达到１４０万例,相较于２０２０年将增长５５％;而全球肝癌导致的死亡人数也预计将达到１３０万人,较２０２０年增加５６．４％[１].肝细胞癌(H C C )是最常见的肝癌类型,约占肝癌病例的９０％[２].当前,全球和中国的肝癌防治形势十分严峻,因此提高肝癌的诊断和治疗水平对于我国的肝癌患者尤为重要.根据R E F L E C T 研究显示,与索拉非尼相比,仑伐替尼在总生存期(O S )㊁客观缓解率(O R R )(２４．１％比９．２％)和无进展生存期(P F S )方面表现出非劣效(P F S７．４个月比３．７个月)[３].在晚期肝癌的系统治疗中,我国广泛使用仑伐替尼,并且取得了显著的疗效.然而,随着治疗时间的延长,１８南昌大学学报(医学版)２０２４年第６４卷第２期㊀J o u r n a l o fN a n c h a n g U n i v e r s i t y(M e d i c a l S c i e n c e s )２０２４,V o l ．６４N o ．２肿瘤耐药问题不可避免,导致患者疾病进展.因此,探索仑伐替尼耐药的机制以及新的耐药途径显得尤为迫切.另外,目前临床上对于仑伐替尼耐药患者的治疗方案尚无统一标准.本文对仑伐替尼治疗H C C耐药机制以及耐药后的临床研究进展进行综述,以期为临床提高参考.１㊀表观遗传与仑伐替尼耐药㊀㊀表观遗传是一种与核苷酸序列变化无关但能够改变生物表型的重要机制.已有大量证据显示,异常的表观遗传调控可能导致肿瘤耐药的发生[４].因此,对于仑伐替尼耐药与表观遗传机制之间的关系进行深入阐述,将为未来逆转耐药策略提供理论基础.１．１㊀R N A修饰R N A修饰是表观遗传学调控中的重要组成部分,包括甲基化修饰㊁羟甲基化修饰㊁乙酰化修饰和磷酸化修饰等常见类型,近年来发现这些修饰在仑伐替尼耐药形成过程中扮演着重要角色.在仑伐替尼耐药细胞中,m６A修饰相关蛋白M E T T L３表达显著上调,进一步机制研究[５]发现,M E T T L３通过m６A修饰调节E G F R的m R N A翻译,针对M E TＧT L３的特异性抑制剂S T M２４５７可以提高细胞对仑伐替尼的敏感性.此外,有研究[６]还发现在耐药细胞中m７G甲基转移酶复合物的关键成分M E T T L１和WD R４上调,通过介导t R N A m７G修饰和调控T R I M２８表达等途径促进了对仑伐替尼的耐药性[７].另外,N A T１０的上调可以通过调节H S P９０A A１m R N A a c４C的修饰水平维持H S P９０A A１的稳定性,促进了内质网应激H C C的转移和仑伐替尼耐药作用[８].此外,Y R D C也在调节K R A S蛋白质翻译方面发挥作用,其低t６A修饰水平的t R N A降低了K R A S的翻译,从而介导肝癌细胞对仑伐替尼的耐药[９].当前,R N A修饰蛋白成为了治疗肿瘤耐药的新靶标,针对M E T T L３的小分子抑制剂已经应用于临床研究,为提升仑伐替尼治疗反应性提供了新的选择.１．２㊀非编码R N A非编码R N A是基因表达调控的关键因素之一.微小R N A s(m i R N A s)㊁长链非编码R N A s(l nＧc R N A s)和环状R N A s(c i r c R N A s)通过影响转录㊁转录后修饰和翻译等生物学过程,对癌症的发生发展和肿瘤耐药发挥着双重作用[１０].１．２．１㊀m i c r o R N A在仑伐替尼耐药的人肝癌细胞株H u h７和S MM CＧ７７２１中,CＧM e t呈现过度表达和活化的现象.有研究[１１]表明,m i RＧ１２８Ｇ３p通过抑制cＧM e t表达,调节介导凋亡途径的A k t和调节细胞周期进程的E R K参与了仑伐替尼的耐药机制.此外,在仑伐替尼耐药的肝癌细胞中,A K R１C１和m i c r o R N A ４６４表达水平显著上调.数据库分析提示A K R１C１和m i c r o R N A４６４可能存在靶向关系,而m i c r o RＧN A４６４被认为是早期诊断仑伐替尼耐药性的一个潜在生物标志物[１２].１．２．２㊀l n c R N A在仑伐替尼耐药的H C C细胞中,L n c R N A MT１J P(MT１J P)呈现上调的情况,导致了MT１J P 和抗凋亡蛋白B C L２L２的过度表达,从而降低了H C C细胞对仑伐替尼的敏感性[１３].MT１J P通过吸附m i RＧ２４Ｇ３p来靶向B C L２L２,进而促进了仑伐替尼的耐药性.此外,有研究[１４]报道了l n c X I S T通过激活H C C细胞中的E Z H２ＧN O D２ＧE R K轴来促进仑伐替尼的耐药性.S O N G等[１５]观察到在仑伐替尼耐药的细胞和组织中P I N K１的高表达,这有助于维持线粒体的结构和功能,并促进抗氧化应激反应,进一步的机制研究发现F G D５ＧA S１/m i RＧ５５９０Ｇ３p/P I N K１轴可以促进肝癌细胞对仑伐替尼的耐药性.机制研究表明L I N C０１６０７/m i RＧ８９２b/P６２促进了线粒体自噬,降低了R O S水平,从而导致肿瘤的耐药性.最后,敲除L I N C０１６０７联合仑伐替尼能够有效地克服类器官模型中仑伐替尼的耐药性[１６].１．２．３㊀c i r c R N A通过对２８例接受仑伐替尼治疗后出现耐药的患者进行外周血检测,发现c i r c M E D２７水平显著上升.相关研究[１７]表明,c i r c M E D２７作为m i RＧ６５５Ｇ３p的竞争内源性R N A发挥着重要作用,其上调促使U S P２８的表达增加,在肝癌的进展和仑伐替尼耐药过程中发挥关键作用.此外,L I U等[１８]首次发现c i r c K C N N２通过m i RＧ５２０cＧ３p/M B D２轴抑制了H C C的复发.潜在的机制可能在于c i r c K C N N２和仑伐替尼都能够抑制F G F R４的表达,从而加强对仑伐替尼的抗肿瘤效果.H A O等[１９]研究发现C i rＧc P A K１通过H i p p o信号通路促进了Y A P的核转运,从而促进了H C C的进展.同时,该研究发现在仑伐替尼耐药的L M３ＧL R和H e pＧ３BＧL R H C C细胞中,C i r c P A K１的表达上调.外泌体中高表达的C i r c P A K１从耐药细胞转运到敏感细胞,诱导细胞对仑伐替尼的耐药性.非编码R N A作为治疗靶点在改善肿瘤耐药方面显示出极具竞争力和前景.然而,在药物的稳定性和传递效率方面仍然存在挑战.２８南昌大学学报(医学版)２０２４年４月,第６４卷第２期２㊀信号通路与仑伐替尼耐药㊀㊀作为一种多靶点酪氨酸激酶抑制剂,仑伐替尼主要作用于血管内皮生长因子(V E G F R)１Ｇ３㊁成纤维细胞生长因子受体(F G F R)１Ｇ４等靶点,从而发挥抗肿瘤的作用.近期的研究逐渐揭示,仑伐替尼治疗导致V E G F R和F G F R的抑制,进而引发E G F R/ S T A T３㊁R A S/R A F/M E K/E R K㊁P I３K/A K T等相关信号通路的反馈激活.这些信号通路的激活被认为是引发肿瘤对靶向治疗产生耐药的关键机制.因此,通过针对H C C内部相关信号通路的交叉对话进行靶向阻断,成为解决耐药问题的一种有效策略.２．１㊀E G F R介导的信号通路J I N等[２０]通过C R I S P RＧC a s９基因筛选,确定了E G F R作为仑伐替尼的合成致死靶点.研究机制显示,仑伐替尼治疗抑制F G F R,进而导致E G F RＧP A K２ＧE R K５信号轴的反馈激活.另一方面,HU 等[２１]的研究表明,A B C B１在E G F R激活下以脂质筏依赖的方式被激活,从而显著增强了仑伐替尼的细胞排出作用.这种激活通过激活E G F R并刺激E G F RＧS T A T３ＧA B C B１轴,导致对仑伐替尼产生耐药性.考虑到E G F R通路在肝癌靶向治疗中的关键作用,L I M等[２２]利用c t D N A分析了肝癌患者在治疗前和治疗进展时E G F R途径的遗传变化.他们发现,在仑伐替尼治疗进展期间,患者显示出E GＧF R的拷贝数增加(４．８拷贝Ｇ７拷贝)和E R B B２的激活突变(S３１０Y).这些E G F R/E R B B２的遗传改变可能是导致仑伐替尼耐药性的遗传机制之一.２．２㊀R A S/M E K/E R K信号通路耐药细胞中V E G F R２的表达以及其下游R A S/M E K/E R K信号轴显著上调,E T SＧ１被确认为介导V E G F R２相关的仑伐替尼耐药的原因.此外,槐定碱被发现能够降低E T SＧ１的表达,从而抑制耐药H C C细胞中V E G F R２及其下游R A S/ M E K/E R K轴的表达[２３].L U等[２４]发现N F１和D U S P９在H C C中是仑伐替尼耐药的关键驱动因素,研究者通过R N A i敲除和C R I S P R/C a s９敲除模型进一步阐明了N F１激活P I３K/A K T和MA P K/E R K信号通路的机制.另外,D U S P９激活MA P K/E R K信号通路,导致F O X O３失活降解,最终诱导耐药发生.在仑伐替尼耐药细胞中,发现３种血管生成细胞因子(V E G F㊁P D G FＧA A㊁A n g)显著上调,加速了肿瘤血管生成,增加了获得性耐药的发生,同时观察到了MA P K/M E K/E R K信号通路的激活和E MT标记物的上调[２５].２．３㊀其他信号通路HO U等[２６]发现,I T G B８通过H S P９０介导的A K T的稳定以及A K T信号的增强来调节仑伐替尼的耐药性.通过使用A K T抑制剂MKＧ２２０６或H S P９０抑制剂１７ＧA A G,可以使耐药细胞重新对仑伐替尼治疗产生敏感性.此外,另一项研究[２７]指出,T HO C２可能通过W n t/βＧc a t e n i n通路参与调控肝癌对仑伐替尼的耐药性.肿瘤细胞异常信号通路的激活在获得性耐药中是常见的机制,针对这些关键靶点进行有效干预是防治耐药的有效策略.例如,已证实E G F R抑制剂㊁cＧM E T抑制剂以及M E K抑制剂在一定程度上可以逆转耐药现象,有望成为临床上的新对策.３㊀肿瘤微环境与仑伐替尼耐药㊀㊀肿瘤微环境构成了一个极为复杂的生态系统,由各种细胞㊁非细胞成分和分泌产物组成,它们之间的相互作用形成了复杂的保护和修复机制,从而导致肿瘤产生耐药性.因此,深入探索新的针对微环境的靶向策略和药物,以改善耐药性并抑制肿瘤的恶性增殖显得尤为重要.作为一种抗血管生成药物,长期使用仑伐替尼可能会导致肿瘤细胞缺氧,部分细胞因此产生耐药性.在缺氧条件下,H I FＧ１α诱导P L C/P R F/５细胞中纤维连接蛋白的生成并削弱了仑伐替尼的作用,进而导致耐药性的产生.进一步的研究[２８]表明,联合抑制纤维连接蛋白和MA P K通路可能是一种有效的治疗策略.肿瘤相关成纤维细胞(C A F)长期处于激活状态,形成致密的纤维间质包绕瘤块,通过分泌可溶性因子和直接细胞间接触等途径,对耐药性的形成起着潜在作用.研究人员发现,C A F和H C C细胞的共培养显著降低了H C C细胞对索拉非尼/仑伐替尼的体内外反应性.C A F分泌的S P P１通过P K Cα信号通路激活R A F/MA P K和P I３K/A K T/m T O R 通路,并通过E MT增强了肝癌患者对酪氨酸激酶抑制剂的抵抗.因此,治疗前血浆S P P１水平可能成为预测治疗反应的潜在生物标志物[２９].４㊀细胞自噬与仑伐替尼耐药㊀㊀自噬是一种细胞死亡编程,与肿瘤的恶性演变和耐药性密切相关,过去的研究[３０Ｇ３１]已经表明在肝癌索拉非尼耐药中自噬发挥着关键作用,近期对仑伐替尼耐药机制的探索中也发现了类似的现象. P A N等[３２]证实L A P T M５的上调会导致细胞自噬水平上升,从而降低H C C对仑伐替尼的敏感性,而３８徐永康等:仑伐替尼在肝细胞癌中的耐药机制和对策研究进展通过L A P T M５的沉默或者使用H C Q来阻断内在的自噬潮,可以与仑伐替尼协同作用来抑制H C C 的生长.此外,HO A I R M１在仑伐替尼耐药细胞系中被发现是一个独立的耐药因子,与仑伐替尼治疗H C C的疗效显著相关.敲低HO T A I R M１可以增加H u h７ＧR和H e p G２ＧR细胞中m i RＧ３４a的水平,并抑制B e c l i nＧ１的表达.因此,HO T A I R M１可能通过下调m i RＧ３４a和上调B e c l i nＧ１来诱导自噬的激活,从而导致H C C对仑伐替尼的耐药性[３３].５㊀铁死亡与仑伐替尼耐药㊀㊀铁死亡是一种铁依赖性的细胞死亡方式,诸多证据表明此过程与肿瘤治疗耐药相关联,调节铁死亡过程可能有效改善耐药性.I S E D A等[３４]分析了仑伐替尼对H C C细胞的细胞毒性,并证实了仑伐替尼通过抑制F G F R４,抑制x C T表达并诱导脂质R O S积累的方式诱导H C C细胞发生铁死亡.此外,活化的N r f２抑制了仑伐替尼诱导的铁死亡,因此抑制N r f２的活化有望提高H C C细胞对仑伐替尼的敏感性,从而改善肝癌的耐药性.另一项研究[３５]发现,K E A P１是驱动索拉非尼耐药的关键基因,K E A P１失活导致了K E A P１/N r f２途径的失活,通过上调N r f２下游基因和降低R O S水平,导致人类H C C细胞对索拉非尼的耐药性增加.同时,该研究还发现K E A P１的破坏抑制了仑伐替尼诱导的细胞活力下降,同时降低了对药物反应产生R O S的能力,这表明K E A P１也可能是仑伐替尼的易感基因之一.６㊀其他机制６．１㊀肿瘤细胞干性肿瘤干细胞(C S C)是一种功能细胞状态,具有自我复制和多谱系分化能力,在肿瘤药物抵抗中发挥关键作用,其耐药机制主要涉及药物转运子高表达㊁强D N A修复能力和募集保护性微环境等方面[３６].WA N G等[３７]研究发现F Z D１０在肝C S C中高度表达,从机制上看,M E T T L３介导F Z D１０m RＧN A的m６A修饰,而m６A读取器Y T H D F２随后与F Z D１０m R N A上的m６A位点结合,保持该m R N A 的稳定性.F Z D１０通过WN T/βＧc a t e n i n和H i p p o 途径增强肝脏C S C的特性,并且F Z D１０/βＧc a t e n i n/ cＧJ u n/M E K/E R K轴促进肝癌细胞对仑伐替尼产生耐药性.采用腺相关病毒靶向F Z D１０或βＧc a t e n i n 抑制剂治疗仑伐替尼耐药H C C可恢复其抗肿瘤反应.另一项研究[３８]表明,T M４S F１通过上调MY H９来调节N O T C H通路,进而促进肝癌中干细胞干性和仑伐替尼耐药性,且C D７３通过上调S O X９的表达和增强其蛋白稳定性,在维持C S C性状方面发挥关键作用.C D７３的过度表达使H C C 细胞对仑伐替尼产生显著的耐药性,同时也在维持肝癌索拉非尼和卡博替尼的耐药性中发挥作用.因此,将C D７３作为靶点可能是根除C S C和逆转肝癌患者对T K I耐药性的一种有希望的策略[３９].６．２㊀糖酵解H C C在缺氧和营养缺乏的环境中,通过适应性机制 W a r b u r g效应 ,优先依靠糖酵解产生能量,相关的转运蛋白㊁关键限速酶和代谢产物能够通过多种机制促使肿瘤进展和耐药.因此,探索糖酵解调控的耐药机制对于癌症治疗具有重要意义.A CＧY P１在糖酵解中扮演直接调节的角色,并通过A CＧY P１/H S P９０/MY C/L D H A轴驱动了仑伐替尼耐药性和H C C的进展,靶向A C Y P１可以与仑伐替尼协同作用,更有效地治疗H C C[４０].另外,果糖Ｇ２,６Ｇ二磷酸酶３(P F K F B３)是糖酵解的有效刺激剂, P F K F B３的表达上调可以导致H C C细胞对仑伐替尼的耐药.联合使用P F K F B３抑制剂可以在仑伐替尼耐药后抑制P F K F B３及MM P s的表达,从而逆转H C C细胞对仑伐替尼的耐药性[４１].７㊀逆转耐药的机制策略和临床对策７．１㊀机制策略７．１．１㊀E G F R抑制剂J I N等[２０]在体外和体内实验中,利用E G F R抑制剂吉非替尼和仑伐替尼的联合作用于表达E G F R 的肝癌细胞系㊁异种肝癌细胞系㊁免疫活性小鼠模型以及病人来源H C C异种移植肿瘤,均观察到显著的抗增殖效果.进一步的临床试验(N C T０４６４２５４７)结果显示,对于１２例经过仑伐替尼治疗后肿瘤仍然进展的E G F R高表达肝癌患者,采用仑伐替尼和吉非替尼联合治疗后,４例部分缓解,４例病情稳定,显示出良好的应用前景.此外, S U N等[４２]的研究表明,E G F R抑制剂吉非替尼与仑伐替尼联合应用能够延缓仑伐替尼耐药细胞的增殖并诱导其凋亡,其机制可能是通过抑制E G F R介导的M E K/E R K和P I３K/A K T通路激活.在体内实验中,仑伐替尼与依拉昔达或吉非替尼联合给药抑制了肿瘤生长和血管生成.HU等[２１]发现另一种E G F R抑制剂厄洛替尼可以抑制A B C B１,从而减少仑伐替尼的胞吐,在体外和体内实验中均表现出对H C C的抑制效果.７．１．２㊀M E K抑制剂L U等[２４]发现一种小分子M E K途径抑制剂曲４８南昌大学学报(医学版)２０２４年４月,第６４卷第２期美替尼可逆转H C C细胞中N F１和D U S P９丢失引起的耐药性,即使在小鼠中敲除N F１,曲美替尼仍然能有效阻止H C C的增殖.此外,HU A N G等[４３]发现M E K抑制剂S e l u m e t i n i b能够消除D U S P４缺乏引起的仑伐替尼耐药性,表明M E K磷酸化和D U S P４抑制依赖性E R K激活是其耐药性产生的关键.７．１．３㊀其他有研究[４４]表明,双硫仑联合铜离子能够增加仑伐替尼对仑伐替尼耐药肝癌细胞H u h７的敏感性,其机制可能与抑制P I３K/A k t通路及促进c a s p a s eＧ９蛋白表达有关.H AMA Y A等[４５]发现化疗也是改善耐药的有效方式,顺铂能够抑制仑伐替尼耐药细胞的增殖,并诱导G２/M细胞周期阻滞.此外,顺铂通过A T M/A T RＧC h k１/C h k２信号通路触发D N A损伤反应.另外,Z H A O等[２３]发现槐定碱可以进一步提高仑伐替尼治疗仑伐替尼耐药H C C的敏感性.７．２㊀仑伐替尼耐药临床对策仑伐替尼已被证明是晚期H C C患者的一线治疗药物,在临床实践中得到了广泛应用.然而,一旦患者出现对仑伐替尼的耐药,目前尚缺乏标准有效的二线治疗方案.当患者出现仑伐替尼耐药时,通常是各临床中心根据自身实际经验选择治疗方式.７．２．１㊀分子靶向治疗抗血管生成药物作为治疗肝癌的重要药物,在仑伐替尼耐药后仍然是临床实践中的有效手段.根据当前的指南推荐,索拉非尼㊁瑞戈非尼㊁雷莫芦单抗等均是仑伐替尼治疗耐药患者的备用方案.T OMO N A R I等[４６]首次报道了１３名在仑伐替尼进展后接受索拉非尼治疗的患者.根据m R EＧC I S T标准,O R R和D C R分别为１５．３％(２/１３)和６９．２％(９/１３).而根据R E C I S T标准,O R R和D C R分别为０％(０/１３)和６９．２％(９/１３),中位P F S 为４．１个月.一项系统评价[４７]分析了４０５４名患者的２０项研究,发现进展后生存期(P P S)与总生存期(O S)之间存在更强的相关性(r＝０．８６９,P＜０．００１).该评价同时探讨了P P S在仑伐替尼耐药患者中的作用,２５例接受二线索拉非尼治疗的患者的O R R和D C R分别为１２％(３/２５)和５２％(１３/２５),P F S为５．７个月(９５％C I:０．８~１０．６个月).另外,一项来自韩国的研究[４８]提示,续贯索拉非尼是一种潜在的治疗选择.该研究发现,索拉非尼治疗的患者的中位O S明显长于接受纳武利尤单抗治疗的患者的中位O S(８．７v s３．０个月;P＝０．０４６).索拉非尼治疗与较低的死亡率相关(H R＝０．１９４;９５％C I:０．０５３~０．７０８;P＝０．０１３).另外,７例H C C患者在仑伐替尼失败后接受雷莫芦单抗作为二线或三线治疗,D C R为２８．６％(２/７例),中位P F S为４１d,具有抑制先前接受仑伐替尼治疗的患者H C C进展以及在治疗期间维持肝功能的潜力[４９].由于肝癌患者发病机制的复杂性,导致药物疗效存在差异性,因此,目前临床对于药物耐药评价以及换药指征把控存在一定差异.一些临床工作者认为,仑伐替尼的高缓解率和低毒性仍会使患者受益.一项通过倾向性匹配来自１１家不同医疗机构的临床数据的研究[５０]发现,相较于其他治疗(包括最佳支持治疗㊁索拉非尼㊁瑞戈非尼㊁雷莫芦单抗),继续仑伐替尼治疗的患者可以获得更好的O S(１０．８/１９．６v s ５．８/１１．２个月,P＜０．００１).７．２．２㊀免疫联合靶向治疗多项免疫联合靶向治疗的优异疗效已经深刻改变了肝癌的系统治疗格局,这些相互联合的治疗方案能够增强治疗效果,其在晚期二线治疗中的应用也在逐渐增加.Z O U等[５１]进行了一项回顾性调查,评估了标准剂量的仑伐替尼与P DＧ１抑制剂的联合治疗对于仑伐替尼治疗进展患者的有效性和安全性,他们发现O R R和D C R分别为２３．９％(１１/４６)和７１．７％(３３/４６),而中位P F S和O S分别为６．９个月和１４．５个月.最常见的治疗相关不良事件包括厌食症(４３．５％)㊁甲状腺功能减退症(４３．５％)和高血压(３６．９％),而３/４级不良事件的发生率为３４．８％(１６/４６).另一项研究[５２]则比较了在仑伐替尼治疗失败患者中,P DＧ１联合仑伐替尼和瑞戈非尼治疗的效果,结果显示联合组的中位P F S和D C R 较单药组有所提高(P F S８．７v s４．２个月,P＝０．０１８;D C R８２．７％v s５３．３％,P＝０．０１).然而,联合组的O S并未显示出显著的获益(１５．３v sN E个月,P＝０．５),且O R R也未显著高于瑞戈非尼组(２７．６％v s１３．３％,P＝０．４９).此外,瑞戈非尼组和联合组的３/４级治疗相关不良反应发生率分别为２６．７％和１０．３％,最常见的不良反应包括丙氨酸氨基转移酶升高㊁疼痛和总胆红素升高.然而,来自广州医科大学附属第二医院朱教授团队[５３]和笔者团队的研究[５４]显示,瑞戈非尼联合P DＧ１抑制剂相较于瑞戈非尼单药治疗在索拉非尼及仑伐替尼一线治疗失败后具有更高的O R R㊁更长的P F S和更好的O S.不过,纳入一线仑伐替尼治疗失败的患者比例较低可能是导致这些研究结果不一致的原因之一.目前,文献报道索拉非尼或免疫联合靶向药５８徐永康等:仑伐替尼在肝细胞癌中的耐药机制和对策研究进展物可能存在一定的获益,但缺乏充分的临床数据支持.仑伐替尼耐药后的治疗方案仍处于探索阶段,但包括C h i C T R２２０００６２８５４㊁C h i C T R２００００３６６６４㊁N C T０５７１８８８２㊁N C T０４６４２５４７等临床试验正在进行中.期待未来会有更多的大型临床研究集中于仑伐替尼耐药患者,以及探索免疫治疗联合仑伐替尼耐药后的治疗方案选择.参考文献:[１]㊀R UM G A Y H,A R N O L D M,F E R L A YJ,e t a l．G l o b a l b u r d e n o f p r i m a r y l i v e rc a n c e r i n２０２０a n d p r e d i c t i o n s t o２０４０[J]．JH e p a t o l,２０２２,７７(６):１５９８Ｇ１６０６．[２]V O G E LA,M E Y E R T,S A P I S O C H I N G,e t a l．H e p a t o c e l l u l a rc a r c i n o m a[J]．L a n c e t,２０２２,４００(１０３６０):１３４５Ｇ１３６２．[３]K U D O M,F I N N R S,Q I N S K,e ta l．L e n v a t i n i bv e r s u ss o rＧa f e n ib i n f i r s tＧl i n e t r e a t m e n t o f p a t i e n t sw i t hu n r e s ec t a b l e h e pＧa t o c e l l u l a r c a r c i n o m a:a r a n d o m i s e d p h a s e３n o nＧi n f e r i o r i t y t r iＧa l[J]．L a n c e t,２０１８,３９１(１０１２６):１１６３Ｇ１１７３．[４]WA N G N,MA T,Y U B．T a r g e t i n g e p i g e n e t i c r e g u l a t o r s t ooＧv e r c o m e d r u g r e s i s t a n c e i n c a n c e r s[J]．S i g n a l T r a n s d u c t T a r g e t T h e r,２０２３,８(１):６９．[５]WA N G L N,Y A N G Q X,Z HO U Q 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r cＧM E D２７a c t s a sa p r o g n o s t i c f a c t o ra n d m e d i a t o r t o p r o m o t eL e n v a t i n i b r e s i s t a n c eo fh e p a t o c e l l u l a r c a r c i n o m a[J]．M o lTＧh e rN u c l e i cA c i d s,２０２１,２７:２９３Ｇ３０３．[１８]L I U D H,L I U W B,C H E N X,e t a l．c i r c K C N N２s u p p r e s s e s t h er e c u r r e n c eo fh e p a t o c e l l u l a rc a r c i n o m aa t l e a s t p a r t i a l l yv i a r e g u l a t i n g m i RＧ５２０cＧ３p/m e t h y lＧD N AＧb i n d i n g d o m a i np r o t e i n２a x i s[J]．C l i nT r a n s lM e d,２０２２,１２(１):e６６２．[１９]H A O X P,Z H A N G Y,S H IX L,e ta l．C i r c P A K１p r o m o t e s t h e p r o g r e s s i o no f h e p a t o c e l l u l a r c a r c i n o m a v i am o d u l a t i o no fY A Pn u c l e u sl o c a l i z a t i o nb y i n t e r a c t i n g w i t h１４Ｇ３Ｇ３ζ[J]．JE x p C l i nC a n c e rR e s,２０２２,４１(１):２８１．[２０]J I N HJ,S H IYP,L V Y Y,e t a l．E G F Ra c t i v a t i o n l i m i t s t h e r e s p o n s eo f l i v e rc a n c e r t oL e n v a t i n i b[J]．N a t u r e,２０２１,５９５(７８６９):７３０Ｇ７３４．[２１]HU BY,Z O U T T,Q I N W,e t a l．I n h i b i t i o no fE G F Ro v e rＧc o m e s a c q u i r e dL e n v a t i n i br e s i s t a n c ed r i ve nb y S T A T３ＧA BＧC B１s i g n a l i n g i n h e p a t o c e l l u l a rc a r c i n o m a[J]．C a n c e r R e s,２０２２,８２(２０):３８４５Ｇ３８５７．[２２]L I M M,F R A N S E SJ W,I M P E R I A L R,e t a l．E G F R/E R B B２a m p l i f i c a t i o n sa n da l t e r a t i o n sa s s o c i a t e d w i t h r e s i s t a n c et oL e n v a t i n i b i nh e p a t o c e l l u l a r c a r c i n o m a[J]．G a s t r o e n t e r o l o g y,２０２３,１６４(６):１００６Ｇ１００８．e３．[２３]Z H A O Z W,Z H A N G D K,WU FZ,e ta l．S o p h o r i d i n es u pＧp r e s s e sL e n v a t i n i bＧr e s i s t a n th e p a t o c e l l u l a r c a r c i n o m a g r o w t hb y i n h i b i t i n g R A S/M E K/E R Ka x i sv i ad ec r e a s i n g V E G F R２e x p r e s s i o n[J]．J C e l lM o lM e d,２０２１,２５(１):５４９Ｇ５６０．[２４]L U Y G,S H E N H M,HU A N G W J,e ta l．G e n o m eＧs c a l eC R I S P RＧC a s９k n o c k o u t s c r e e n i n g i nh e p a t o c e l l u l a r c a r c i n o m aw i t hL e n v a t i n i b r e s i s t a n c e[J]．C e l lD e a t hD i s c o v,２０２１,７(１):３５９．[２５]A OJ J,C H I B A T,S H I B A T AS,e t a l．A c q u i s i t i o no fm e s e nＧc h y m a lＧl i k e p h e n o t y p e s a n do v e r p r od u c t i o no f a n g i o ge n i cf a cＧt o r s i nL e n v a t i n i bＧr e s i s t a n t h e p a t o c e l l u l a r c a r c i n o m a c e l l s[J]．B i o c h e m B i o p h y sR e sC o mm u n,２０２１,５４９:１７１Ｇ１７８．[２６]H O U W,B R ID GE M A N B,M A L N A S S Y G,e t a l．I n t e g r i ns u bＧu n i t b e t a８c o n t r i b u t e s t oL e n v a t i n i b r e s i s t a n c e i nH C C[J]．H e p aＧt o l C o mm u n,２０２２,６(７):１７８６Ｇ１８０２．[２７]陈家诚,刘路政,陈良,等．肝癌细胞仑伐替尼耐药的基因筛选及其通路研究[J]．肝胆胰外科杂志,２０２２,３４(３):１５７Ｇ１６３．[２８]T A K A HA S H I M,O K A D A K,O U C H R,e ta l．F i b r o n e c t i n６８南昌大学学报(医学版)２０２４年４月,第６４卷第２期p l a y s am a j o r r o l e i nh y p o x i aＧi n d u c e dL e n v a t i n i b r e s i s t a n c e i nh e p a t o c e l l u l a rc a r c i n o m a P L C/P R F/５c e l l s[J]．P h a r m a z i e,２０２１,７６(１２):５９４Ｇ６０１．[２９]E U NJW,Y O O NJH,A H N H R,e t a l．C a n c e rＧa s s o c i a t e d f iＧb r o b l a s tＧd e r i v e d s ec r e t ed p h o s p h o p r o te i n１c o n t r i b u t e s t o r eＧs i s t a n c eo fh e p a t o c e l l u l a r c a r c i n o m a t os o r a f e n i ba n dL e n v aＧt i n i b[J]．C a n c e rC o mm u n(L o n d),２０２３,４３(４):４５５Ｇ４７９．[３０]L I NZY,N I U Y,WA N A,e t a l．R N A m６A m e t h y l a t i o n r e gＧu l a t e s s o r a f e n i br e s i s t a n c ei nl i v e rc a n c e rt h r o u g h F O X O３Ｇm e d i a t e d a u t o p h a g y[J]．E M B OJ,２０２０,３９(１２):e１０３１８１．[３１]X U W P,L I UJP,F E N GJF,e t a l．m i RＧ５４１p o t e n t i a t e s t h e r e s p o n s e o f h u m a n h e p a t o c e l l u l a r c a r c i n o m a t o s o r a f e n i bt r e a t m e n t b y i n h i b i t i n g a u t o p h a g y[J]．G u t,２０２０,６９(７):１３０９Ｇ１３２１．[３２]P A N J M,Z HA N G M,D O N G L Q,e ta l．G e n o m eＧs c a l eC R I S P Rs c r e e n i d e n t i f i e sL A P TM５d r i v i n g L e n v a t i n i b r e s i s tＧa n c e i nh e p a t o c e l l u l a r c a r c i n o m a[J]．A u t o p h a g y,２０２３,１９(４):１１８４Ｇ１１９８．[３３]G U DY,T O N G M,WA N GJ,e t a l．O v e r e x p r e s s i o no f t h e l nＧc R N A H O T A I R M１p r o m o t e s L e n v a t i n i b r e s i s t a n c e b yd o w nＧr e g u l a t i n g m i RＧ３４a a n d a c t i v a t i n g a u t o p h a g y i nh e p a t o c e l l u l a rc a r c i n o m a[J]．D i s c o vO n c o l,２０２３,１４(１):６６．[３４]I S E D A N,I T O HS,T O S H I D AK,e t a l．F e r r o p t o s i s i s i n d u c e db y L e n v a t i n i b t h r o u g h f i b r o b l a s t g r o w t h f ac t o r r e c e p t o rＧ４i nＧh i b i t i o n i nh e p a t o c e l l u l a r c a r c i n o m a[J]．C a n c e rS c i,２０２２,１１３(７):２２７２Ｇ２２８７．[３５]Z H E N G A,C H E V A L I E R N,C A L D E R O N I M,e t a l．C R I S P R/C a s９g e n o m eＧw i d e s c r e e n i n g i d e n t i f i e sK E A P１a sas o r a f e n i b,L e n v a t i n i b,a n d r e g o r a f e n i b s e n s i t i v i t yg e n e i nh e pＧa t o c e l l u l a r c a r c i n o m a[J]．O n c o t a r g e t,２０１９,１０(６６):７０５８Ｇ７０７０．[３６]G A R C I AＧMA Y E AY,M I RC,MA S S O NF,e t a l．I n s i g h t s i n t o n e w m e c h a n i s m s a n dm o d e l s o f c a n c e r s t e mc e l lm u l t i d r u g r eＧs i s t a n c e[J]．S e m i nC a n c e rB i o l,２０２０,６０:１６６Ｇ１８０．[３７]WA N GJH,Y U H M,D O N G W,e t a l．N６ＧM e t h y l a d e n o s i n eＧm e d i a t e du pＧr e g u l a t i o no fF Z D１０r e g u l a t e s l i v e r c a n c e r s t e mc e l l s p r o p e r t i e sa n dL e n v a t i n i br e s i s t a n c e t h r o u g h WN T/βＧc a t e n i na n dh i p p os i g n a l i n gp a t h w a y s[J]．G a s t r o e n t e r o l o g y,２０２３,１６４(６):９９０Ｇ１００５．[３８]Y A N G SB,Z HO U Z H,L E IJ,e ta l．T M４S F１u p r e g u l a t e s MY H９t oa c t i v a t et h e N O T C H p a t h w a y t o p r o m o t ec a n c e rs t e m n e s s a n dL e n v a t i n i br e s i s t a n c e i n H C C[J]．B i o lD i r e c t,２０２３,１８(１):１８．[３９]MA X L,HU B,T A N G W G,e ta l．C D７３s u s t a i n e dc a n c e rＧs t e mＧc e l l t r a i t sb yp r o m o t i n g S O X９e x p r e s s i o na n ds t a b i l i t yi nh e p a t o c e l l u l a rc a r c i n o m a[J]．J H e m a t o l O n c o l,２０２０,１３(１):１１．[４０]WA N GS,Z HO ULY,J IN,e t a l．T a r g e t i n g A C Y P１Ｇm e d i a t e dg l y c o l y s i s r e v e r s e sL e n v a t i n i b r e s i s t a n c e a n d r e s t r i c t s h e p a t oＧc e l l u l a r c a r c i n o m a p r o g r e s s i o n[J]．D r u g R e s i s tU pd a t,２０２３,６９:１００９７６．[４１]李秋婷．P F K F B３促进肝癌增殖侵袭的机制及其对仑伐替尼耐药性的影响[D]．武汉:华中科技大学,２０２１．[４２]S U N D W,L I U J,WA N G Y F,e ta l．C oＧa d m i n i s t r a t i o no f M D R１a n dB C R Po rE G F R/P I３Ki n h i b i t o r so v e r c o m e sL e nＧv a t i n i b r e s i s t a n c e i nh e p a t o c e l l u l a rc a r c i n o m a[J]．F r o n tO nＧc o l,２０２２,１２:９４４５３７．[４３]HU A N G S Z,MA Z Y,Z H O U Q,e ta l．G e n o m eＧw i d eC R I S P R/C a s９l i b r a r y s c r e e n i n g i d e n t i f i e dt h a tD U S P４d e f iＧc i e n c y i nd u ce sL e n v a t i n i b r e s i s t a n c e i nh e p a t o c e l l u l a r c a r c i n oＧm a[J]．I n t JB i o l S c i,２０２２,１８(１１):４３５７Ｇ４３７１．[４４]董博文,李子一,李伟东,等．双硫仑联合铜离子对乐伐替尼耐药肝癌细胞H u h７增殖及凋亡的影响[J]．中国普外基础与临床杂志,２０２０,２７(２):１６８Ｇ１７２．[４５]HAMA Y AS,F U J I HA R AS,I WAMA H,e t a l．C h a r a c t e r i z aＧt i o no f c i s p l a t i ne f f e c t s i nL e n v a t i n i bＧr e s i s t a n th e p a t o c e l l u l a rc a r c i n o m a c e l l s[J]．A n t i c a n c e rR e s,２０２２,４２(３):１２６３Ｇ１２７５．[４６]T OMO N A R IT,S A T O Y,T A N A K A H,e ta l．S o r a f e n i ba s s e c o n dＧl i n e t r e a t m e n t o p t i o n a f t e r f a i l u r e o f L e n v a t i n i b i n p aＧt i e n t sw i t h u n r e s e c t a b l e h e p a t o c e l l u l a rc a r c i n o m a[J]．J G HO p e n,２０２０,４(６):１１３５Ｇ１１３９．[４７]T A J I R IK,T O K I M I T S U Y,K AWA IK,e t a l．I m p a c t o f p o s tＧp r o g r e s s i o ns u r v i v a l o no u t c o m e s o fL e n v a t i n i b t r e a t m e n t f o ru n r e s e c t a b l eh e p a t o c e l l u l a rc a r c i n o m a:a s y s t e m a t i cr e v i e wa n d r e t r o s p e c t i v ec o h o r ts t u d y[J]．A n t i c a n c e rR e s,２０２２,４２(１２):６００７Ｇ６０１８．[４８]K I M Y,L E EJ S,L E EH W,e t a l．S o r a f e n i b v e r s u s n i v o l u m a ba f t e rL e n v a t i n i bt r e a t m e n t f a i l u r e i n p a t i e n t sw i t ha d v a n c e dh e p a t o c e l l u l a rc a r c i n o m a[J]．E u rJ G a s t r o e n t e r o l H e p a t o l,２０２３,３５(２):１９１Ｇ１９７．[４９]K A S U Y A K,K AWAMU R A Y,K O B A Y A S H IM,e t a l．E f f iＧc a c y a nd s a fe t y of r a m u c i r u m a b i n p a t i e n t sw i t hu n r e s e c t a b l eh e p a t o c e l l u l a rc a r c i n o m a w i t h p r o g r e s s i o n a f t e rt r e a t m e n tw i t hL e n v a t i n i b[J]．I n t e r n M e d,２０２１,６０(３):３４５Ｇ３５１．[５０]H I R A O K A A,K UMA D A T,T A D A T,e ta l．W h a tc a nb ed o ne t os o l v e t h eu n m e t c l i n i c a l n e e dof h e p a t o c e l l u l a r c a r c iＧn o m a p a t i e n t s f o l l o w i n g L e n v a t i n i b f a i l u r e?[J]．L i v e rC a n cＧe r,２０２１,１０(２):１１５Ｇ１２５．[５１]Z O UJX,HU A N GPX,G E N L,e t a l．A n t iＧP DＧ１a n t i b o d i e s p l u s l e n v a t i n i bi n p a t i e n t s w i t h u n r e s e c t a b l eh e p a t o c e l l u l a rc a r c i n o m aw h o p r o g r e s s e do nL e n v a t i n i b:ar e t r o s p e c t i v ec oＧh o r t s t u d y o fr e a lＧw o r l d p a t i e n t s[J]．J G a s t r o i n t e s t O n c o l,２０２２,１３(４):１８９８Ｇ１９０６．[５２]G U A NRG,M E I J,L I SH,e t a l．C o m p a r a t i v e e f f i c a c y o f P DＧ１i n h i b i t o r s p l u sL e n v a t i n i ba n dr e g o r a f e n i ba f t e rL e n v a t i n i bf a i l u r ef o ra d v a n c e d h e p a t o c e l l u l a rc a r c i n o m a:ar e a lＧw o r l ds t u d y[J]．H e p a t o l I n t,２０２３,１７(３):７６５Ｇ７６９．[５３]HU A N G JJ,G U O Y J,HU A N G W S,e ta l．R e g o r a f e n i bc o m b i n ed w i t h P DＧ１b l o c k a d ei mm u n o t he r a p y v e r s u sr e g oＧr a f e n i ba ss e c o n dＧl i n et r e a t m e n t f o ra d v a n c e dh e p a t o c e l l u l a rc a r c i n o m a:am u l t i c e n t e r r e t r o s p e c t i v e s t ud y[J]．JHe p a t o c e l lC a r c i n o m a,２０２２,９:１５７Ｇ１７０．[５４]B A R B I E R I I,K O U Z A R I D E S T．R o l eo fR N A m o d i f i c a t i o n si n c a n c e r[J]．N a tR e vC a n c e r,２０２０,２０(６):３０３Ｇ３２２．(责任编辑:李松旻)７８徐永康等:仑伐替尼在肝细胞癌中的耐药机制和对策研究进展。
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Rudin CM, et al. ASCO 2016. Abstract LBA8505. Slide credit:
Rovalpituzumab Tesirine in R/R SCLC: Phase I Study Design
N = 74 SCLC pts progressed after ≥ 1 systemic therapy Dose-escalation design evaluated rovalpituzumab tesirine 0.05-0.8 mg/kg for Q3W or Q6W
Treatment-Emergent AE, % All Grades 88 35 31 27 19 18 16 16 16 20 35 49 Grade ≥ 3 38 4 8 3 0 0 11 3 0 12 11 8
Individual treatment-emergent AE in ≥ 15% of pts All Fatigue Pleural effusion Peripheral edema Nausea Hypoalbuminemia Thrombocytopenia Maculopapular rash Decreased appetite
Rudin CM, et al. ASCO 2016. Abstract LBA8505.
Slide credit:
Rovalpituzumab Tesirine in R/R SCLC: Conclusions
Rovalpituzumab tesirine showed favorable single-agent activity in R/R SCLC
This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.
Rudin CM, et al. ASCO 2016. Abstract LBA8505. Slide credit:
Go Online for More CCO Coverage of ASCO 2016!
Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in:
Rovalpituzumab Tesirine in R/R SCLC: Study Background
Recurrent SCLC is frequent and has a poor prognosis
– Topotecan only FDA-approved agent for recurrent SCLC – No biomarker-directed therapies
– DLTs (decreased platelets, LFT abnormalities) observed at 0.8 mg/kg Q3W – Cumulative toxicity (serosal effusions) observed at 0.4 mg/kg Q3W – Expansion cohorts: 0.2 mg/kg Q3W, 0.3 mg/kg Q6W – RP2D established at 0.3 mg/kg Q6W x 2, with retreatment at progressive disease – 0.2-0.4 mg/kg active doses pooled for current analysis
DLL3: atypical inhibitory Notch ligand
– Aberrantly expressed on surface of > 80% SCLCs
ቤተ መጻሕፍቲ ባይዱ
– Not expressed on surface of normal adult tissue
Rovalpituzumab tesirine: a novel antibody–drug conjugate targeting DLL3
Safety profile deemed manageable by study investigators Pivotal phase II registrational trial in third line for DLL3expressing R/R SCLC currently enrolling (NCT02674568) First line trials planned in DLL3-expressing SCLC, solid tumors (NCT02709889), and in combination with immunotherapy
76
28
53 31 9 7
4.1 (0.2-89.1) 53/47 88 67
Rudin CM, et al. ASCO 2016. Abstract LBA8505.
Slide credit:
Rovalpituzumab Tesirine in R/R SCLC: Treatment-Emergent Adverse Events
ORR CBR
Pts With ≥ 50% DLL3 Expression* 2nd-line Tx (n = 14) 29 86 3rd-line Tx (n = 12) 50 92
*Evaluable pts receiving active doses of rovalpituzumab tesirine (0.2-0.4 mg/kg). Rudin CM, et al. ASCO 2016. Abstract LBA8505. Slide credit:
Rudin CM, et al. ASCO 2016. Abstract LBA8505.
Slide credit:
Rovalpituzumab Tesirine in R/R SCLC: Response Rates
All Pts* Response, % Investigator (n = 60) 18 68 All Pts* Response, % 2nd-line Tx (n = 32) ORR CBR 13 72 3rd-line Tx (n = 28) 25 64 IRC (n = 56) 16 64 Pts With ≥ 50% DLL3 Expression* Investigator (n = 26) 39 89 IRC (n = 26) 31 85
Rudin CM, et al. ASCO 2016. Abstract LBA8505. Slide credit:
Rovalpituzumab Tesirine in R/R SCLC: Baseline Characteristics
Characteristic
Group events with highest grade 3 incidence Thrombocytopenia Serosal effusions* Skin reaction
*Included pleural or pericardial effusion, ascites, or “capillary leak syndrome” (serosal effusions, peripheral edema, and/or hypoalbuminemia).
– Anti-DLL3 mAb (SC16) linked to PBD dimer toxin
First-in-human phase I study evaluated safety and activity in SCLC with progression following first or second line therapy
Rovalpituzumab Tesirine Safe, Active in Previously Treated SCLC
CCO Independent Conference Coverage*
of the 2016 ASCO Annual Meeting, June 3-7, 2016
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
Breast, genitourinary, and lung cancers Hematologic malignancies Immunotherapy
/oncology
Median age, yrs (range) Female, % ECOG PS 0/1/2, %
Pts (N = 74)
61 (38-81) 43 28/68/4
Extensive disease, %