癌症靶向治疗药物综述    
2017年05月02日
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Overview of Targeted Therapies for Cancer

Targeted cancer therapies are drugs designed to interfere with specific molecules necessary for tumor growth and progression. Traditional cytotoxic chemotherapies usually kill rapidly dividing cells in the body by interfering with cell division. A primary goal of targeted therapies is to fight cancer cells with more precision and potentially fewer side effects.

靶向癌症治疗方法是药物设计上即精准针对在肿瘤发生和生长中作为必要条件的特定分子进行干扰。传统的细胞毒药物治疗通常是通过干扰细胞分裂,灭杀体内快速分裂的细胞。靶向治疗的首要目标是尽最大可能针对杀灭癌细胞,同时尽可能避免潜在的副作用。

Classification and naming

分类和命名

Targeted cancer agents are broadly classified as either monoclonal antibodies or small molecules.

靶向抗癌药粗略可以分为单克隆抗体和小分子化合物

Therapeutic monoclonal antibodies target specific antigens found on the cell surface, such as transmembranereceptorsor extracellular growth factors. In some cases, monoclonal antibodies are conjugated to radio-isotopes or toxins to allow specific delivery of these cytotoxic agents to the intended cancer cell target.

单克隆抗体治疗靶点是基于细胞表面的特殊抗原,比如跨膜受体或细胞外生长因子。在某些情况下,单克隆抗体结合放射性同位素或毒素允许基因定位转运这些细胞毒药物到达选定的癌细胞靶点。

Small molecules can penetrate the cell membrane to interact with targets inside a cell. Small molecules are usually designed to interfere with the enzymatic activity of the targetprotein.

As with any drug, targeted cancer therapies typically have several different names. One or more names is used to designate the chemical compound during development; if successful, the drug receives a generic name and then a brand name used by the pharmaceutical company for marketing. For example, the small molecule STI-571 became known as imatinib (generic name) and is marketed by Novartis under the brand name Gleevec?.

小分子化合物能够穿透细胞膜,与细胞内的一个靶点产生相互作用。小分子化合物通常旨在干扰靶蛋白的酶活性。与其他药物一样,靶向癌症治疗药物通常在药物研发过程中有几个不同的名字,一般习惯会给化合物指定一个或多个名称。如果研发成功,这个小分子化合物会得到一个通用名和一个制药公司用于销售的商品品牌名称。例如,小分子化合物STI-571被称为伊马替尼(通用名称),诺华制药公司销售的药物品牌名称是Gleevec?.(格列卫?)。

The name of a targeted agent provides clues to the type of agent and its cellular target.

药物靶点的命名要求标示靶点的类型和它们针对的细胞靶点。

Monoclonal antibodies end with the stem “-mab” (monoclonal antibody). Small molecules end with the stem “-ib” (indicating that the agent has proteininhibitory properties). Monoclonal antibodies have an additional substem designating the source of the compound, e.g., “-ximab” for chimeric human-mouse antibodies, “-zumab” for humanized mouse antibodies, and “-mumab” for fully human antibodies. Both monoclonal antibodies and small molecules contain an additional stem in the middle of the name describing the molecule’s target; examples for monoclonal antibodies include “-ci-” for a circulatory system target and “-tu-” for a tumor target, while examples for small molecules include “-tin-” for tyrosinekinase inhibitors and “-zom-” for proteasome inhibitors. At the beginning of the generic name is a prefix that is unique for each agent. Some examples include:

单克隆抗体名称后缀“-mab”(单克隆抗体)。小分子化合物名称后缀 “-ib”(提示目标靶点有蛋白质抑制特性)。单克隆抗体有一个附加的词缀,表明来源不同,例如“-ximab”是人-鼠嵌合抗体?!?zumab” 人源化抗体,”-mumab” 是全人源化抗体。单克隆抗体和小分子化合物都含有一个附加的词缀,在名字中描述分子的靶点;例如单克隆抗体包含“-ci-”针对循环系统靶点,“-tu-”针对肿瘤靶点,小分子化合物包含“-tin-”表明是酪氨酸激酶抑制剂,“-zom-”表明是蛋白酶体抑制剂。每个靶向药物通用名称开头的前缀都是独一无二的。下面举例说明:

Monoclonal antibodies 单克隆抗体
bevacizumabhumanized monoclonal antibodywith a circulatory system target (VEGF-A) 以循环系统为靶点的人源化单克隆抗体(血管内生长因子)
cetuximabchimeric monoclonal antibody with a tumor target (EGFR) 以肿瘤为靶点的嵌合单克隆抗体(表皮生长因子受体)
ipilimumabfully human antibody with animmune system target (CTLA-4) 以免疫系统为靶点的全人源抗体 (CTLA-4 细胞毒性淋巴细胞抗原)
Small molecules 小分子化合物
bortezomibsmall molecule proteasome inhibitor 小分子蛋白酶体抑制剂
imatinibsmall molecule tyrosine kinase inhibitor 小分子酪氨酸激酶抑制剂
seliciclibsmall molecule cyclin-dependent kinase inhibitor 小分子细胞周期蛋白依赖性激酶抑制剂

博金冠代理在哪里 www.6cstc.com.cn The FDA has approved multiple targeted drug cancer therapies, and many more are being studied in clinical trials either alone or in combination with other treatments. A partial list of currently approved targeted therapies for solid malignancies and their molecular targets is provided below.

FDA已经批准了多种癌症的靶向治疗药物临床使用,以及更多的单独或联合其他治疗的靶向药物临床试验。下表是目前批准的部分名单,靶向治疗针对难治的恶性肿瘤及其分子靶点。

Agent 药名Target(s) 靶点FDA-approved indication(s) 适用范围
Ado-trastuzumab emtansine (Kadcyla)HER2 (ERBB2/neu)· Breast cancer乳腺癌 (HER2+)
Afatinib (Gilotrif)EGFR (HER1/ERBB1), HER2 (ERBB2/neu)· Non-small cell lung cancer非小细胞肺癌 (with EGFR exon 19 deletions or exon 21 substitution (L858R) mutations)
Aldesleukin (Proleukin)
· Renal cell carcinoma 肾细胞癌 · Melanoma 黑色素瘤
Alectinib (Alecensa)ALK· Non-small cell lung cancer非小细胞肺癌(with ALK fusion)
Alemtuzumab (Campath)CD52· B-cell chronic lymphocytic leukemia 细胞慢性淋巴细胞白血病
Axitinib (Inlyta)KIT, PDGFRβ, VEGFR1/2/3· Renal cell carcinoma肾细胞癌
Belimumab (Benlysta)BAFF· Lupus erythematosus 红斑狼疮
Belinostat (Beleodaq)HDAC· Peripheral T-cell lymphoma 外周T细胞淋巴瘤
Bevacizumab (Avastin)VEGF ligand· Cervical cancer 宫颈癌 · Colorectal cancer 大肠癌 · Fallopian tube cancer 输卵管癌 · Glioblastoma 胶质母细胞瘤 · Non-small cell lung cancer 非小细胞肺癌 · Ovarian cancer 卵巢癌 · Peritoneal cancer 肾细胞癌 · Renal cell carcinoma 腹膜癌
Bortezomib (Velcade)Proteasome· Multiple myeloma 多发性骨髓瘤 · Mantle cell lymphoma 套细胞淋巴瘤
Bosutinib (Bosulif)ABL· Chronic myelogenous leukemia 慢性粒细胞性白血病(Philadelphia chromosomepositive)
Brentuximab vedotin (Adcetris)CD30· Hodgkin lymphoma 霍奇金淋巴瘤 · Anaplastic large cell lymphoma 间变性大细胞淋巴瘤
Cabozantinib (Cabometyx [tablet], Cometriq [capsule])FLT3, KIT, MET, RET, VEGFR2· Medullary thyroid cancer 甲状腺髓样癌 · Renal cell carcinoma 肾细胞癌
Canakinumab (Ilaris)IL-1β· Juvenile idiopathic arthritis 青少年特发性关节炎 · Cryopyrin-associated periodic syndromes
Carfilzomib (Kyprolis)Proteasome· Multiple myeloma 多发性骨髓瘤
Ceritinib (Zykadia)ALK· Non-small cell lung cancer 非小细胞肺癌(with ALK fusion)
Cetuximab (Erbitux)EGFR (HER1/ERBB1)· Colorectal cancer 大肠癌 (KRAS wild type) · Squamous cell cancer of the head and neck头颈部鳞状细胞癌
Cobimetinib (Cotellic)MEK· Melanoma 黑色素瘤 (with BRAF V600E or V600K mutation)
Crizotinib (Xalkori)ALK, MET, ROS1· Non-small cell lung cancer 非小细胞肺癌 (with ALK fusion or ROS1 genealteration)
Dabrafenib (Tafinlar)BRAF· Melanoma 黑色素瘤 (with BRAF V600 mutation)
Daratumumab (Darzalex)CD38· Multiple myeloma 多发性骨髓瘤
Dasatinib (Sprycel)ABL· Chronic myelogenous leukemia 慢性粒细胞白血病(Philadelphia chromosomepositive) · Acute lymphoblastic leukemia 急性淋巴细胞白血病(Philadelphia chromosomepositive)
Denosumab (Xgeva)RANKL· Giant cell tumor of the bone 骨巨细胞瘤
Dinutuximab (Unituxin)B4GALNT1 (GD2)· Pediatric neuroblastoma 小儿神经母细胞瘤
Elotuzumab (Empliciti)SLAMF7 (CS1/CD319/CRACC)· Multiple myeloma 多发性骨髓瘤
Erlotinib (Tarceva)EGFR (HER1/ERBB1)· Non-small cell lung cancer 非小细胞肺癌 · Pancreatic cancer 胰腺癌
Everolimus (Afinitor)mTOR· Pancreatic, gastrointestinal, or lung origin neuroendocrine tumor 起源于胰、肠胃或肺的神经内分泌肿瘤 · Renal cell carcinoma 肾细胞癌 · Nonresectable subependymal giant cell astrocytoma associated with tuberous sclerosis不可切除的室管膜下巨细胞星状细胞瘤关联的结节性硬化症 · Breast cancer 乳腺癌 (HR+, HER2-)
Gefitinib (Iressa)EGFR (HER1/ERBB1)· Non-small cell lung cancer 非小细胞肺癌 (with EGFR exon 19 deletions or exon 21 substitution (L858R) mutations)
Ibritumomab tiuxetan (Zevalin)CD20· Non-Hodgkin’s lymphoma 非霍奇金淋巴瘤
Ibrutinib (Imbruvica)BTK· Mantle cell lymphoma 套细胞淋巴瘤 · Chronic lymphocytic leukemia 慢性淋巴细胞白血病 · Waldenstrom’s macroglobulinemia 巨球蛋白血症
Idelalisib (Zydelig)PI3Kδ· Chronic lymphocytic leukemia慢性淋巴细胞白血病 · Follicular B-cell non-Hodgkin lymphoma 卵泡B细胞非霍奇金淋巴瘤 · Small lymphocytic lymphoma 小淋巴细胞淋巴瘤
Imatinib (Gleevec)KIT, PDGFR, ABL· GI stromal tumor (KIT+)胃肠道间质瘤 · Dermatofibrosarcoma protuberans 隆突性皮纤维肉瘤 · Multiple hematologic malignancies including Philadelphia chromosome-positive ALL and CML
Ipilimumab (Yervoy)CTLA-4· Melanoma 黑色素瘤
Ixazomib (Ninlaro)Proteasome· Multiple Myeloma 多发性骨髓瘤
Lapatinib (Tykerb)HER2 (ERBB2/neu), EGFR(HER1/ERBB1)· Breast cancer 乳腺癌(HER2+)
Lenvatinib (Lenvima)VEGFR2· Thyroid cancer 甲状腺癌
Necitumumab (Portrazza)EGFR (HER1/ERBB1)· Squamous non-small cell lung cancer 鳞状非小细胞肺癌
Nilotinib (Tasigna)ABL· Chronic myelogenous leukemia 慢性粒细胞性白血病(Philadelphia chromosomepositive)
Nivolumab (Opdivo)PD-1· Melanoma黑色素瘤 · Non-small cell lung cancer 非小细胞肺癌 · Renal cell carcinoma 肾细胞癌
Obinutuzumab (Gazyva)CD20· Chronic lymphocytic leukemia 慢性淋巴细胞白血病 · Follicular lymphoma 卵泡淋巴瘤
Ofatumumab (Arzerra, HuMax-CD20)CD20· Chronic lymphocytic leukemia 慢性淋巴细胞白血病
Olaparib (Lynparza)PARP· Ovarian cancer 卵巢癌 (with BRCA mutation)
Osimertinib (Tagrisso)EGFR· Non-small cell lung cancer 非小细胞肺癌 (with EGFR T790M mutation)
Palbociclib (Ibrance)CDK4, CDK6· Breast cancer 乳腺癌 (ER+, HER2-)
Panitumumab (Vectibix)EGFR (HER1/ERBB1)· Colorectal cancer 大肠癌(KRAS wild type)
Panobinostat (Farydak)HDAC· Multiple myeloma 多发性骨髓瘤
Pazopanib (Votrient)VEGFR, PDGFR, KIT· Renal cell carcinoma 肾细胞癌
Pembrolizumab (Keytruda)PD-1· Melanoma 黑色素瘤 · Non-small cell lung cancer 非小细胞肺癌 (PD-L1+)
Pertuzumab (Perjeta)HER2 (ERBB2/neu)· Breast cancer 乳腺癌(HER2+)
Ponatinib (Iclusig)ABL, FGFR1-3, FLT3, VEGFR2· Chronic myelogenous leukemia 慢性粒细胞性白血病 · Acute lymphoblastic leukemia 急性淋巴细胞白血病 (Philadelphia chromosomepositive)
Ramucirumab (Cyramza)VEGFR2· Colorectal cancer 大肠癌 · Gastric cancer or Gastroesophageal junction (GEJ) adenocarcinoma 胃癌或胃食管交界处(GEJ)腺癌 · Non-small cell lung cancer 非小细胞肺癌
Regorafenib (Stivarga)KIT, PDGFRβ, RAF, RET, VEGFR1/2/3· Colorectal cancer 大肠癌 · Gastrointestinal stromal tumors 胃肠间质瘤
Rituximab (Rituxan, Mabthera)CD20· Non-Hodgkin’s lymphoma 非霍奇金淋巴瘤 · Chronic lymphocytic leukemia 慢性淋巴细胞白血病 · Rheumatoid arthritis 类风湿性关节炎 · Granulomatosis with polyangiitis 伴随小管炎的肉芽肿病
Romidepsin (Istodax)HDAC· Cutaneous T-cell lymphoma 皮肤T细胞淋巴瘤 · Peripheral T-cell lymphoma 外周T细胞淋巴瘤
Ruxolitinib (Jakafi)JAK1/2· Myelofibrosis 骨髓纤维化
Siltuximab (Sylvant)IL-6· Multicentric Castleman’s disease 多心性Castleman病
Sipuleucel-T (Provenge)
· Prostate cancer 前列腺癌
Sonidegib (Odomzo)Smoothened· Basal cell carcinoma 基底细胞癌
Sorafenib (Nexavar)VEGFR, PDGFR, KIT, RAF· Hepatocellular carcinoma 肝细胞癌 · Renal cell carcinoma 肾细胞癌 · Thyroid carcinoma 甲状腺癌
Temsirolimus (Torisel)mTOR· Renal cell carcinoma 肾细胞癌
Tocilizumab (Actemra)IL-6R· Rheumatoid arthritis 类风湿性关节炎 · Juvenile idiopathic arthritis 青少年多发性关节炎
Tofacitinib (Xeljanz)JAK3· Rheumatoid arthritis 类风湿性关节炎
Tositumomab (Bexxar)CD20· Non-Hodgkin’s lymphoma 非霍奇金淋巴瘤
Trametinib (Mekinist)MEK· Melanoma 黑色素瘤 (with BRAF V600 mutation)
Trastuzumab (Herceptin)HER2 (ERBB2/neu)· Breast cancer 乳腺癌(HER2+) · Gastric cancer 胃癌 (HER2+)
Vandetanib (Caprelsa)EGFR (HER1/ERBB1), RET, VEGFR2· Medullary thyroid cancer 甲状腺髓样癌
Vemurafenib (Zelboraf)BRAF· Melanoma 黑色素瘤(with BRAF V600 mutation)
Venetoclax (Venclexta)BCL2· Chronic lymphocytic leukemia 慢性淋巴细胞白血病 (with 17p deletion)
Vismodegib (Erivedge)PTCH, Smoothened· Basal cell carcinoma 基底细胞癌
Vorinostat (Zolinza)HDAC· Cutaneous T-cell lymphoma 皮肤T细胞淋巴瘤
Ziv-aflibercept (Zaltrap)PIGF, VEGFA/B· Colorectal cancer 大肠癌

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