• 精準醫療及小分子靶向藥物綜述

    —— 研發總監 楊世瓊 博士

    作者簡介:
    楊世瓊博士2011年畢業于比利時天主教魯汶大學(Katholieke Universiteit Leuven),獲得藥物化學博士學位,隨后在復旦大學陳芬兒院士實驗室從事博士后研究,于2014年加入北卡醫藥任研發總監。

    精準醫療(Precision Medicine)是一種將個人基因、環境與生活習慣差異考慮在內的疾病預防與處置的新興方法。精準醫療由個性化醫療(personalized medicine)的概念衍生而來的。個性化醫療所關注的疾病治療和預防的核心是個體,根據每個病人的個人特征制定個性化治療方案。當前的藥物越來越趨向于精確面向患有特定疾病的大量患者中少量特定人群,這部分人群有相同的分子特征,同時在分子層面上產生的問題上也保持一致。在具體實踐過程中,精準醫療是指以個人基因組信息為基礎,結合蛋白質組、代謝組等相關內環境信息,為患者量身設計出最佳治療方案,以期達到治療效果最大化和副作用最小化的一門定制醫療模式。

    腫瘤治療被選為精準醫療的短期目標。惡性腫瘤是一種嚴重威脅人類健康的常見病和多發病。世界衛生組織(WTO)指出,惡性腫瘤每年奪去全世界700多萬人的生命,人類因惡性腫瘤而引起的死亡率居所有疾病死亡率的第二位,僅次于心腦血管疾病。隨著人口老齡化的進程加快,近年來,惡性腫瘤的發病率更呈現上升趨勢。據有關數據顯示,我國居民惡性腫瘤死亡率比70年代中期增加了83.1%。據近幾年我國癌癥普查的結果顯示,平均每十萬人里有癌癥患者286人,而死亡人數達到181人,死亡率比較高。研究人員已發現,許多分子病變是驅動癌癥的誘因,這表明不同癌癥都有自己的基因印記、腫瘤標記物以及變異類型。雖然癌癥主要是由日常生活中基因損傷積累所導致的,但可遺傳性基因變異通常會增加患癌風險。這種對致癌機制的新理解已影響了在藥物和抗體設計過程中,對癌癥風險、分類診斷以及治療策略的評估。

    目前臨床常用的抗腫瘤化療藥物對患者治療的有效性低于70%,約20%-35%的患者接受了不恰當的藥物治療。化療藥物是通過對細胞的毒害發揮作用,由于不能準確識別腫瘤細胞,因此在殺滅腫瘤細胞的同時也會殃及正常細胞,所以產生了較大的毒副作用。由于患者沒有時間承受反復實驗和不斷摸索,如果在腫瘤治療過程中能夠實施個體化治療,將能夠大大提高療效,避免過度治療和降低患者經濟負擔,減少醫療資源的浪費。隨著藥物基因組學以及蛋白質組學、轉錄組學等高通量分子檢測技術的出現,分子靶向技術治療癌癥的個體化治療手段——即從個體基因組中分析和鑒別患者之間存在的疾病相關的個體差異,并利用這些差異來合理的指導臨床治療,已經成為醫學界廣泛共識。

    所謂靶向治療(targeted therapy)是指根據腫瘤的不同的特異性位點,抗腫瘤藥物靶向性地與其發生作用從而殺死腫瘤細胞,而對正常組織影響較小。這是目前最理想的治療模式。然而,同化療藥物一樣,不同靶向藥物對所有患者的有效率都非常低,通常在25%以下。造成效率低下的主要原因在于患者體內存在單核苷酸多態性(SNP)。SNP的復雜性,決定了藥物反應的多態性,藥物療效及最佳用藥劑量很大程度上取決于藥物相關基因變異。所以個體化用藥,基因突變檢測分析及精準醫療已經成為惡性腫瘤等重大慢性疾病臨床治療的發展方向和最有效的手段。

    由于現有抗腫瘤藥物存在毒性大、易產生耐藥性等缺點,所以研制靶向性抗腫瘤藥物一直是全球藥業公司、科研機構及各國政府重點關注和發展的領域。藥物發現已從傳統的動物模型篩選發展到針對致病機理中關鍵酶或受體來精確設計靶向性藥物,通過小分子抑制劑特異性結合到靶蛋白上,選擇性地阻斷腫瘤細胞的過度增生,從而有效控制和治療疾病,進一步實現精準醫療。

    在分子靶向藥物中,蛋白酪氨酸激酶抑制劑(tyrosine kinase inhibitor,TKI)等的開發尤為引入注目,涉及多個受體及非受體家族:例如表皮生長因子受體(EGFR)家族、血管內皮細胞生長因子受體(VEGFR)家族、血小板衍化生長因子受體(PDGFR)家族、ABL家族、JAK家族、SRC家族和FAK家族等。從2001年的伊馬替尼(Gleevec, 諾華)到2014年的色瑞替尼(Zykadia, 諾華)、2015年的osimertinib (Tagrisso, 阿斯利康)等,至今已有37個藥物先后被美國食品藥品監督管理局(FDA)批準上市,而且超過100個藥物分子正在進行臨床研究。在中國,伊馬替尼、吉非替尼、厄洛替尼、索拉非尼、舒尼替尼、達沙替尼、拉帕替尼、埃克替尼、尼洛替尼、克里唑替尼和阿昔替尼共11個已被中國國家藥品監督管理局(SFDA)批準上市。

    基于基因導向的精準醫療體現了藥物基因組學與臨床醫學的完美結合。新的小分子靶向藥物的不斷涌現會導致病人群的細分,即某種藥物只適合于某個腫瘤的特定病人群,而單一品種適應癥的增加,可以導致多靶點酪氨酸激酶抑制劑成為抗腫瘤藥物的研究熱點。腫瘤治療的效果可望進一步提高。

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