Yvonne Carter Professor of Pathology, University of Warwick Medical School, University Hospitals Coventry and Warwickshire, Coventry CV2 2DX, UK.
J Control Release. 2013 Dec 10;172(2):405-9. doi: 10.1016/j.jconrel.2013.07.007. Epub 2013 Jul 16.
The concept of personalised medicine for cancer is not new. It arguably began with the attempts by Salmon and Hamburger to produce a viable cellular chemosensitivity assay in the 1970s, and continues to this day. While clonogenic assays soon fell out of favour due to their high failure rate, other cellular assays fared better and although they have not entered widespread clinical practice, they have proved to be very useful research tools. For instance, the ATP-based chemosensitivity assay was developed in the early 1990s and is highly standardised. It has proved useful for evaluating new drugs and combinations, and in recent years has been used to understand the molecular basis of drug resistance and sensitivity to anti-cancer drugs. Recent developments allow unparalleled genotyping and phenotyping of tumours, providing a plethora of targets for the development of new cancer treatments. However, validation of such targets and new agents to permit translation to the clinic remains difficult. There has been one major disappointment in that cell lines, though useful, do not often reflect the behaviour of their parent cancers with sufficient fidelity to be useful. Low passage cell lines - either in culture or xenografts are being used to overcome some of these issues, but have several problems of their own. Primary cell culture remains useful, but large tumours are likely to receive neo-adjuvant treatment before removal and that limits the tumour types that can be studied. The development of new treatments remains difficult and prediction of the clinical efficacy of new treatments from pre-clinical data is as hard as ever. One lesson has certainly been that one cannot buck the biology - and that understanding the genome alone is not sufficient to guarantee success. Nowhere has this been more evident than in the development of EGFR inhibitors. Despite overexpression of EGFR by many tumour types, only those with activating EGFR mutations and an inability to circumvent EGFR blockade have proved susceptible to treatment. The challenge is how to use advanced molecular understanding with limited cellular assay information to improve both drug development and the design of companion diagnostics to guide their use. This has the capacity to remove much of the guesswork from the process and should improve success rates.
癌症个体化医学的概念并不新鲜。可以说，它始于 20 世纪 70 年代 Salmon 和 Hamburger 试图生产可行的细胞化学敏感性检测，并且一直延续至今。虽然克隆形成测定法由于其高失败率很快不再流行，但其他细胞测定法表现更好，尽管它们尚未广泛应用于临床实践，但已被证明是非常有用的研究工具。例如，基于 ATP 的化学敏感性测定法于 20 世纪 90 年代初开发，高度标准化。它已被证明对评估新药和组合非常有用，并且近年来已用于了解药物耐药性和对抗癌药物敏感性的分子基础。最近的发展允许对肿瘤进行无与伦比的基因分型和表型分析，为开发新的癌症治疗方法提供了大量的靶点。然而，验证这些靶点和新药物以允许向临床转化仍然很困难。尽管细胞系很有用，但它们并没有像有用那样经常反映其亲本癌症的行为，这是一个主要的失望。低传代细胞系 - 无论是在培养物中还是异种移植物中 - 都被用于克服其中的一些问题，但它们本身也存在一些问题。原代细胞培养仍然有用，但在切除前，大肿瘤很可能接受新辅助治疗，这限制了可以研究的肿瘤类型。新疗法的开发仍然很困难，并且从临床前数据预测新疗法的临床疗效仍然像以往一样困难。有一点肯定是，人们不能违背生物学 - 仅仅了解基因组是不足以保证成功的。在 EGFR 抑制剂的开发中，这一点表现得最为明显。尽管许多肿瘤类型都过度表达 EGFR，但只有那些具有激活的 EGFR 突变并且无法规避 EGFR 阻断的肿瘤才对治疗敏感。挑战在于如何利用有限的细胞测定信息来提高药物开发和伴随诊断设计的先进分子理解，以指导其使用。这有能力从该过程中消除很多猜测，并应提高成功率。
