Despite enormous global investment, translational medical research faces considerable challenges and patients, and their doctors are frequently frustrated by the apparent lack of research activity or progress. Understanding the factors that prevent innovative research discoveries from making it to clinical trials is a multifaceted problem. However, one question that must be addressed is whether the nature of current research activity and the factors that influence the conduct of pre-clinical research, permit, or hamper the timely progression of laboratory-based observations to proof of concept (PoC) clinical trials. Inherent in this question is to what extent a deep mechanistic understanding of a potential new therapy is required before commencing PoC studies, and whether patients are better served when mechanistic and clinical studies progress side by side rather than in a more linear fashion. Here we address these questions by revisiting the historical development of hugely impactful and paradigm-changing innovations in the treatment of hematological cancers. First, we compare the history and route to clinical PoC, of two molecularly-targeted therapies that are BCR:ABL inhibitors in chronic myeloid leukaemia and all-trans retinoic acid (ATRA) in acute promyelocytic leukaemia (APL). We then discuss the history of arsenic trioxide as additional APL therapy, and the repurposing of thalidomide as effective multiple myeloma therapy. These stories have surprising elements of commonality that demand debate about the modern-day hard and soft governance of medical research and whether these processes appropriately align the priorities of advancing scientific knowledge and the need of patients.
尽管全球投入巨大，转化医学研究仍面临重大挑战，患者及其医生常因表面上的研究活动或进展不足而感到失望。理解阻碍创新研究发现进入临床试验的因素是一个多层面的问题。然而，必须解决的一个核心议题是：当前研究活动的本质及影响临床前研究的因素，究竟是在促进还是阻碍着基于实验室的观察成果及时推进至概念验证临床试验。这一问题本质上涉及：在启动概念验证研究之前，对潜在新疗法的深层机制理解需要达到何种程度；以及，当机制研究与临床研究并行推进而非线性展开时，是否更能造福患者。本文通过回顾血液癌症治疗领域中那些具有巨大影响力和范式转变意义的创新历史发展，来探讨这些问题。首先，我们比较了两种分子靶向疗法的临床概念验证历程：慢性粒细胞白血病中的BCR-ABL抑制剂与急性早幼粒细胞白血病中的全反式维甲酸。随后，我们探讨了三氧化二砷作为急性早幼粒细胞白血病附加疗法的历史，以及沙利度胺被重新用于有效治疗多发性骨髓瘤的过程。这些案例展现出惊人的共同特征，促使我们必须反思当代医学研究的硬性与软性管理模式，以及这些流程是否恰当地协调了推动科学认知的优先事项与患者需求之间的关系。
肿瘤(癌症)患者之家