CSIRO Manufacturing, Clayton, Victoria 3168, Australia; Australian Regenerative Medicine Institute, Monash University, Victoria 3800, Australia.
CSIRO Manufacturing, Clayton, Victoria 3168, Australia; Australian Regenerative Medicine Institute, Monash University, Victoria 3800, Australia.
Biochim Biophys Acta Rev Cancer. 2021 Jan;1875(1):188459. doi: 10.1016/j.bbcan.2020.188459. Epub 2020 Oct 29.
For a drug candidate to be fully developed takes years and investment of hundreds of millions of dollars. There is no doubt that drug development is difficult and risky, but vital to protecting against devastating disease. This difficulty is clearly evident in BRCA1 and BRCA2 related breast cancer, with current treatment options largely confined to invasive surgical procedures, as well as chemotherapy and radiotherapy regimes which damage healthy tissue and can leave remnant disease. Consequently, patient survival and relapse rates are far from ideal, and new candidate treatments are needed. The preclinical stages of drug discovery are crucial to get right for translation to hospital beds. Disease models must take advantage of current technologies and be accurate for rapid and translatable treatments. Careful selection of cell lines must be coupled with high throughput techniques, with promising results trialled further in highly accurate humanised patient derived xenograft models. Traditional adherent drug screening should transition to 3D culture systems amenable to high throughput techniques if the gap between in vitro and in vivo studies is to be partially bridged. The possibility of organoid, induced pluripotent stem cell, and conditionally reprogrammed in vitro models is tantalising, however protocols are yet to be fully established. This review of BRCA1 and BRCA2 cancer biology and current modelling systems will hopefully guide the design of future drug discovery endeavours and highlight areas requiring improvement.
将一个药物候选物完全开发出来需要数年时间和数亿美元的投资。毫无疑问，药物开发既困难又有风险，但对于预防毁灭性疾病至关重要。这种困难在 BRCA1 和 BRCA2 相关乳腺癌中显而易见，目前的治疗选择主要局限于侵入性手术，以及会损害健康组织并留下残留疾病的化疗和放疗方案。因此，患者的存活率和复发率远不理想，需要新的候选治疗方法。药物发现的临床前阶段对于转化为病床至关重要。疾病模型必须利用当前的技术，并具有快速和可转化治疗的准确性。必须仔细选择细胞系，并结合高通量技术，在高度准确的人源化患者衍生异种移植模型中进一步试验有前途的结果。如果要部分缩小体外和体内研究之间的差距，则传统的贴壁药物筛选应过渡到适用于高通量技术的 3D 培养系统。类器官、诱导多能干细胞和条件重编程的体外模型具有诱人的可能性，但方案尚未完全建立。对 BRCA1 和 BRCA2 癌症生物学和当前建模系统的回顾有望指导未来药物发现工作的设计，并突出需要改进的领域。
