Peter MacCallum Cancer Centre, Melbourne 3000, Australia
The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne 3010, Australia.
Cold Spring Harb Perspect Med. 2023 Aug 1;13(8):a041333. doi: 10.1101/cshperspect.a041333.
The steady, incremental improvements in outcomes for both early-stage and advanced breast cancer patients are, in large part, attributable to the success of novel systemic therapies. In this review, we discuss key conceptual paradigms that have underpinned this success including (1) targeting the driver: the identification and targeting of major oncoproteins in breast cancers; (2) targeting the lineage pathway: inhibition of those pathways that drive normal mammary epithelial cell proliferation that retain importance in cancer; (3) targeting precisely: the application of molecular classifiers to refine therapy selection for specific cancers, and of antibody-drug conjugates to pinpoint tumor and tumor promoting cells for eradication; and (4) exploiting synthetic lethality: leveraging unique vulnerabilities that cancer-specific molecular alterations induce. We describe promising examples of novel therapies that have been discovered within each of these paradigms and suggest how future drug development efforts might benefit from the continued application of these principles.
早期和晚期乳腺癌患者的治疗效果不断稳步提高,在很大程度上归因于新型全身治疗的成功。在这篇综述中,我们讨论了支持这一成功的关键概念模式,包括:(1)针对驱动因素:鉴定和靶向乳腺癌中的主要致癌蛋白;(2)针对谱系途径:抑制那些驱动正常乳腺上皮细胞增殖的途径,这些途径在癌症中仍然很重要;(3)精准靶向:应用分子分类器来优化特定癌症的治疗选择,以及抗体药物偶联物来精确定位肿瘤和促进肿瘤的细胞进行清除;(4)利用合成致死性:利用癌症特异性分子改变引起的独特弱点。我们描述了在这些范例中的每一个范例中发现的有前途的新型疗法的例子,并建议未来的药物开发工作如何从这些原则的持续应用中受益。