Department of Pathology and Biomedical Science, University of Otago, Christchurch.
Haematologica. 2021 Jan 1;106(1):14-25. doi: 10.3324/haematol.2020.259283.
The past decade has seen a proliferation of drugs that target epigenetic pathways. Many of these drugs were developed to treat acute myeloid leukemia, a condition in which dysregulation of the epigenetic landscape is well established. While these drugs have shown promise, critical issues persist. Specifically, patients with the same mutations respond quite differently to treatment. This is true even with highly specific drugs that are designed to target the underlying oncogenic driver mutations. Furthermore, patients who do respond may eventually develop resistance. There is now evidence that epigenetic heterogeneity contributes, in part, to these issues. Cancer cells also have a remarkable capacity to 'rewire' themselves at the epigenetic level in response to drug treatment, and thereby maintain expression of key oncogenes. This epigenetic plasticity is a promising new target for drug development. It is therefore important to consider combination therapy in cases in which both driver mutations and epigenetic plasticity are targeted. Using ascorbate as an example of an emerging epigenetic therapeutic, we review the evidence for its potential use in both of these modes. We provide an overview of 2-oxoglutarate dependent dioxygenases with DNA, histone and RNA demethylase activity, focusing on those which require ascorbate as a cofactor. We also evaluate their role in the development and maintenance of acute myeloid leukemia. Using this information, we highlight situations in which the use of ascorbate to restore 2-oxoglutarate dependent dioxygenase activity could prove beneficial, in contrast to contexts in which targeted inhibition of specific enzymes might be preferred. Finally, we discuss how these insights could be incorporated into the rational design of future clinical trials.
过去十年中，靶向表观遗传途径的药物大量涌现。其中许多药物是为治疗急性髓系白血病而开发的，这种疾病中表观遗传景观的失调已得到充分证实。虽然这些药物显示出了一定的前景，但仍存在一些关键问题。具体来说，患有相同突变的患者对治疗的反应差异很大。即使是针对潜在致癌驱动突变设计的高度特异性药物也是如此。此外，对治疗有反应的患者最终可能会产生耐药性。现在有证据表明，表观遗传异质性在一定程度上导致了这些问题。癌细胞在受到药物治疗时，还具有在表观遗传水平上“重新布线”自身的显著能力，从而维持关键致癌基因的表达。这种表观遗传可塑性是药物开发的一个很有前途的新靶点。因此，在针对驱动突变和表观遗传可塑性的联合治疗中，考虑组合疗法是很重要的。我们以抗坏血酸为例，讨论了其作为新兴的表观遗传治疗药物的潜在用途。我们综述了它在这两种模式中的潜在应用的证据。我们概述了依赖 2-氧戊二酸的双加氧酶的 DNA、组蛋白和 RNA 去甲基化酶活性，重点介绍了那些需要抗坏血酸作为辅助因子的酶。我们还评估了它们在急性髓系白血病的发生和维持中的作用。利用这些信息，我们强调了在某些情况下，使用抗坏血酸恢复 2-氧戊二酸依赖的双加氧酶活性可能会有益，而在其他情况下，靶向抑制特定酶可能更为可取。最后，我们讨论了如何将这些见解纳入未来临床试验的合理设计中。
