Center for Gene Therapy, City of Hope, Beckman Research Institute and Hematological Malignancy and Stem Cell Transplantation Institute at the City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA.
Virol J. 2021 Jan 13;18(1):18. doi: 10.1186/s12985-021-01488-1.
Viral oncogenic transformation of healthy cells into a malignant state is a well-established phenomenon but took decades from the discovery of tumor-associated viruses to their accepted and established roles in oncogenesis. Viruses cause ~ 15% of know cancers and represents a significant global health burden. Beyond simply causing cellular transformation into a malignant form, a number of these cancers are augmented by a subset of viral factors that significantly enhance the tumor phenotype and, in some cases, are locked in a state of oncogenic addiction, and substantial research has elucidated the mechanisms in these cancers providing a rationale for targeted inactivation of the viral components as a treatment strategy. In many of these virus-associated cancers, the prognosis remains extremely poor, and novel drug approaches are urgently needed. Unlike non-specific small-molecule drug screens or the broad-acting toxic effects of chemo- and radiation therapy, the age of designer nucleases permits a rational approach to inactivating disease-causing targets, allowing for permanent inactivation of viral elements to inhibit tumorigenesis with growing evidence to support their efficacy in this role. Although many challenges remain for the clinical application of designer nucleases towards viral oncogenes; the uniqueness and clear molecular mechanism of these targets, combined with the distinct advantages of specific and permanent inactivation by nucleases, argues for their development as next-generation treatments for this aggressive group of cancers.
病毒将健康细胞转化为恶性状态的致癌转化是一种已被证实的现象，但从发现肿瘤相关病毒到它们在致癌作用中被接受和确立作用，这一过程历经了数十年。病毒导致约 15%的已知癌症，这是一个重大的全球健康负担。除了简单地将细胞转化为恶性形式外，这些癌症中的许多还被病毒因子的亚群增强，这些病毒因子显著增强了肿瘤表型，在某些情况下，还处于致癌成瘾的状态，大量研究已经阐明了这些癌症中的机制，为靶向失活病毒成分作为治疗策略提供了依据。在许多与病毒相关的癌症中，预后仍然非常差，迫切需要新的药物方法。与非特异性小分子药物筛选或化疗和放疗的广泛作用毒性不同，设计核酸酶的时代允许对致病靶标进行合理的失活，从而永久性地失活病毒元件以抑制肿瘤发生，越来越多的证据支持它们在这一作用中的功效。尽管针对病毒致癌基因的设计核酸酶的临床应用仍然存在许多挑战，但这些靶标的独特性和明确的分子机制，以及核酸酶特异性和永久性失活的独特优势，为将其作为这组侵袭性癌症的下一代治疗方法进行开发提供了依据。
