利用DNA损伤反应来对抗癌症

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DNA损伤反应会发生什么?

The DNA Damage Response (DDR) is one of the scientific mechanisms we are focusing on to improve the clinical paradigm in oncology. Our understanding of the role the DDR plays in cancer is enabling us to push our research further to target a broad range of cancers including difficult to treat or aggressive cancers.1

Damage to DNA occurs on a daily basis due to exposure to internal or external DNA damaging agents (such as UV light, 电离辐射及化学治疗剂)1,2 DDR描述了检测和修复DNA损伤的多种方式. 影响DDR的一个关键因素是DNA损伤的类型.1 虽然某些类型的DNA损伤可以快速修复，但复杂的DNA损伤需要更长的时间来修复.3 在这种情况下，通路被激活以暂停细胞周期，并为修复留出时间.

Importantly, 大多数癌症对DDR有更大的依赖性, 由于在癌症发展过程中失去了一种或多种DDR能力.1 通过理解和识别这些依赖关系, we can use precision medicine approaches and targeted DDR inhibitors to maximise DNA damage and selectively kill cancer cells. This provides a truly targeted approach to cancer treatment with the potential to improve patient outcomes across multiple tumour types.1

It is through our science-driven approach in targeting DDR mechanisms that we have been able to contribute to advances in precision medicine in oncology.

澳门第一赌城在线娱乐对肿瘤DDR的承诺

凭借澳门第一赌城在线娱乐行业领先的产品组合和针对DDR机制的研究, 澳门第一赌城在线娱乐正在追求澳门第一赌城在线娱乐的雄心壮志，希望有一天能够消除癌症这一致死原因.

澳门第一赌城在线娱乐的方法基于突破性的科学, we continue to further our understanding of targeted therapy with the aim of achieving a tangible patient benefit. We are working hard to continually advance what we know about the role of DDR in cancer and drive the development of targeted DDR therapies to enable precision medicine. To achieve this, we need to be able to identify and test which patients have genetic biomarkers indicating underlying DDR defects, 让病人得到正确的治疗.

Our oncology pipeline continues to deliver potential biomarker-selected treatment strategies for patients across multiple tumour types including ovarian, breast, prostate and pancreatic cancers. We are also using a range of technologies and exploratory endpoints to both develop assays to inform patient selection and monitor patient relapse, 目的是找到进一步开发新的靶向治疗方法的机会. We are committed to pushing the boundaries of science and harnessing our DDR targets to achieve the best possible outcomes for patients worldwide.

Susan Galbraith

肿瘤学执行副总裁&D, AstraZeneca
Mark O'Connor

澳门在线赌城娱乐早期肿瘤发现首席科学家

The gateway to oncology

Approaches to cancer treatment have transitioned from the conventional chemotherapy and radiotherapy options to a more personalised and targeted approach. 正如个性化医疗所期望的那样, 有不同的生物标志物可以利用, 这增加了可以实现的个性化水平. 近年来，澳门第一赌城在线娱乐看到了令人钦佩的进步，特别是在卵巢方面, breast, 前列腺癌和胰腺癌——包括并扩展基于BRCA1/2基因的患者选择, 它们参与了被称为同源重组修复的DDR途径, shifting focus to a broader indication in ovarian cancer and prostate cancer defined as Homologous Recombination Deficiency.1,4,5 澳门第一赌城在线娱乐很自豪地把注意力集中在DDR上，开创了靶向治疗的新时代, 继续为精准医疗的价值做出贡献.

We have come so far in pioneering DDR research and will continue to push the boundaries of our knowledge in this important area of cancer therapy. 此外，澳门第一赌城在线娱乐致力于应对新出现的耐药性，并实现更持久的应对措施. Central to this, 澳门第一赌城在线娱乐正在探索DDR抑制剂组合的效果，包括那些与其他靶向治疗的组合.

Understanding DDR pathways 

Understanding DDR pathways and the proteins involved allows us to target tumour-specific DDR dependencies to preferentially kill cancer cells.

Normal cell

Normal cell

每天都有数以万计的DNA损伤事件发生在人类细胞中.6  修复这些DNA损伤事件，使细胞正常运作, 一系列的过程发生了, 统称为DNA损伤反应(DDR).1 If left unrepaired, DNA损伤的水平可能累积到致命的水平，并导致细胞死亡.1

DNA damage

DDR取决于DNA损伤的类型

许多蛋白质参与不同的修复途径，包括但不限于:

  • PARP1 and PARP2 – poly [ADP-ribose] polymerases are enzymes involved in various cellular processes including DNA single-strand break repair (SSBR), 与碱基切除修复(BER)中使用的蛋白质和复合物重叠的途径7
  • ATM – a protein kinase involved in DNA double-strand break (DSB) repair by Homologous Recombination Repair (HRR) or Non-Homologous End Joining (NHEJ)1,8
  • DNA-PK – 这种DNA依赖性蛋白激酶在NHEJ途径修复DNA DSB中起关键作用9
  • BRCA1 and BRCA2 – 这些基因编码的蛋白质是通过HRR修复DNA DSB的关键, 是肿瘤抑制蛋白1

Value of HRR and HRD

The value of HRR and HRD

Cells with deficiencies in Homologous Recombination Repair (HRR) pathways have reduced capacity to accurately repair DNA double-strand breaks.9

HRR gene mutations (HRRm) represent any mutation to an HRR gene that results in the loss-of-function or complete loss of the protein, such as to BRCA1/2 and ATM. This renders the repair pathway ineffective and can contribute to genomic instability and cancer cell development.1,10,11,12

同源重组缺乏症(Homologous Recombination Deficiency, HRD)是用来描述一条功能性HRR通路缺失的术语. 因此，人力资源管理可以导致人力资源开发.13

HRD在许多不同的肿瘤类型中都可以观察到, 比如卵巢癌, can be highly enriched. In these HRD tumour types, 抑制PARP1可导致基因组不稳定性的积累并导致癌细胞死亡.14

癌症中的基因突变

利用HRD和癌症中的基因突变

DDR targeted therapy, such as PARP inhibitors, 是否可以通过阻断PARP1酶活性来利用癌细胞中的同源重组缺陷(HRD),1 阻止DNA单链断裂修复并将PARP1捕获到DNA上. In replicating cells this can lead to DNA double-strand breaks that would normally be repaired through the HRR pathway. 在HRD肿瘤中，例如那些 BRCA1/2 loss of function mutations, PARP抑制剂治疗可导致无法承受的基因组不稳定性和癌细胞死亡.15,16 Normal cells, 哪些保留了HRR能力, 不受这种方式的影响-使其成为真正有针对性的癌症治疗方法.15,16

Cell cycle

DDR受细胞周期的影响

DNA replication stress

DNA复制是细胞增殖的必要条件. 任何干扰正常DNA复制的东西都被称为“DNA复制压力”. 癌症的复制压力比正常细胞高得多. DDR的一个重要方面是涉及ATR等蛋白质的复制应激反应(RSR), WEE1 and DNA-PK.17,18

  • ATR 是一种关键的蛋白激酶，通过各种方式，负责调节RSR. In addition, 它起着关键的细胞周期检查点作用，并通过HRR促进DNA双链断裂修复16
  • WEE1 一种蛋白酪氨酸激酶在调节细胞周期进程中起双重作用吗, 通过s阶段和G2/M检查点. WEE1 is a key RSR protein19
  • DNA-PK 是一种在NHEJ中起作用的蛋白激酶吗. 此外，它还与RSR联系在一起

Cell division

肿瘤要生长，就必须进行细胞分裂.

  • Aurora B 是一种在细胞分裂过程中协助DNA染色体排列的蛋白激酶吗. Its inhibition causes either unequal splitting of the chromosomes between the daughter cells or failure of the cell to divide, leading to cell death20,21
  • Aurora B 是否在肝癌、结肠癌、乳腺癌、肾癌、肺癌和甲状腺癌中过度表达. Inhibition of Aurora B kinase has the potential to increase mitotic stress and therefore be combined with other DDR agents22

这些DDR蛋白一起确保细胞周期不会随着受损的DNA而进行. 因此，DNA修复和细胞周期检查点调节因子内在地相互联系.

应用科学实现有形的靶向治疗的好处 oncology

 

继续探索联合治疗，在临床中获得更广泛和更持久的反应

率先使用DDR抑制剂来利用癌症中的复制应激

The power of combinations

超越DDR抑制剂单药治疗，以澳门第一赌城在线娱乐的临床前科学为主导, 澳门第一赌城在线娱乐有广泛的临床试验，正在调查以ddr为基础的联合治疗的效果. DDR疗法可以联合使用, to achieve better outcomes, to extend therapies beyond patients who are expected to respond to DDR monotherapy and to overcome resistance in the clinic.23

澳门第一赌城在线娱乐还研究了DDR和免疫肿瘤学(IO)药物联合使用的效果. 抑制DDR通路可能引发抗肿瘤免疫反应, 这意味着针对DDR和免疫反应途径的联合治疗可能会改善结果.24  The diversity of our oncology pipeline spanning different scientific platforms of focus allows us to address some of the most common to the most life threatening and rare cancers and look beyond initial response to long-term outcomes and, eventually, a potential cure.

Join AstraZeneca

并帮助澳门第一赌城在线娱乐提供改变生活的药物

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References

1. Alhmoud J, et al. 癌症中的DNA损伤/修复管理. Cancers (Basel). 2020 Apr; 12(4): 1050.

2. Li L, et al. DNA修复途径在癌症治疗和耐药性中的作用. Front. Pharmacol.2021.

3. Vitor A, et al. 研究DNA双链断裂修复:一个不断增长的工具箱. Front. Mol. Biosci. 2021.

4. Krzyszczyk P, et al. 精准和个性化医疗在癌症治疗中的作用越来越大. Technology (Singap World Sci). 2018 Sep-Dec; 6(3-4): 79–100.

5. Wong W, et al. 胰腺癌中的BRCA突变:谱、当前管理、挑战和未来展望. Cancer Manag Res. 2020; 12: 2731–2742.

6. Verma N, et al. DNA损伤应激:崔提示? Int J Mol Sci. 2019 Mar; 20(5): 1073.

7. Ronson GE, et al. PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation. Nat Commun. 2018 Feb 21;9(1):746.

8. Balmus G, et al. ATM协调dna损伤反应，以对抗断裂复制分叉处的毒性非同源末端连接. Nat Commun. 2019; 10: 87.

9. Mohiuddin and Kang. DNA-PK作为癌症治疗的新靶点. Frontiers in Oncology. 2019;9(635).

10. Keung M, et al. PARP抑制剂作为治疗乳腺癌同源重组缺乏症的药物. 临床医学杂志. 2019;8(4), pp.435.

11. Norquist B, et al. Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: an NRG Oncology/Gynecologic Oncology Group Study. Clin Cancer Res. 2018 Feb 15; 24(4): 777–783.

12. Pawlyn C, et al. Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition? Leukemia. 2018;32, pp.1561–1566.

13. Heeke A, et al. 同源重组相关基因突变在多种癌症类型中的流行. JCO Precis Oncol. 2018;2018:PO.17.00286.

14. da Cunha Colombo Bonadio R， et al. 卵巢癌同源重组缺乏症的流行病学及治疗进展. 诊所(巴西圣保罗). 2018;73(suppl 1), e450s.

15. Chaudhuri and Nussenzweig. PARP1在DNA修复和染色质重塑中的多重作用. 分子细胞生物学. 2017;18(10):610-621.

16. Rose M, et al. PARP抑制剂:临床相关性、作用机制和肿瘤耐药. Front Cell Dev Biol. 2020 Sep 9;8:564601.

17. Forment and O’Connor. 靶向癌症中的复制应激反应. Pharmacology & Therapeutics. 2018;188:155-167.

18. Ubhi and Brown. 利用DNA复制压力治疗癌症. Cancer Res. 2018;2018:PO.17.00286.

19. Moiseeva T, et al. WEE1激酶抑制剂AZD1775在未受干扰的G1期和s期细胞中诱导CDK1激酶依赖性起源放电. PNAS. 2019;116(48):23891-23893.

20. McVey S, et al. 着丝点中的极光B张力传感机制确保染色体准确分离. Int J Mol Sci. 2021 Aug; 22(16): 8818.

21. Luserna di Rora A, et al. 急性白血病有丝分裂死亡和有丝分裂滑脱之间的平衡:一个新的治疗窗口? Journal of Hematology & Oncology. 2019;12:123.

22. Du R, et al. 靶向AURKA在癌症中的作用:肿瘤治疗的分子机制和机遇. Molecular Cancer. 2021;20(15).

23. Pilie P, et al. PARP抑制剂:扩展BRCA突变癌症以外的益处. Clin Cancer Res. 2019年7月1日;25(13):3759-3771.

24. Samstein R, et al. 免疫治疗和放射治疗中的DNA损伤反应. 放射肿瘤学进展. 2018:3;527-533.

Veeva ID: Z4-51061
筹备日期:2022年12月