Combatting cancer by exploiting the DNA Damage Response


Why is AstraZeneca focusing on the DNA Damage Response?

The DNA Damage Response (DDR) is one of the scientific platforms 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, and the DDR describes the multiple ways in which DNA damage is detected and repaired. Two key factors influence the DDR – the type of DNA damage, and when the damage occurs during the cell cycle.5 While some types of DNA damage are repaired quickly, complex DNA damage takes longer to repair. In this scenario, pathways are activated to pause the cell cycle and allow time for repair. More can be read about the science of DDR.

Importantly, most cancers have a greater dependency on the DDR, due to the loss of one or more DDR capabilities during the development of cancer.8 By understanding and identifying these dependencies, 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.1,2,5

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.



Our commitment to DDR

 

With our industry-leading portfolio and research targeting DDR mechanisms, we are pursuing our bold ambition to one day eliminate cancer as a cause of death.

Basing our approach on using ground-breaking science, 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, to allow patients to be matched to the right treatment.

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 end-points to both develop assays to inform patient selection and monitor patient relapse, with the aim of identifying further opportunities for developing new targeted therapies. 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 Senior Vice President and Head of Research and Early Development, Oncology R&D

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Mark O'Connor Chief Scientist, Oncology, IMED Biotech Unit

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The gateway to oncology

Approaches to cancer treatment have transitioned from the conventional chemotherapy and radiotherapy options to a more personalised and targeted approach. As expected with personalised medicine, there are different biomarkers that can be utilised, and this adds to the level of personalisation that can be achieved. We have seen admirable advancements in recent years – particularly in pancreatic, prostate and ovarian cancers – to both include and expand beyond patient selection based on BRCA1/2 genes, which are involved in a DDR pathway known as Homologous Recombination Repair, shifting focus to a broader indication in ovarian cancer defined as Homologous Recombination Deficiency.1,3,4 We are proud to focus our attention on DDR and usher in a new era of targeted therapy, continuing to contribute to the value of precision medicine.

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. In addition, we are committed to tackling emerging resistance and achieving more durable responses. Central to this, we are exploring the effects of DDR inhibitor combinations including those with other targeted therapies.

Understanding DDR pathways 

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



Applying the science to achieve tangible targeted therapy benefits in oncology

 

Exploit HRD to induce cancer cell death through our DDR portfolio

Continue to explore combination therapies to achieve broader and more durable responses in the clinic

Pioneer the use of DDR inhibitors to exploit replication stress in cancers


The power of combinations

Looking beyond DDR inhibitor monotherapy and led by our pre-clinical science, we have a broad range of clinical trials that are investigating the effects of DDR-based combination treatments. DDR therapies can be combined, such as PARP and ATR inhibitors, to achieve better outcomes, extend therapies beyond those patients who are expected to respond to DDR monotherapy and overcome resistance in the clinic.29

We also look at the effects of combining DDR and Immuno-Oncology (IO) agents. The inhibition of DDR pathways may prime an anti-tumour immune response, meaning combination therapies that target DDR and immune response pathways could result in improved outcomes.30 The diversity of our oncology pipeline spanning different scientific platforms of focus allows us to address 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.


References

1. Ledermann et al. (2016). Homologous recombination deficiency and ovarian cancer. European Journal of Cancer, 60, pp.49-58.

2. [1]O'Connor (2015). Targeting the DNA Damage Response in Cancer. Molecular Cell, 60(4) pp.547-560. doi:10.1016/j.molcel.10.040

3. Krzyszczyk et al. (2018). The growing role of precision and personalized medicine for cancer treatment. Technology, 6(3), pp.79-100.

4. Wong et al. (2020). BRCA Mutations in Pancreas Cancer: Spectrum, Current Management, Challenges and Future Prospects. Cancer Management and Research, 12, pp.2731–2742.

5. Ciccia et al. (2010). The DNA Damage Response: Making it Safe to Play with Knives. Molecular Cell, 40(2), pp.179-204. 

6. Jackson and Bartek. (2009). The DNA-damage response in human biology and disease. Nature, 461(7267), pp.1071–1078.

7. Cannan et al. (2016). Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin. Journal of cellular physiology, 231(1), pp.3–14.

8. Hakem. (2008). DNA-damage repair; the good, the bad, and the ugly. The EMBO Journal, 27, pp.589–605.

9. Nowsheen and Yang. (2012). The intersection between DNA damage response and cell death pathways. Exp Oncology, 34(3), pp.243–254.

10. Ronson et al. (2018). PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation. Nature Communications, 9(746).

11. Weber and Ryan. (2015). ATM and ATR as Therapeutic Targets in Cancer. Pharmacology and therapeutics, 149, pp.124-38.

12. Mohiuddin and Kang. (2019). DNA-PK as an Emerging Therapeutic Target in Cancer. Frontiers in Oncology, 9(635).

13. Keung et al. (2019). PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers. Journal of clinical medicine, 8(4), pp.435.

14. Utah Genome Project. Homologous Recombination Repair Genetics (HRR genes). Available at: https://uofuhealth.utah.edu/utah-genome-project/projects-list/breast-ovarian-pancreatic-cancers.php#:~:text=Homologous%20Recombination%20Repair%20Genetics%20(HRR,homologous%20recombination%20repair%2C%20HRR). [Accessed August 2020].

15. Pawlyn et al. (2018). Loss of heterozygosity as a marker of homologous repair deficiency

16. in multiple myeloma: a role for PARP inhibition? Leukemia, 32, pp.1561–1566.

17. Heeke et al. (2018). Prevalence of Homologous Recombination–Related Gene Mutations Across Multiple Cancer Types. JCO Precision Oncology, 2018.

18. da Cunha Colombo Bonadio et al. (2018). Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics (Sao Paulo, Brazil)73(suppl 1), e450s.

19. Duesberg et al. (2000). Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy. Proceedings of National Academy of Sciences of the United States of America, 97(26), pp.14295–14300.

20. Morales et al. (2014). Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Critical reviews in eukaryotic gene expression24(1), pp.15–28.  

21. Chaudhuri and Nussenzweig. (2019). The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nature Reviews Molecular Cell Biology, 18(10), pp.610–621.

22. Ellisen. (2012). PARP Inhibitors in Cancer Therapy: Promise, Progress and Puzzles. Cancer Cell, 19(2), pp.165–167.

23. Forment and O’Connor (2018). Targeting the replication stress response in cancer. Pharmacology & Therapeutics, 188, pp.155-167.

24. Ubhi and Brown. (2019). Exploiting DNA Replication Stress for Cancer Treatment. Cancer Research, 18(3631).

25. Awasthi et al. (2015). ATM and ATR signaling at a glance. Journal of Cell Science, 128(23), pp.4255-4262.

26. Moiseeva et al. (2019). WEE1 kinase inhibitor AZD1775 induces CDK1 kinase-dependent origin firing in unperturbed G1- and S-phase cells. PNAS, 116(48), pp.23891-23893.

27. Carmena et al. (2012). The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat Rev Mol Cell Biol, 13, pp.789–803.

28. Bavetsias and Linardopoulos. (2015). Aurora Kinase Inhibitors: Current Status and Outlook. Frontiers in oncology, 5, pp.278.

29. Gavriilidis et al. (2015). Aurora Kinases and Potential Medical Applications of Aurora Kinase Inhibitors: A Review. Journal of clinical medicine research, 7(10), pp.742–751.

30. Pilié et al. (2019). PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers. Clin Cancer Res, 25(13) pp.3759-3771

31. Samstein and Riaz. (2018). The DNA damage response in immunotherapy and radiation. Advances in Radiation Oncology, 3(4), pp.527-533.


Veeva ID: Z4-25285
Date of Prep: August 2022