Exploiting the DNA damage response (DDR) to transform the treatment paradigm
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As we reflect on the presentations being shared as part of the 2020 ASCO Virtual Scientific Program, it’s interesting to think about how our understanding of targeted therapies and the treatment paradigm has evolved. Cancer is a highly complex and heterogenous disease and while the diversity in tumour biology can be one of the most challenging aspects in the treatment of cancer, it is also a weakness we can exploit.1 We have made important strides in our ability to more effectively treat the disease through better understanding cancer biology and the genetic factors which drive tumour development, as well as the specific biology of the individuals it impacts.

Certain cancers are particularly hard to treat, whether that is because they have developed a resistance to treatment - such as castration-resistant prostate cancer which no longer responds to hormonal therapy - or because of where the cancer sits within the body - such as pancreatic cancer which sits at the intersection of major blood vessels, making surgery difficult.2,3 For these cancers a more personalised, targeted approach is needed.

This is where we delve into the genetic profile of the tumour, assessing which of the features that contribute to cancer aetiology can be used to our advantage. Cancer cells are known to have incredibly high mutation rates, and this results in dysfunctional cellular machinery and damaged DNA, and while cancer cells can survive with a certain level of damage, there is a limit.4 There is an Achilles heel.

Our goal is to develop innovative, targeted and biomarker-driven treatments that can exploit this weakness - and to match treatments to the patients most likely to benefit from them.

One of our key areas of focus is on the DNA damage response (DDR). The DDR comprises of hundreds of proteins that monitor, recognise and repair damaged DNA.5,6 Many cancers have defects in various DNA repair pathways, which make the cells more susceptible to DNA damage and more dependent on the remaining repair pathways.4 By inhibiting alternative repair pathways or the cell cycle checkpoints that allow time for repair, we can maximise DNA damage to selectively trigger cancer cell death, but how do we know which types of cancer to target?

 


The homologous recombination repair (HRR) DNA repair mechanism is the most accurate of all DNA repair processes and includes proteins coded for by HRR genes, including the two BReast CAncer susceptibility (BRCA) genes – BRCA1 and BRCA2 – which are particularly well-known HRR genes and actionable biomarkers.7,8,9

When fully functional, the BRCA genes code for proteins which repair otherwise lethal double stranded breaks in DNA and act as tumour suppressors.9 Certain cancers are known to have higher incidence of BRCA mutations than others, specifically breast, ovarian, colorectal, stomach, prostate and pancreatic cancer.8,10 If we can identify that a tumour has a BRCA mutation, and has therefore lost one of its DNA repair pathways, we can use targeted therapies to inhibit another pathway and potentially selectively kill cancer cells.4

As our understanding of the molecular biology advances, we have been able to widen the array of actionable genetic abnormalities. Tumours which have mutations in other HRR genes (HRRm) and those which have a deficiency in HRR (HRD) can also be susceptible to certain targeted therapies, ultimately compromising the tumour cells’ ability to repair DNA.4

We strive to bring the greatest benefits to patients, particularly in rare and aggressive cancer types where the unmet medical need is high, and to this we must continue to identify actionable biomarkers. We are in a new era of precision medicine and testing for genetic abnormalities, such as HRRm, BRCAm and HRD, is of paramount importance to achieve our vision of redefining cancer treatment and to one day potentially eliminate cancer as a cause of death.

 

References

1. Cancer Network. (2020). Heterogeneity And Cancer. Available at: https://www.cancernetwork.com/oncology-journal/heterogeneity-and-cancer. [Accessed May 2020].

2. Oberstein et al. (2013). Pancreatic cancer: why is it so hard to treat?. Therapeutic advances in gastroenterology, 6(4), 321–337. https://doi.org/10.1177/1756283X13478680

3. Cancer.Net. (2014). Treatment Of Metastatic Castration-Resistant Prostate Cancer. Available at: https://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer [Accessed May 2020].

4. 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.

5. O’Connor M (2015). Targeting The DNA Damage Response In Cancer. Molecular Cell. 60(4): 547-560.

6. Oncologypro.esmo.org. (2020). DNA Repair Mechanisms. Available at: https://oncologypro.esmo.org/oncology-in-practice/anti-cancer-agents-and-biological-therapy/parp-inhibition-and-dna-damage-response-ddr/dna-damage-response/ddr-in-health-and-disease/dna-repair-mechanisms [Accessed May 2020].

7. Li et al. (2008). Homologous recombination in DNA repair and DNA damage tolerance. Cell Research, 18(1), pp.99-113.

8. Pilarski, R., 2019. The Role of BRCA Testing in Hereditary Pancreatic and Prostate Cancer Families. American Society of Clinical Oncology Educational Book, (39), pp.79-86.

9. Paul et al. (2014). The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers. Frontiers in bioscience (Landmark edition)19, 605–618.

10. Gorodetska et al. (2019). BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance. Journal of Cancer, 10(9), 2109–2127. https://doi.org/10.7150/jca.30410

 

Veeva ID: Z4-24619
Date of preparation: May 2020
Date of Expiry: May 2022