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Freelance health journalist and former neuroscientist interested in a wide variety of life science topics. David also writes for The Guardian, BBC, National Geographic, NBC News, Wired, TIME and others.
In recent years, oncologists have gained a vital new weapon in the ongoing fight against cancer through the rise of DNA damage response (DDR) inhibitors, a form of precision medicine which kills cancer cells by preventing them from repairing damage to their DNA. Because DDR inhibitors can be used alone, or in combination with immunotherapy, chemotherapy or radiotherapy as a means of preventing tumours recovering from the damage inflicted by these treatments, they offer a versatile method of attacking various forms of cancer.
Poly (ADP-ribose) polymerase (PARP) inhibitors, the leading form of DDR inhibitors, have already emerged as a new option for certain specific cancer types such as non-BRCA-related advanced ovarian cancer, and metastatic BRCA1/2-positive, HER2-negative breast cancer. Because these treatments are administered orally, they offer the potential to both extend patients’ lives as well as improving their quality of life.
While the Covid-19 pandemic has had a major impact on the field, halting recruitment for a whole range of clinical trials, DDR inhibitors are expected to be one of the most rapidly expanding areas of cancer medicine in the coming years. Pharma giants Merck and Novartis are investing billions in partnerships with various biotechs to develop new drug targets based on cancer DNA repair pathways, while UK-based Artios Pharma raised £110 million in venture capital funding in 2021 to pursue its DDR programs.
At the Lunenfeld-Tanenbaum Research Institute in Toronto, Daniel Durocher – who has 3,149 topic citations for DNA Damage Response on Insciter.com – is one of the world’s leading researchers in the realm of DDR inhibitors.
According to Durocher, scientists have now successfully elucidated the basics of many of the key genes and proteins relating to DNA repair, which is now helping them link the gene mutations found in specific tumours with different DNA repair mechanisms. These repair pathways can then be targeted with DDR inhibitors, providing the basis for a number of ongoing clinical trials.
“Since we know what DNA repair process is impacted by these mutations, it can give us ideas about the treatment we should consider using,” says Durocher. “The long-term goal is what we refer to as precision oncology, matching the genetic or molecular make-up of tumours to the most effective treatment.”
This work has been aided by advances in tumour genome sequencing, allowing scientists to identify tell-tale signatures of DNA repair deficiencies in different cancer cells. Durocher refers to these signatures as ‘genetic fossils,’ which can tell oncologists that a specific tumour has a DNA repair defect, or experienced a certain type of mutagenic DNA damage.
Scientists have also uncovered a link between DNA repair pathways and the immune system response, which could potentially be utilised to make tumours more susceptible to different immunotherapies.
“It offers the possibility to augment the immunogenicity of tumours by inhibiting DNA repair and thus increase the expression of neoantigens on the surface of tumours,” says Fabrizio D’Adda di Fagagna, a cancer researcher at the FIRC Institute for Molecular Oncology in Milan, who ranks No.6 for DNA Damage Response with 4,606 topic citations on Insciter.com.
While PARP inhibitors have been the first DDR inhibitors to make it to the clinic, with the US Food and Drug Administration approving them for specific forms of ovarian, prostate, and breast cancer, there are newer DDR inhibitors on the way.
“PARP inhibitors are an amazing success, and they will continue to be used and tested in more tumour types,” says Durocher. “They will be a tool in our toolkit but they are likely to be used in combination with other agents.”
The next generation DDR inhibitors target different proteins involved in the DNA repair process, such as ATM, DNA-PK, ATR, and also Pol theta. According to David Cortez, a researcher at Vanderbilt-Ingram Cancer Center, who has the second most topic citations for ATR on Insciter.com, there is particular interest from the pharma industry in ATR inhibitors. These therapies can either be used on their own or in combination with chemotherapies as research suggests that they can hypersensitise cancer cells to these treatments.
“Pol theta inhibitors are also in development by several companies since they seem to be useful in similar patients as PARP inhibitors but may be useful even in at least some cases of PARP inhibitor resistance,” says Cortez. “WRN inhibitors may be useful in patients with cancers containing mismatch repair deficiencies.”
As ever in cancer medicine, the major problem for oncologists is tumours inevitably developing resistance to DDR inhibitors. Resistance has already been observed towards PARP inhibitors but scientists say that there is some preclinical evidence that combining PARP inhibitors with ATR inhibitors could help overcome this in some cases.
“Therapeutic resistance is almost unavoidable with any cancer therapy,” says Durocher. “PARP inhibitors are not an exception, and I am not sure it tells us anything unique about this class of treatment. However, we are starting to understand better how resistance emerges and developing strategies that will either delay the emergence of resistance, or reverse it. As with most targeted cancer therapies, the future will likely be in the development of effective combination therapies.”
With increasing numbers of cancer patients now living with the disease for years or even decades, a secondary concern is whether DDR therapies themselves can have longer term risks, by causing damage to healthy tissue as well as cancer cells. Some research has suggested that the combination of radiotherapy and chemotherapy with DDR inhibitors may increase DNA mutations in surviving cells, potentially leading to the development of secondary tumours further down the line.
D’Adda di Fagagna says that there is a need for more research looking into how common this is, and ways of preventing this from happening.
“This is an issue which in my opinion, has always been hugely overlooked with PARP inhibitors,” he says. “Is DNA repair inhibition safe in the long term? Are we sure that it will not cause increased risk of cancer in 10 or 20 years? We know this is exactly what happens in children with leukemia, treated with chemotherapy. Of course, PARP inhibitors are milder than these quite toxic treatments, but we need to look into this.”
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