Targeting DNA-Repair Defects To Battle Cancer
Cancer, without a doubt, is a grim aspect of our lives. Every year, millions of people fall victim to one of the variants of this horrible disease. So, it’s natural that scientists all around the globe work restlessly to come up with a cure for this problem. Recent research shows that targeting DNA-repair defects can play a major part in fighting cancer.
What Is a DNA-Repair Defect?
DNA repair refers to a range of processes that a cell uses to identify and fix the damage done to its DNA molecules responsible for encoding its genome. There can be different reasons behind such damage in human cells, including routine metabolic activities as well as environmental factors like radiation, leading to thousands of molecular lesions in a cell every day. These lesions can result in structural damage to the DNA molecule, while others can induce harmful mutations in the genome of the cell.
To avoid these cell mutations, the DNA repair process remains active all the time, constantly responding to any such abnormalities and damage to the structure of the DNA.
That is, of course, in the case of normal cells. However, when the cell is cancerous, the changes it undergoes make it unable to repair DNA sufficiently. This means that even a smallest mutation can easily spread and duplicate itself. Therefore, many cancers are said to originate from DNA-repair defects, and it has been theorised that all of them possess DNA-repair defect abilities.
Along with cancer, other diseases that result from the DNA repair defects include:
- Bloom’s syndrome
- Ataxia telangiectasia (Louis-Bar syndrome)
- Fanconi anaemia
- Xeroderma pigmentosum
- Cockayne’s syndrome
- Trichothiodystrophy
How Does It Affect The Advancement Of Cancer?
The DNA-repair defects can be a cause of oncogenic genomic instability. This instability can then lead to more mutations that play their part in dysregulating growth, promoting invasion of the cancer cells and metastasis. As previously mentioned, in this case even the smallest irregularity can be spread and multiplied.
However, the same problem that causes cancer can be used to fight it. In order to multiplicate at a fast rate typical to cancer cells, they need several components of DNA repair. In order to substitute the repair component’s previous oncogenic loss caused by DNA instability, cancerous cells must find replacement components to continue spreading. By identifying and targeting these replacement components for DNA repair, it is possible to minimize and even stop the spread of cancer.
Another aspect of this issue is associated with treatment efficiency. Cancer therapies often involve purposeful damaging of the DNA structure in order to cripple cancer. When the mutated cells have a sufficient ability to repair those damages, the treatment loses its effectiveness. Therefore, by targeting cancer’s ability to repair therapeutically-induced damage, the efficiency of anti-cancer treatments can be greatly increased.
What Therapies Are Possible To Reverse Those Defects?
As of now, the topic of DNA-repair defects and its effect on cancer development is relatively new. That is because the link between those two had previously been believed to be marginal and insignificant. Modern research, however, considers this untrue, and in recent years, the idea of cancer-related DNA-repairing is looked into more closely. According to this study, scientists have found out just how significant targeting the defects in a DNA-repair pathway can be when it comes to cancer treatment. Different therapies are in use today that target DNA-repair defects and fix DNA damage to treat cancer. These include:
1. Drugging different DNA-repair pathways
DNA-repair pathways work in the form of related networks. Cancers that arise due to loss of a DNA-repair component usually get addicted to different other DNA-repair pathways for their survival and proliferation. Drugging the rescue repair pathway can help prevent cancer cells with repair-defects from replicating further, causing apoptosis also known as synthetic lethality. The selective pressure from inhibition of the rescue repair pathway, however, can lead to further mutations that offer resistance to these synthetic lethal drugs.
Currently, many drugs of this type are in clinical use for inhibiting PARP1, a DNA-repair component. It’s evident that the drugs that induce synthetic lethality can have a therapeutic effect on cancers that have acquired DNA-repair defects.
Some commonly targeted DNA-repair pathways that are being drugged include:
- Base Excision Repair
- Mismatch Repair
- Nucleotide Excision Repair
- HR and CrossLink Repair
- NHEJ
According to a 2017 study on Drugging the Cancers Addicted to DNA-Repair, the clinical drugging with PARP1 inhibitors proved to be the most effective. Multiple such compounds inhibit PARP2 as well to a certain extent. However, it is believed that their activity is because of their PARP1 inhibition.
2. Radiation Therapy
Standardized radiation therapy stands on top of all treatments for cancer. However, it has been observed that some cancer variations develop a resistance to this method, because of their increased repair ability gained from spare pathways. To combat this, Ionizing Radiation is given along with chemotherapy which induces DNA damage. This combination lowers the cells’ DBS repair activity, which makes it much more vulnerable to radiation and allows it to destroy cancerous cells as it would normally do.
3. Targeting homology directed repair and Rad51
Rad51 is a protein that is crucial to genetic stability. In almost every type of cancer, it is observed that this protein tends to increase. Paradoxically, the abundance of this protein does not mean an increased repair ability for cells. Instead, both too much and too little of this protein negatively impact the patient’s chances of survival. For example, patients with colon cancer had a much smaller survival period when they had a strong Rad51 expression compared to the ones with a weaker expression. Therefore, science is in the process of developing Rad51 inhibitors that can help control the amount of this protein.
Proper DNA-repair systems are crucial for avoiding various different diseases, including cancers. Due to the DNA-repair defects, cancerous cells tend to develop mutations that can easily replicate with no repair work being done by the natural DNA-repair mechanism.
Continued research is going on when it comes to targeting DNA-repair defects to battle cancer. And, different therapies have already been devised to fix the DNA-repair defects to help fight cancer.
Dr. Paul Zhang at the Institute of Integrative BioOncology in Houston provides evidence-based treatments for a wide range of cancers. Call today for more information.
