When the injury is finished – how ICR scientists deal with DNA injury restore

Image: DNA double helix (computer visualization). Photo credit: Arek Socha via Pixabay

DNA damage is the leading cause of cancer. As you read this, many of your cells are producing new DNA, and some of that DNA have errors in their sequence because the cell makes small manufacturing errors.

Your cells are very good at spotting these errors and fixing them quickly and safely, either by pressing a preprogrammed self-destruct button if the error is too serious to be fixed, or by repairing the damage with certain proteins that are causing the problem can fix bugs.

Sometimes DNA errors slide the web and cancer can develop when cells replicate out of control. While DNA damage is a strength for cancer, it is also a fundamental weakness that can be exploited in the development of cancer treatments.

Weakness and strength

Weakness and strength are very closely coordinated in nature. Scientists at the ICR are working hard to turn cancer’s weaknesses into our drug development strengths. It takes many teams, many years, and many successes and failures to achieve results that help create smarter, friendlier treatments.

Olaparib, a drug developed at the ICR, also uses the targeted DNA repair mechanisms. As a precision medicine, it selectively targets and kills cancer cells that have faulty DNA repair machines in place.

The discovery and development of the drug was underpinned by more than twenty years of research at the ICR in many teams of scientists and clinicians.

Cancers caused by faulty BRCA1 or BRCA2 genes are susceptible to these drugs, which means they can be used in patients with defects in these genes for breast, ovarian, and prostate cancers.

The ICR story

The BRCA genes are involved in DNA repair – a discovery made by former ICR chief professor Alan Ashworth together with colleagues from across the ICR. Their key role in DNA repair means that cancers with BRCA mutations are particularly susceptible to DNA damage.

Olaparib is a type of drug known as a PARP inhibitor. Cells with faulty BRCA genes already have a hard time repairing DNA damage, and they rely on an enzyme called PARP for all repair needs. Stopping PARP removes the emergency repair kit and cancer cells die while healthy cells survive.

The drug was already approved by US and European drug agencies for use in ovarian and breast cancer. Last year the drug was approved in the United States and Europe for use in advanced prostate cancer.

Professor Johann de Bono, Professor of Experimental Cancer Medicine at the Institute of Cancer Research in London and Consulting Medical Oncologist at the Royal Marsden NHS Foundation Trust, said:

“Olaparib is now one of the first precision drugs against prostate cancer. It’s the perfect example of how understanding a patient’s genetics and their cancer can be used to target the Achilles heel of the disease and personalize treatment.

“It is incredibly exciting to see this drug get approved in the US for this patient population. This is the result of so much hard work by scientists at the ICR over many decades. “

Try the latest treatments

A recent Phase I clinical trial led by Professor Johann de Bono and colleagues at The Royal Marsden tested a drug called berzosertib, the first in a new family of drugs that block an important DNA repair protein called ATR.

Typically, in a Phase I study, scientists are only trying to determine a safe dose for use and do not expect clinical benefit at such early stages of research.

Incredibly, in this study, more than half of the patients given berzosertib saw their cancer stopped growing. Some patients received the drug alone, while others received the drug in combination with chemotherapy.

Patients who had both in combination saw an even greater impact on their tumors, suggesting the drug allows us to tame cancer growth and kick it while it’s down.

These are just a few examples of the outstanding work done by scientists and clinicians in developing cancer treatments that require a deep understanding of the basic biology of cancer. Only when we thoroughly understand the problem can we develop the most effective solutions.