Cancer immunotherapy is 2.5 times more effective for mitochondrial DNA mutations

Cancer immunotherapy is 2.5 times more effective for mitochondrial DNA mutations

Concept art biology and genetics of cancer cell

Scientists have discovered that mutations in mitochondrial DNA can predict a patient’s response to immunotherapy, which could lead to more personalized and effective cancer treatments. Credit:

A pioneering study showed that mitochondria DNA Gene mutations are key indicators of a patient’s likelihood of responding to immunotherapy, revolutionizing cancer treatment approaches.

Scientists funded by Cancer Research UK have made an unusual discovery that could help identify patients who are up to two and a half times more likely to respond to currently available cancer drugs.

Scientists at Cancer Research UK in Scotland and Memorial Sloan Kettering Cancer Center in the USA have “rewired” the DNA of mitochondria – the energy factories found in every living cell. They found that creating mutations in parts of this DNA determines the extent to which the cancer responds to immunotherapy, which are treatments that harness the body’s natural defenses to attack cancer cells.

This discovery opens new ways to identify patients who could benefit most from immunotherapy by testing for mitochondrial DNA mutations. Half of all cancers have mutations in mitochondrial DNA (mtDNA), and this discovery shows for the first time that they can be exploited to improve cancer treatment.

In the future, combining treatments that mimic the effect of these mutations with immunotherapy may increase the chances of successful treatment for multiple types of cancer.

In a paper published in the journal Cancer of nature Today (January 29).y), scientists have demonstrated for the first time a direct link between mitochondrial DNA (mtDNA) mutations and response to cancer treatment. Surprisingly, they found that tumors with high levels of mtDNA mutations were up to two and a half times more likely to respond to treatment with the immunotherapy drug nivolumab.

Nivolumab works by releasing the “brakes” on the immune system to attack cancer cells. It is currently used to treat many different types of cancer, including skin cancer, lung cancer, liver cancer, and bowel cancer. Scientists believe they could routinely test for mitochondrial DNA mutations in the future, enabling doctors to know which patients will benefit most from immunotherapy before starting treatment.

They also believe that mimicking the effects of mitochondrial DNA mutations could make treatment-resistant cancers sensitive to immunotherapy, enabling thousands of cancer patients to benefit from this pioneering treatment.

The technology behind the discovery is now the subject of patents filed by Cancer Research Horizons, the innovation arm of Cancer Research UK. This will help bring technology to market to allow the development of new treatments that disrupt the energy sources that cancer uses to spread and grow. To date, Cancer Research Frontiers has brought 11 new cancer drugs to market, which have been used in more than six million cancer treatment courses worldwide.

Group Leader at Cancer Research UK in Scotland and University of Glasgow Co-lead author of the study, Dr Payam Gammage, said:

“Cancer is a disease that affects our bodies. Because cancer cells can look similar to healthy cells on the outside, getting our immune system to recognize and destroy cancer cells is a complex task.

“More than half of all cancers have mutations in mitochondrial DNA. But when we engineered these mutations in the lab, we found that tumors with the most mutated mitochondrial DNA were more sensitive to immunotherapy.

“Thanks to this research, we now have a powerful tool that gives us a completely new approach to stopping cancer in its tracks.”

Assistant computational oncologist at Memorial Sloan Kettering Cancer Center and lead author of the study, Dr. Ed Resnick, said:

“Mitochondrial DNA has been a mystery for decades. Each cell contains thousands of copies, and until now it has been very difficult to consistently engineer mutations to study how mtDNA mutations affect cancer.

“For the first time, we can see exactly what mitochondrial DNA mutations do when we create them in the lab. But what surprised us was how much the cells surrounding the tumor were affected, which we could exploit to make the tumor susceptible to treatment.

“This research opens up a whole world where we can rewire tumors’ energy sources — and potentially shorten them to beat cancer sooner.”

Cancer Research UK’s Executive Director of Research and Innovation and Chief Executive of Cancer Research Horizons, Dr Ian Foulkes, said:

“After years of painstaking laboratory research funded by Cancer Research UK, we have identified a vital vulnerability in cancer. Mitochondrial DNA mutations are a common part of cancer, and this amazing discovery has limitless potential.

“Therapies that exploit overburdened mitochondria in cancer are now possible. We now need clinical trials to find out which combinations work best in which patients. Through our innovation engine, Cancer Research Frontiers, we plan to accelerate this discovery into the clinic and ensure as many as possible benefit.” Of patients.

The paper will be published today (January 29).y) in Cancer of nature.

Reference: “Mitochondrial DNA mutations drive aerobic glycolysis to promote checkpoint blockade in melanoma” 29 January 2024, Cancer of nature.
doi: 10.1038/s43018-023-00721-s

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