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Reprogramming tumour cells using an antimalarial drug

17/02/2021

Results from a University of Oxford clinical trial have shown that the anti-malarial drug Atovaquone can reduce very low oxygen tumour environments, which has the potential to make cancers behave less aggressively and to improve the impact of everyday cancer treatments.

Cancers metabolise a large amount of oxygen in order to create the energy needed to divide, grow and spread rapidly. This results in oxygen-starved, or 'hypoxic', environments around tumour cells.

This is problematic as hypoxic tumours behave more aggressively and are more resistant to most treatments, especially radiotherapy, which relies on oxygen to attack cancer cells. Previous studies have shown that to destroy tumours in hypoxic environments doses of radiation need to be three times higher than in oxygen-rich environments.

Researchers from the University of Oxford and Oxford University Hospitals (OUH) NHS Foundation Trust have investigated the potential for the commonly used antimalarial and pneumonia drug Atovaquone to improve lung tumour receptiveness to cancer treatments such as chemotherapy and radiotherapy.

The ATOM study, published on 17 February 2021 in the Clinical Cancer Research journal, administered Atovaquone to patients with non-small cell lung cancer before the surgical removal of their tumours. Using state-of-the-art scans to measure tumour hypoxia, this study found that tumours had 55 percent less hypoxic volumes than those who didn't receive the drug.

Following genetic analysis, it was shown that Atovaquone successfully disrupted the metabolic pathways of the tumour that are involved in the consumption of oxygen to create energy for tumour cells. The drug successfully reprogrammed the tumour cell metabolism so that more oxygen was present around the tumour, making it more susceptible to treatments.

Atovaquone is a highly promising clinical drug, as it is already in wide circulation in the prevention and treatment of malaria. As an FDA-approved drug that is cheap and has hardly any side effects, it could be quickly adopted into clinical use if shown to improve the impact of cancer treatments such as radiation therapy.

Laboratory experiments have shown its effect is not lung cancer-specific and it is likely to decrease the hypoxic environment of many types of tumour and so may improve treatment outcomes for many different cancer patients.

Professor Geoff Higgins, Consultant Oncologist at OUH and lead researcher of the ATOM study, said:

"Although radiotherapy is already an extremely effective treatment, there is scope to further increase its ability to cure patients. Reprogramming a cancer cell to make it more receptive is one way of doing this.

"I'm delighted that the results from the study are so positive so that we can take the next step towards repurposing a well-established drug as a new, effective anti-cancer treatment."

Professor Higgins' team is now investigating the potential of this drug further in a study called the ARCADIAN trial. In this study they hope to demonstrate the safety of using Atovaquone in combination with chemotherapy and radiotherapy, before assessing whether combining this drug with such treatments improves survival of patients with lung cancer.

The ATOM study was funded by the Howat Foundation, which supports translational research for the benefit of cancer patients.