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12th November 2021
The use of oral arginine increased the effectiveness of radiation therapy in patient with unresectable brain metastases from solid tumours. This was the conclusion of a study by researchers from the Hematology and Oncology Division, Cornell University, New York, USA. Brain metastases (BMs) occur in 10% to 20% of adult patients with solid organ cancers and are 10 times more common than primary brain tumours. Use of compounds that improve blood flow to tumours might enhance the efficacy of both chemo- and radiotherapy and one suggested agent is nitric oxide (NO) which has been shown to act as an intrinsic radio-sensitiser in vivo.
For the present study, the US researchers considered the use of arginine, which is an endogenous substrate of the nitric oxide synthase enzyme, that naturally produces NO. Although its use in cancer patients has not previously been examined, data from patients with acute metabolic strokes has shown that administration of arginine therapy yields significant therapeutic benefit. Based on the fact that the amino acid appears to have a metabolic effect, the researchers measured levels of the tumour lactate concentration, in patients with BMs, which serves as a biomarker and driver of radio-resistance. The results showed that arginine consistently and significantly reduced tumour lactate concentrations in a small number of patients with BMs. Based on these findings the team undertook a proof-of-concept randomised trial to explore whether arginine increased the effect of radiation therapy in patients with unresectable BM from solid tumours.
A total of 63 patients with solid tumour cancers (including breast, melanoma and non-small cell lung cancer) and BMs were randomised to placebo (32) or oral arginine (10g) which was given 60 minutes before radiation therapy. Patients were followed for a median of 5 months and the overall response rate was 22% in the placebo group but 77.4% in the arginine arm, with a symptomatic response rate of 50% and 93.5% (placebo vs arginine, p = 0.002). In addition, the number of patients free from neurological progression at 6 months was 82% for arginine but only 20% for placebo. Finally, disease progression was observed in only 9.6% of those taking arginine compared to 43.7% of the placebo group.
The authors also reported that in those receiving arginine, functional imaging revealed a marked reduction in tumour lactate concentration, suggesting that the amino acid induced a metabolic effect on cancerous cells. They concluded that the amino acid could be used therapeutically in combination with radiation therapy in patients with brain metastases.
Marullo R et al. The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases. Sci Adv 2021
13th October 2021
There are limited treatment options for people with breast cancer that has spread to the brain and a lot of drugs are unable to reach these tumours because of the brain’s natural protection, meaning new treatment discoveries are urgently needed.
Talazoparib is an existing PARP inhibitor drug which works by preventing cancer cells with altered BRCA genes from repairing their DNA, forcing them to die. Although the drug is licensed for use in certain patients with BRCA mutated, HER2 negative locally advanced or secondary (metastatic) breast cancer, it hasn’t been assessed for use on the NHS
Now, a team led by Professor Leonie Young and Dr Damir Vareslija from RCSI University of Medicine and Health Sciences will investigate if the drug could be used to treat secondary breast cancer in the brain.
Through previous research, which analysed tumour samples donated by people whose breast cancer has spread to the brain, the team established that almost half of the tumours had changes in the way they repair their DNA and this could make these tumours vulnerable to PARP inhibitors like talazoparib.
Using tumours and breast cancer cells donated by patients, researchers will now test in the lab if talazoparib is effective in treating secondary breast cancer in the brain. Through further tests using mice and sophisticated laboratory models mimicking the brain’s protective system, the researchers will see if the drug can also reach tumours in the brain. The researchers aim to identify key features of a tumour that responds to this type of treatment to establish who could benefit most.
The study is being funded by the Breast Cancer Now Catalyst Programme, which aims to accelerate progress in world-class breast cancer research through innovation and collaboration. As part of the Programme, Pfizer have provided Breast Cancer Now with funding through an independent medical research grant and given the charity’s researchers access to several Pfizer medicines.
Professor Leonie Young, Professor in the Department of Surgery at RCSI University of Medicine and Health Sciences said: “Our previous research has shown that, in many cases, secondary breast cancer tumours in the brain have changes in the way they repair their DNA and we believe this could make them vulnerable to PARP inhibitor drugs like talazoparib.
“People are always at the heart of the research we do and we are always trying to answer questions that are important to our patients. The support of Breast Cancer Now will enable us to learn more about the effectiveness of these powerful drugs to hopefully treat people with secondary breast cancer which has spread to the brain in the future.”
Dr Simon Vincent, Director of Research, Support and Influencing at Breast Cancer Now, said: “An estimated 35,000 people in the UK are living with incurable secondary breast cancer, and the fear and uncertainty around when this devastating disease will cut their lives short. We desperately need to discover new ways to treat this incurable disease, including for those whose breast cancer has spread to the brain and who have very limited treatment options.
“That’s why we’re delighted, this Secondary Breast Cancer Awareness Day, to announce that we’re funding Professor Young’s project through The Breast Cancer Now Catalyst Programme. We hope this study will be successful and lead to effective new treatments for those who badly need them.”