Treatment with arginine, one of the amino-acid building blocks of proteins, enhanced the effectiveness of radiation therapy in cancer patients with brain metastases, in a proof-of-concept, randomised clinical trial from investigators at Weill Cornell Medicine and Angel H Roffo Cancer Institute.
The study, published in Science Advances, reported the results of administering arginine, which can be delivered in oral form, before standard radiation therapy in 31 patients who had brain metastases. Nearly 78% had a complete or partial response in their brain tumours over the follow-up period of up to four years, while only 22% of the 32 patients who received a placebo prior to radiotherapy had such a response.
The trial was designed to gauge the effectiveness of arginine as a “radiosensitiser” that enhances the effects of radiation treatment. However, the results, and arginine's apparent mechanism of action, suggest that the amino acid might be useful more broadly as an anticancer therapy.
“Based on these findings we should continue to investigate arginine in combination with radiotherapy but also in combination with chemotherapy or immunotherapy, and even arginine on its own,” said senior author Dr Leandro Cerchietti, an associate professor of medicine in the Division of Haematology and Medical Oncology, who participated in designing and implementing the trial at Angel H. Roffo Cancer Institute in Argentina where he was an attending oncologist. The trial was co-led by Dr Alfredo Navigante at the Roffo Cancer Institute.
Arginine, also called L-arginine, is inexpensive and widely available, generally considered safe, and can get relatively easily from the bloodstream into the brain. The idea of using it to treat cancer arose from observations that tumours often aid their own survival by producing high levels of the related molecule nitric oxide (NO). The latter regulates multiple processes in the body including the flow of blood through blood vessels, and tumours’ cells often make more NO by upregulating their
production of special enzymes, called NO synthases, which synthesise NO from arginine.
Reducing NO production is one possible way of exploiting tumours’ dependence on this molecule, but hasn’t worked well, in part because of adverse side effects. The investigators hypothesised that boosting NO production instead, by adding its precursor arginine, might be beneficial, because while tumours can use NO to aid their growth and survival, they must keep its production below certain limits.
“Nitric oxide is a reactive molecule that on its own, or through other reactive molecules derived from it, can stress and damage a cell, so a cell can tolerate only so much of it,”said study lead author Dr Rossella Marullo, an instructor in medicine in the Division of Haematology and Medical Oncology at Weill Cornell Medicine.
Overloading a high-NO tumour with much more NO before radiation treatment could weaken the tumour’s ability to repair radiation-induced DNA damage, she added, and indeed, her preclinical experiments in mice confirmed this effect.
In the clinical trial, patients were treated with high-dose arginine or placebo oral suspensions an hour before radiotherapy for their brain metastases: tumours in the brain that represent the spread from primary tumours elsewhere, such as the lungs.
Six months after their courses of radiotherapy, 82% of the arginine group had improvement, or at least no worsening, of their neurological symptoms, compared with 20% in the placebo group. Most of the arginine-treated patients who died during the study did so because of their cancer’s spread elsewhere in the body.
Moreover, although metastatic cancer usually has a dire prognosis, there were some arginine-treated patients whose tumours in and outside the brain disappeared, suggesting the possibility of cures.
Evidence from this study and prior research also suggests that arginine
can not only directly hobble tumour cells but also boost the activity of anti-tumour immune cells, Cerchietti said.
The promising results have prompted the team to start and plan further studies of arginine on its own or in combination with other anticancer treatments.
“In principle any tumour that over-expresses NO-producing enzymes would be vulnerable to arginine treatment, and such tumours are very common,” said Cerchietti, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. He cautions that further studies are needed and patients should consult their doctor about the use of any supplements outside a clinical trial. The doses of arginine used in this study are available in formulations that can be obtained only at a medical facility.
The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases.
Rossella Marullo, Monica Castro, Shira Yomtoubian, M. Nieves Calvo-Vidal, Maria Victoria Revuelta, Jan Krumsiek, Andrew Cho, Pablo Cresta Morgado, ShaoNing Yang, Vanina Medina, Berta M. Roth, Marcelo Bonomi, Kayvan R. Keshari, Vivek Mittal, Alfredo Navigante, Leandro Cerchietti.
Published in Science Advances on 5 November 2021
Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate L-arginine decreases tumour lactate in BM patients.
In a placebo-controlled trial, we showed that administration of L-arginine before each fraction enhanced the effect of radiation, improving the control of BM. Studies in preclinical models demonstrated that L-arginine radiosensitisation is a NO-mediated mechanism secondary to the metabolic adaptation induced in cancer cells. We showed that the decrease in tumour lactate was a consequence of reduced glycolysis that also impacted ATP and NAD+ levels. These effects were associated with NO-dependent inhibition of GAPDH and hyperactivation of PARP upon nitrosative DNA damage.
These metabolic changes ultimately impaired the repair of DNA damage induced by radiation in cancer cells while greatly sparing tumour-infiltrating lymphocytes.
We showed that L-arginine administration directly affects the metabolism of cancer cells affecting their capacity of survival upon sublethal DNA damage, a mechanism that we therapeutically capitalised to increase the response to radiation therapy for patients with BM.
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