Following a three-year, joint study conducted by researchers at McGill University and the University of British Columbia, and partially funded by TFRI, the dietary supplement alanine has been found to be effective in the treatment of aggressive cancers in preclinical models, such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), a rare and lethal tumour that occurs predominantly in women in their mid-twenties.
SCCOHT is characterized by recurrent loss-of-function mutations in the SMARCA4 gene which provides instructions for making a protein called BRG1, a tumour suppressor that keeps cells from growing and dividing too rapidly or in an uncontrolled way. In addition to SMARCA4 inactivation, SCCOHT tumour cells do not express the SMARCA2 gene which encodes BRM, another tumour suppressor closely related to BRG1. Dual loss of SMARCA4/2 is also found in other malignancies including a subset of lung cancers. Currently, there are few effective treatments available for these SMARCA4/2-deficient cancers, which are often highly resistant to conventional chemotherapies and have very poor outcomes.
According to Sidong Huang, associate professor of biochemistry at McGill- and the Rosalind and Morris Goodman Cancer Institute, and co-lead author of the report recently published in Nature Communications, “What we essentially uncovered is a metabolic dependency of these tumour cells. SMARCA4/2 loss triggers a metabolic shift in cancer cells, resulting in a preference for utilizing glutamine over glucose as the primary carbon source to fuel the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS).
Consequently, SMARCA4/2-deficient cancer cells and tumours are highly sensitive to clinically available inhibitors targeting OXPHOS, as well as the supplementation of alanine that competes with glutamine import, providing multiple potential effective treatment options for targeting these hard-to-treat malignancies.”
“Through an unbiased genome-wide screen, our teams identified the key metabolic change that enables the development of the aggressive SMARCA4/2-deficient cancers,” adds co-lead author Yemin Wang, staffscientist at British Columbia Cancer Research Institute and adjunct professor at the University of British Columbia. “This finding not only helps us better understand the biology of these cancers, but also provided multiple putative treatment strategies, alone or in combination with chemotherapy or immunotherapy, for clinical validation.”
As with the other amino acids, alanine is found in meat and poultry, fish, eggs and dairy products, as well as some protein-rich plant foods. It is also available in powder form as a dietary supplement, sold by health food retailers. It has been known to boost the body’s immune system and is popular within the body-building community.
Having established alanine’s efficacy in the lab, Professor Huang is anxious to take it to clinical trials. “The next important stage is to have proper clinical testing to be conclusive, to say whether or not this is actually effective. Even though it is very safe for most people, if you have an underlying condition such as a metabolism disease, it might not be safe to take this. We just want to be sure patients can tolerate high-dose alanine. It’s important to talk to your doctor.”
The researchers are currently involved in efforts to present the research findings to the oncology community. “We hope that our study will spike interest and initiate a clinical study, and at the same time, continue to understand, as we have shown in the paper, that alanine is effective against tumours, in combination with other treatments such as immunotherapy, and so on,” says Prof. Huang.
Funding from TFRI is provided through the Terry Fox New Frontiers Program Project Grant in New Vistas on Cancer Biology and Treatment: Conceptual Advancements from the Forme Fruste Project, led by Dr. David Huntsman (UBC, BC Cancer), based in BC. “This is exactly the type of discovery our TFRI program was built to make," says Huntsman, "where studying a very rare cancer could lead to impactful insights into how to treat that and more common cancers.”
A second TFRI PPG titled Precision Oncology for Endometrial Carcinoma Patients also funded work by Yemin Wang.
Adapted from a McGill University press release.