A team of TFRI-funded scientists at the Princess Margaret Cancer Centre in Toronto has made a discovery that could unlock precision medicine treatments for patients diagnosed with triple negative breast cancer (TNBC), an aggressive form of disease that tends to affect younger women.
In a study published in Nature Communications (August 2020), the team led by Drs. Cheryl Arrowsmith and Mathieu Lupien, revealed that RB1, a protein involved in cell metabolism, is over-expressed in some patients with TNBC. They also found that the expression of this protein could be a biomarker for positive response to a metabolic drug-like compound.
“Our discovery is a first step to develop targeted therapies for TNBC,” said Dr. Lupien, a senior scientist at Princess Margaret and Associate Professor in the Department of Medical Biophysics at the University of Toronto. "TFRI’s support was instrumental. It enabled clinicians and scientists to work towards a shared goal."
Altered metabolism drives explosive cancer growth
All cancers have altered metabolic states, explains Dr. Arrowsmith, who is also a senior scientist at Princess Margaret and the Chief Scientist for the Structural Genomics Consortium Toronto laboratories.
According to Dr. Arrowsmith, the explosive growth of cancer cells requires huge amounts of energy, such as glucose, to nourish their survival and growth. Because of this, cancer researchers often search for metabolic vulnerabilities that can be exploited to stop cancer growth.
In this particular case, the research team used a collection of different patient-derived cell lines from TNBC to test whether they were sensitive to ‘chemical probes’ (experimental, drug-like compounds) that inhibit a protein called GLUT1, part of the pathway transporting glucose into a cell to increase metabolic energy. The team found that cells with varying levels of RB1 were particularly sensitive to these GLUT1-inhibiting compounds.
By blocking this pathway, the compounds essentially “starved” the cancer cells, demonstrating this as a promising target for new anticancer approaches.
This work shows that differing levels of RB1 can be used as a biological biomarker to discriminate between treatment responders and non-responders in the future, says Dr. Arrowsmith.
A much needed advance
Triple negative breast cancer is a highly aggressive subtype of breast cancers, representing 15-20% of breast cancer cases, but accounting for 25% of breast cancer deaths. In addition, it has a higher metastatic rate within five years of diagnosis and poorer overall survival rate compared to receptor positive cancer subtypes.
Scientists don’t know why, but this cancer is also more common among Black and younger women.
“There are no precision medicine treatments for this disease,” says Dr. Lupien, “so patients are treated with chemotherapy because we don’t have a defined therapeutic target. Initially, it works for some patients, but close to a quarter of patients recur within five years from diagnosis, and many develop chemotherapy-resistant tumours.
“These savage statistics mean that we must improve our understanding of the molecular basis for this cancer’s development to discover effective, precise targets for drugs, and a companion test to identify which patients are most likely to benefit the most from such a therapy.”
GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer
Qin Wu, Wail ba-alawi, Genevieve Deblois, Jennifer Cruickshank, Shili Duan, Evelyne Lima-Fernandes, Jillian Haight, Seyed Ali Madani Tonekaboni, Anne-Marie Fortier, Hellen Kuasne, Trevor D. McKee, Hassan Mahmoud, Michelle Kushida, Sarina Cameron, Nergiz Dogan-Artun, WenJun Chen, Yan Nie, Lan Xin Zhang, Ravi N. Vellanki, Stanley Zhou, Panagiotis Prinos, Bradly G. Wouters, Peter B. Dirks, Susan J. Done, Morag Park, David W. Cescon, Benjamin Haibe-Kains, Mathieu Lupien & Cheryl H. Arrowsmith
This study was partially funded by a Terry Fox Program Project Grant to New era of precision medicine in triple-negative breast cancer