An international team led by researchers from Baylor College of Medicine, Texas Children’s Hospital, McGill University and the University of Pittsburgh School of Medicine has discovered what drives the growth of a deadly pediatric brain tumor called posterior fossa type A (PFA) ependymoma.
Researchers report in the journal Nature Androgens, commonly known as male hormones, promote the growth of PFA ependymomas, but not other brain tumors. Importantly, blocking androgen signaling reduces tumor proliferation. The findings open the possibility of a novel treatment approach for this currently untreatable childhood cancer.
“What causes the growth of PFA ependymomas has long been a mystery,” said Dr. Jiao Zhang, co-first author and assistant professor of Pediatrics – Hematology/Oncology at Baylor and Texas Children’s. “Unlike other malignant brain tumors, this cancer lacks clear genetic drivers, which has delayed the development of effective treatments. In the present work, we studied the tumor from a different angle.”
Previous studies have shown that most PFA ependymoma patients are male and their survival rates are lower than that of females. Yet the mechanisms underlying these gender differences remain unknown. It is also known that, in populations with similar early developmental stages, female brain cells appear to progress further in their development than those of males.
“Sex differences play an important role in cancer development,” Zhang said. “We decided to study whether gender differences could explain why boys are more susceptible than girls to PFA ependymoma. Understanding how gender-specific factors contribute to PFA tumor progression and therapeutic response could potentially help us develop better treatments to improve the survival and quality of life of affected children.”
Working with animal models and cancer cells developed in the laboratory, the team investigated whether the observed gender difference in susceptibility to PFA ependymoma depended on sex chromosomes – XX for women and XY for men – or on sex hormones – androgens in men and estradiol or progesterone in women.
“We found that, as it happens in normal brain cells, PFA ependymoma cells grow less in male than in female patients,” Zhang said. “This difference is driven by androgens, which keep these tumor cells in a less-developed, growth-prone state. We did not see any differences due to chromosomal factors, and female sex hormones did not alter PFA cell growth compared to controls.”
Further studies supported this observation, showing that androgen supplementation promotes the growth of PFA ependymomas and enhances their low-growth properties.
“Our study provides a biological basis for understanding the long-recognized gender difference in PFA ependymoma.” said co-corresponding author Dr. Claudia Kleinman, professor in the Department of Human Genetics and investigator at the Lady Davis Institute for Medical Research, McGill University.
“We reveal a previously unknown link between early hormone exposure and tumor formation, and we suggest that anti-androgen therapy may be a promising treatment option for this devastating disease,” said co-author Dr. Kulandaimanuvel Antony Michelraj, assistant professor of neurological surgery at the University of Pittsburgh School of Medicine.
“Our findings have potential clinical implications because they suggest that androgen-blocking treatments may represent a rational direction for targeted treatment strategies in the future,” said co-corresponding author Dr. Michael D. Taylor, professor of pediatrics – hematology/oncology and neurosurgery at Baylor and staff neurosurgeon at Texas Children’s.
