MONTREAL DOCTORS MAY HAVE FOUND AN ‘UNPRECEDENTED’ TREATMENT FOR THE MOST COMMON OF ALL RARE DISEASES AND IT INVOLVES A REPURPOSED CANCER DRUG. ‘WE HAVE A GLIMMER OF HOPE HERE.’
Cancer drug used to reverse lethal symptom
IT MAY COME BACK VERY QUICKLY AND BE VERY DIFFICULT TO CONTROL.
• Lyana Deslauriers was born with eyes a magnetic, ethereal blue, lowset ears and a heart two sizes too large.
That thick, dense heart would keep growing and threaten to kill the Joliette, Que., toddler before her Montreal doctors tried something never before attempted — a “Hail Mary” that could turn the world’s most common, incurable rare disease into a treatable one.
For the first time in the history of Noonan syndrome, a genetic condition that prevents various parts of the body from developing normally and that afflicts one baby in every 2,500 born, Montreal doctors have reversed the most lethal symptom: hypertrophic cardiomyopathy, an excessive thickening of the heart that, in its most severe form, kills 70 per cent of babies before they turn a year old. The doctors used a repurposed cancer drug to keep Lyana’s heart from essentially suffocating itself, and they’re now preparing to stop treatment in the hope the disease has essentially burned itself out. There is no guarantee, however, that it won’t come roaring back. “It may come back very quickly and be very difficult to control, or it could remain as is,” said pediatric cardiologist Dr. Gregor Andelfinger, of the Université de Montréal and Saint-Justine Hospital. Lyana’s mother, Lynn, was eight months pregnant when a routine ultrasound showed something doctors at first couldn’t fully explain: Lyana’s heart structure seemed off.
More sophisticated scans showed all four valves, the flaps that open and close with each heartbeat to allow blood to flow in or out, were abnormal, and the heart muscle worryingly thick. Lynn was kept in hospital until Lyana was born in November 2017, and when the baby was delivered she was whisked off to the neonatal intensive care unit before Lynn could hold or see her. It was there the picture became clear: Lyana’s face — the extra fold of skin in the inner corner of her eyes, the grove between her nose and mouth — spoke Noonan’s. Noonan syndrome is a RASopathy. RAS genes make proteins that control how cells communicate with one another. A chain of proteins transmits signals from a loading dock outside the cell to the nucleus inside, like runners in a relay race passing a baton. When the final runner in that cell-signalling pathway reaches the nucleus, the cell is instructed to respond in one of several ways: divide, multiply or die. With Noonan mutations, the RAS genes become hyperactive, disrupting the normal flow of conversation between cells. The cells can start proliferating madly, causing hyper or too little growth in the affected tissues. About a third of children are born with some sort of heart defect — none as potentially lethal as rapidly progressing hypertrophic cardiomyopathy, the condition threatening Lyana’s life. The muscle cells become too thick, as does the heart as a whole. The muscle stiffens, making it hard for the organ to relax, and the thickening blocks the flow of blood out of the heart — and while it usually affects just the left ventricle, the main pumping chamber, both sides of Lyana’s heart were obstructed. So were her valves.
Three days after birth, the doctors started Lyana on the standard treatment — aggressive doses of Propranolol, a drug that reduces the force of contraction of the heart muscles. But with each week her heart grew thicker. When they maxed out the Propranolol, the Montreal team considered a mechanical assist device. But with very young kids with little, thickened hearts, it’s extraordinarily difficult getting the devices in.
They needed something to buy time, and quickly. Andelfinger reached out to Dr. Bruce Gelb, a pediatric cardiologist at Mount Sinai Hospital in New York City who discovered of some of the first Noonan genes. Gelb knew of another baby in Germany with a different mutation in the same gene as Lyana who was in even more dire shape, connected to a ventilator in intensive care. The Montreal and German researchers went into the literature. Over the years, scientists had begun to realize that the mutations that drive Noonan’s overlap with the mutations that drive about a third of human cancers — solid tumours like breast cancer, lung cancer and melanoma. Teams had started experimenting with mice genetically engineered to develop human Noonan’s. When the mice were treated with an anti-cancer drug that blocked the growth cycle, the effects disappeared.
The researchers began administering the cancer drug trametinib to Lyana and her German counterpart. Lynn and her husband Joel were told there were no guarantees of success, and no guarantees there would be no “deleterious effects.” The parents consented.
The treatment began when Lyana was 14 weeks old. After three months, the improvement was dramatic: Both babies’ hearts began shrinking. Now, after more than 17 months of treatment, Lyana’s heart has gone from a heart triple its normal size “to pretty much a normal heart,” Andelfinger said. The findings are published this week in the Journal of the American College of Cardiology. If they hold in larger studies, they will be unprecedented.