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Hamstrung. That is how Mark Kieran, MD, PhD, felt when treating children diagnosed with diffuse intrinsic pontine glioma (DIPG), a rare and deadly form of childhood brain cancer.
Little is known about DIPG tumors because, for a long time, no one was able to look inside them. The tumors grow aggressively in the pons, a nub in the brain stem at the base of the head, making biopsies particularly risky. "The brain stem is the nervous system's central relay station," says Liliana Goumnerova, MD, director of Neurosurgical Oncology at Dana-Farber/Children's Hospital Cancer Center (DF/CHCC). "It is so condensed that, if you injure even a small area, it can cause devastating effects."
Attempts to biopsy these tumors stopped in the 1980s because, far too often, the surgery resulted in paralysis and death. When it came to pontine gliomas, the dogma among neurosurgeons was clear: Do not touch them.
When biopsies stopped, so did progress in treating DIPG. About 200 children in the United States, typically between ages 4 and 10, are diagnosed with DIPG each year. For the last three decades, no treatment has increased survival times for those young patients. Without biopsies, researchers can only examine tumors after the fact, at which point the tumor has been changed by radiation and chemotherapy, leaving doctors with little but guesswork and frustration.
In 2003, Kieran, director of Medical Neuro-oncology at DF/CHCC, started lobbying to reintroduce DIPG biopsies to learn more about the disease and guide therapy. By then, surgical advances had made brain stem biopsies, which surgeons perform for other types of cancer and other conditions such as infection or multiple sclerosis, less risky.
While serious complications are still possible, modern techniques significantly lower risks by increasing precision and accuracy. Surgeons create a 3-D map of the tumor using magnetic resonance imaging (MRI). Computers then generate a point of entry at the skull base and map a safe needle trajectory to the tumor. Surgeons use laser sights and computer guidance to track the needle throughout the 2- to 3-hour procedure.
Despite the advances, no one wanted to consider DIPG biopsies. Year after year, Kieran stood up at conferences in front of fellow oncologists and neurosurgeons and presented his idea. And year after year, his colleagues were unmoved. "We thought that after 30 years of abject failure, people would be desperate to consider something new," says Kieran. "I guess they call it dogma for a reason. It is not easy to change."
The frustration grew, but Kieran did not stop trying. Then, in 2007, French surgeons broke ranks. They biopsied 24 children with DIPG with no mortality and only two complications. Soon after, Kieran convinced neurosurgeon Nalin Gupta, MD, PhD, from the University of California at San Francisco, to join him in advocating for change. For the first time, people were receptive. "Asking a surgeon to propose a surgical procedure was a fundamental twist," says Kieran.
Meanwhile, tumor tissue was becoming diagnostically valuable. Researchers started analyzing tumor tissue to identify oncogenes, genetic drivers of cancer that can be targeted by drugs. Today's technology allows decoding of a tumor's entire genome using just a tiny sample of tissue. "The surgeons made it so getting the sample wasn't as risky and the molecular biologists made it so we can actually learn something," says Kieran. "The two together made it possible to move forward."
Finally, in December 2011, Kieran and his colleagues received approval to start a phase 2 clinical trial to biopsy tumors of children with DIPG, test them for two molecular markers, and assign the children to one of four treatment strategies based on the results. The trial is now open at DF/CHCC. Nineteen other centers will soon join. The first patient to join the trial was Hailey Olson.
Hailey was just six years old, when, in late November 2011, her mother, Hilary Olson, noticed that one of Hailey's eyes had turned in and her smile drooped on one side. She took her to a neurologist, and an MRI confirmed the diagnosis, DIPG. At the time, Hailey's hair hung in a short bob because, just a few months earlier, she'd cut the rest of it off and donated it to Locks of Love, an organization that creates custom wigs for children with cancer. "She was so excited to be able to help kids with cancer," says her grandmother, Jeannie Olson. "Hailey has always been a giver."
A few days after the diagnosis, Hilary got a phone call. Through Kieran's trial, doctors could now biopsy the tumor. They would use the sample to match Hailey with a treatment plan and to learn more about DIPG.
"I thought, this was meant to be," says Hilary. "We're going to figure out what's going on and we're going to help other kids."
Hailey's biopsy, performed by Goumnerova in mid-December, went smoothly. As with all participants in the trial, Hailey will receive radiation therapy for 6 weeks and a drug called Avastin, which restricts the growth of blood vessels in and around the tumor, for one year. The doctors will use the biopsy to test for the presence of two proteins that indicate whether either or both of two additional drugs might be beneficial.
The immediate aim of the trial is to determine if any of the treatment strategies improve survival. "We used to treat everyone the same," says Goumnerova, who helped design the surgical protocols for the trial. "It is very exciting to be able to test for genetic abnormalities and assign each patient personalized therapy."
The trial will also scan the tumor tissue in an effort to find new molecular targets and, potentially, new drugs to treat the disease. For the families supporting this trial – all $2.5 million in funding came from family foundations – this effort brings hope that future families who face a DIPG diagnosis will have better treatment options.
So far, Hailey is doing well and has even shown some improvement with radiation. Her family is hopeful, but realistic. "There was never a question about the trial," says Jeannie. "What if somebody had done this 10 years ago and it saved Hailey?"
While only a handful of children have signed on to Kieran's trial, he has already – with the help of the pioneering French surgeons – begun to use tumor samples to better understand pontine gliomas. In 2011, Kieran convinced the French surgeons to share 20 of their samples with him. Molecular analysis of those samples revealed that about 20 percent expressed a mutation in the PI3K pathway, a cellular signaling pathway that controls cell death. That same mutation has been seen in other forms of cancer.
Kieran is now working with the pharmaceutical firm Novartis, which has developed an experimental drug that targets that pathway, to design a phase 1 clinical trial to test the safety of this drug in children confirmed – based on their biopsies – to have the PI3K mutation. "It's a proof of principle that this whole strategy could work," says Kieran.
It also stands as proof of the power of persistence, and how Kieran's relentless pursuit may soon begin to offer promise to a group of patients who once had none.
Elizabeth Dougherty is a freelance science writer based in central Massachusetts. Learn more about her writing.
Paths of Progress Fall/Winter 2012 Table of Contents