Scientists Tackle Lethal Childhood Brain Cancer
In precision medicine era legacy gifts of patient brain tissue reveal disease mechanisms and new therapeutic approaches.
Sandra Smith, a pastor’s wife and mother of three in DeWitt, Mich. and her son were both diagnosed with cancer during the same week. She with an aggressive form of breast cancer and her son, six-year-old Andrew, with Diffuse Intrinsic Pontine Glioma (DIPG), a fatal childhood brain cancer that typically strikes between the ages of 4-10 and kills most within a year of diagnosis.
In DIPG, the malignant cells entwine with normal brain tissue in a region that controls critical functions such as breathing and heart rate, making it impossible for a surgeon to remove the tumour. Radiation therapy has been proven to be the only treatment that helps, and then only to extend life by a few short months. Andrew outlived the “typical” DIPG patient by surviving just over two years after his diagnosis, passing away at the end of 2009.
DIPG accounts for about 10% of childhood brain and spinal cord tumours. It is the second-most common paediatric brain tumour and the leading cause of cancer death in children. Treatment options and survival rate for DIPG have not changed in 40 years.
Today, however, the outlook for DIPG and other childhood brain cancers looks more promising, thanks to a surge of new research made possible by advances in gene-sequencing methods and tumour tissue donations from families who have lost children, such as Andrew, to these diseases.
Michelle Monje, an assistant professor of neurology at Stanford University, first encountered DIPG around 2002 as an MD/PhD student there. Working with her clinical mentor to care for a nine-year-old girl dying of DIPG, it was “the first time I’d come upon a disease we had no idea how to treat,” Monje says. “I felt so close to this patient and was devastated by my inability to help her.”
In those days there was minimal molecular data on DIPG; no animal models and no cell cultures, because generating these types of research tools requires tumour samples from patients. Because MRI scans can reliably diagnose typical DIPG and getting brain stem tissue is not trivial, biopsies were rarely done. Due to the minimal alount of tumour tissue to study in the lab, research progress on DIPG had stalled for decades.
Around 2007 this changed when a team of surgeons in France reported safely obtaining biopsy samples from 24 children with DIPG using stereotactic techniques that use computer imaging to guide needle placement. That study invigorated longstanding efforts by a paediatric neuro-oncologist Mark Kieran, clinical director of the Brain Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who had spent years pushing for DIPG biopsies in the U.S., initially without success.
Since 2009 researchers at Dana-Farber have sequenced brain tumours in nearly 1,000 children. Among kids with tumours classified as a low-grade glioma, up to 10% have a mutation in a gene called BRAF that is seen in some adult skin tumours. A few years ago, 32 children from Europe and North America with BRAF-positive gliomas entered a clinical trial of dabrafenib, a targeted therapy approved for melanoma patients with this mutation. At a conference in Copenhagen earlier this month, Kieran reported that 23 of the 32 kids improved on the BRAF-inhibiting drug—a response rate high enough that his team is offering continued therapy to trial participants with the mutation.
In 2012 Kieran and collaborators launched a clinical trial to biopsy tumours of children with DIPG, test them for several molecular markers and, based on the results, assign one of four treatment strategies. Two years ago a team led by Sabine Mueller, a paediatric neuro-oncologist at the University of California, San Francisco, initiated another DIPG trial.
Although helpful for some individuals, precision medicine is expensive, and some scientists suspect it may only modestly improve the lives of cancer patients in general. Cells within a single tumour can acquire different mutations, such that “even if there is an effective agent, it is likely to have limited benefit because molecular pathways that are active in other parts of the tumour will lead to tumour growth from different clones of tumour cells,” researchers wrote in a New England Journal of Medicine commentary published in September. And without specific drugs approved for DIPG, there is ongoing debate about whether biopsies offer real benefit to these patients.
Some labs have taken a less controversial route to DIPG samples – obtaining them as legacy gifts from families who agree to donate tumour tissue once their child passes. Smith, the Michigan mom, learned about legacy gifts through an online DIPG support group in spring of 2008, a half year after her son Andrew was diagnosed. Reading that post about removing the brain after death and donating the tissue “was horrifying to me,” Smith recalls. “But I understood [that without patient samples] there was no way for researchers to look at this tumour.”
This led to Andrew’s mom facilitating donations of other DIPG children’s brains once they had passed, and put her in contact with Monje, who had just worked out a way to culture cells from autopsy tissue and use those cells to create mouse models of DIPG.
Autopsy tissue donations have “transformed the research landscape from an unapproachable problem, due to lack of material for research, to an unprecedented analysis of the DIPG genome,” says neurobiologist Suzanne Baker, who helps lead the Neurobiology and Brain Tumor Program at St. Jude Children’s Research Hospital.
Further studies have revealed a lot about the DIPG gene signature, and a collaborative study of 83 potential drugs at 13 far-flung labs revealed some interesting results:
A drug called panobinostat, which inhibits enzymes that chemically modify histone proteins and which is U.S. Food and Drug Administration approved for the treatment of multiple myeloma, showed some interesting results, which were published in the journal Nature Medicine.
The results helped launch a clinical trial of panobinostat, led by Monje, that will measure side effects and determine the best doses of the drug for treating children with DIPG. Panobinostat is not going to be a silver bullet, however. The lab data showed some DIPG cells develop resistance to the drug, suggesting it will need to be combined with other therapies to achieve a survival benefit in patients
One challenge with panobinostat is shared by many brain cancer therapies—delivering them effectively into the brain.
“Many drugs don’t cross the blood–brain barrier so they are not getting to the tumour,” says U.C. San Francisco’s Mueller.
Some researchers are using a procedure called convection-enhanced delivery to place drugs through small catheters directly into the brain tumour. Others are using nanotechnology to reformulate drugs so they can be more specific and durable – e.g. by inserting molecular tags that direct the drug to molecules found uniquely on the tumour.
“It is possible that good drugs for DIPG already exist,” Mueller says, but “we just don’t know how to deliver them correctly.” She is planning a future trial using convection-enhanced delivery of panobinostat in kids with DIPG.
In the meantime Monje’s lab and other groups are doing additional drug screens with epigenetic agents and combination regimens.
The Wetzels, one of the DIPG families who donated their late daughter McKenna’s tumour tissue for research, have since helped other DIPG families with tumour donations and also created the McKenna Claire Foundation to raise awareness and fund research in pediatric brain cancer. The foundation covers the cost of tissue donations to Monje’s lab and pays for a technician who maintains the lab’s DIPG cultures and has shipped samples to some 80 labs around the world. Support varies but usually amounts to about $100,000 per year, Monje says.
Posted on 1 November, 2016, in Blog, Brain Cancer, Research and tagged brain cancer, brain cancer awareness, cancer, cancer cells, cancer research, cancer treatment, childhood brain cancer, childhood cancer, Childhood Cancer Awareness, DIPG, LFCT, Little Fighters Cancer Trust, paediatric cancer. Bookmark the permalink. Leave a comment.