Scientists Tackle Lethal Childhood Brain Cancer

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Childhood Brain Cancer
Childhood Brain Cancer

Nine years ago on a Monday afternoon, Sandra Smith, a pastor’s wife and mother of three in DeWitt, Mich., learned she had an violent form of breast cancer. The actual bad news, though, would hit the family later that week.

At first they thought their youngest, six-year-old Andrew, was now battling the flu. Then he started vomiting. He’d also developed a facial droop, and his gait seemed off. Smith remembers wondering if they were “making a big contract out of nothing,” even as they rushed to the emergency room.

Nothing could be additional from the truth. An MRI scan exposed a large area of swelling in Andrew’s brain stem—clear evidence of a fatal childhood Brain cancer that naturally strikes between the ages of four and 10 and kills the majority within a year of analysis. Unlike the cells dividing non stop in Smith’s breast, her son’s cancer, called diffuse intrinsic pontine glioma (DIPG), could not be fought with surgery or conventional chemotherapy. In DIPG the malignant cells tangle with normal brain tissue in a region that controls critical functions such as breathing and heart rate, making it not possible for a surgeon to remove. In more than 200 drug trials nothing has worked better than emission therapy, which itself can only extend life a few short months in kids with DIPG. Andrew outlived the “typical” DIPG patient by surviving just over two years after his diagnosis, transitory away at the end of 2009.

DIPG accounts for about 10 % of childhood brain and spinal cord tumors. It is the second-the majority common pediatric brain tumor and the leading cause of cancer death in kids. Treatment options and continued existence rate for DIPG have not changed in 40 years—a quandary that likely helped nudge brain cancer past leukemia as the deadliest childhood growth in the nation, according to a recent report from the U.S. Centers for Disease manage and avoidance.

Today, however, the outlook for DIPG and other childhood brain cancers looks more promising, thanks to a surge of original study made possible by advances in gene-sequencing methods and tumor tissue donations from families who have lost children, such as Andrew, to these diseases. In new years researchers around the world have used patients’ tumor tissue to produce dozens of cell lines and mouse models to study the basic biology of pediatric brain cancers. The time is mature. In the dawn of accuracy medicine, which aims to modify disease treatment to the individual enduring, genetics and basic science findings suggest why past trials may have failed and are guiding possible and ongoing efforts to know effective therapeutics for these devastating 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 scientific 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 luxury,” Monje says. “I felt so close to this patient and was overwhelmed by my inability to help her.”

Back then there was little molecular data on DIPG. No animal models. No cell cultures. Generating such research tools needed tumor samples from patients. Yet since MRI scans can dependably diagnose typical DIPG and getting brain stem tissue is not trivial, biopsies were rarely done. With precious little tumor tissue to study in the lab, Monje says, research progress on DIPG had stalled for decades.

The tide started turning by 2007, 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 direct spine placement. That study refreshed longstanding labors by a pediatric neuro-oncologist Mark Kieran, clinical manager 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., at first without success.

By that time technological advances had complete it possible to read DNA sequences from minute bits of tissue, giving additional impetus for a tricky surgical process now shown to be safe in trained hands. The Boston team began offering patients genomic sequencing of their tumors biopsied at diagnosis and relapse, to “see how the tumor is developing and redirect the suitable drugs to it,” Kieran says. Tumor profiles could help determine which patients might advantage from a newer class of drugs called under attack therapies, which hit exact proteins in the tumor rather than just kill off any dividing cell. Targeted therapies are a foundation stone of precision medicine.

Since 2009 researchers at Dana–Farber have sequenced brain tumors in nearly 1,000 children. Among kids with tumors secret as a low-grade glioma, up to 10 percent have a change in a gene called BRAF that is seen in some adult skin tumors. 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 previous this month, Kieran reported that 23 of the 32 kids improved on the BRAF-inhibiting drug—a reply rate high sufficient that his team is offering continued therapy to trial participant with the change.

 

In 2012 Kieran and collaborators launched a clinical trial to biopsy tumors of children with DIPG, test them for more than a few molecular markers and, based on the results, assign one of four treatment strategies. Two years ago a team led by Sabine Mueller, a pediatric neuro-oncologist at the University of California, San Francisco, initiated another DIPG trial. This study probes patient tumors using a more complicated technique, whole exam sequencing, which scours the whole protein-indoctrination piece of the genome rather than just checking for pre-specified markers. Based on each patient’s tumor profile the U.C. San Francisco team future up to four drugs that seem appropriate. It will take one more one to two years to see if the drugs help.

Although helpful for some persons, precision medicine is luxurious, and some scientists suspect it may only self-effacingly improve the lives of cancer patients in general. Cells within a single tumor can obtain different mutations, such that “even if there is an effectual agent, it is likely to have limited benefit because molecular pathway that are active in other parts of the tumor will lead to tumor growth from different clones of tumor cells,” researchers wrote in a New England Journal of Medicinecommentary published in September. And without exact drugs approved for DIPG, there is continuing debate about whether biopsies offer real advantage to these patients.

Some labs have taken a less contentious route to DIPG samples—obtaining them as legacy gifts from families who agree to give tumor tissue once their child passes. Smith, the Michigan mom, learned about inheritance 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 horrific to me,” Smith recalls. “But I understood [that with no patient samples] there was no way for researchers to look at this tumor.” She shared the thought on a Yahoo group for DIPG families that she and her friend reasonable.

Autopsy tissue donations are logistically challenging. Once a child pass, the brain needs to be removed, with tumor hankie placed into disinfected tubes, within six hours. Yet patients tend to die at home, far from the medical center, sometimes in the middle of the night or during a blizzard on a holiday weekend. Some labs book on-call service from a tissue revival team close to where the child lives. To have the biggest crash, samples should go to labs that can get and process them the same day.

As Smith helped other families position growth donations, she got to know some of the leading DIPG researchers, including Monje, who had just worked out a way to culture cells from autopsy tissue and use those cells to make mouse models of DIPG. In July 2011 Smith learned of a seven-year-old girl named McKenna, who was battling DIPG. Smith and Monje worked with the family and “complete sure we had the necessary documents when the time came,” says McKenna’s mother, Kristine Wetzel, a high school teacher in Huntington seashore, Calif.

McKenna faded suddenly, and the family decided to donate her growth tissue within an hour of her death. Although painful, the choice was “surprisingly comforting,” Wetzel says. “It was a way to brawl back against the monster that had stolen our daughter.” The Wetzels have since helped other DIPG families with tumor donations and shaped a base to raise consciousness and fund research in pediatric brain cancer. The foundation wrap the cost of tissue donations to Monje’s lab and pays for a technician who preserve the lab’s DIPG cultures and has shipped samples to some 80 labs around the world. Support varies but more often than not amounts to about $100,000 per year, Monje says.

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.

A wave of papers by Baker, Kiernan and others at Washington University School of Medicine in St. Louis and elsewhere, revealed a surprise. Although DIPG has a gene signature distinct from other brain cancers, the rare childhood tumors share one striking feature: Nearly 80 percent of them have mutations in a gene that codes for a protein called histone H3. Histone proteins are like spools around which DNA wraps. A key player in epigenetics—the study of biological mechanisms that turn genes on or off—histones influence how easily DNA is accessed by enzymes that translate genetic code into working proteins. “Histone H3 is so fundamental…I would think lots of cancers would have these mutations,” Baker says. Yet they seem to be unique to DIPG and about a third of non–brain stem tumors in kids.

The genetic insights could not have come at a better time. Whereas some labs were busy plumbing whole genome sequencing data from DIPG tumor cells, others were testing potential drugs in cell cultures and mouse models generated from patient brain tumor samples. The idea was to carefully vet compounds in the lab before choosing which ones to test in a longer, costlier clinical trial. The approach is not revolutionary. Generally it is “the way you do medical research,” Monje says. But for DIPG, “we’d been unable to do this” for decades because there had been no cell cultures or experimental mice modeling the disease.

The situation improved in 2010 when Charles Keller, then at Oregon Health & Science University, organized a global screening attempt. By then many labs were creating cell cultures from DIPG tumor tissue. As co-chair of a committee proposing drugs for DIPG medical trials, Keller rallied the Monje lab and 12 other groups to pool capital for a collaborative study. His group dispensed 83 possible drugs onto well plates and sent them to the other labs for testing. At these far-flung labs researchers loaded the plates with DIPG cell cultures and looked for wells that turned blue—a substance sign that the drug was killing tumor cells. Top drug applicant also improved survival in mice with implanted DIPG tumors.

In adding, the labs cleanse genetic fabric from their DIPG cell lines and sent DNA and RNA samples to Oregon for sequencing to establish a clear tie between the cells’ gene glitch and drug response. Checking for these connections is key, Keller says, since many drugs that looked talented based on mutations in the DIPG cells showed no result in the cellular says.

But there emerged a winner—a drug called panobinostat, which slow up enzymes that chemically modify histone proteins. by accident, the U.S. Food and Drug Administration approved panobinostat as a treatment for another cancer, multiple myeloma, as the global screening manuscript went to press in Nature Medicine. The results helped open a clinical trial of panobinostat that opened for enrollment in May. Led by Monje, this trial 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 projectile, 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