How a new research initiative is empowering U-M physician-scientists to fight DIPG, one of the deadliest brain cancers, in innovative ways.
Brain tumors don't get much worse than diffuse intrinsic pontine gliomas. Highly aggressive brain tumors found at the base of the brain, DIPGs are inoperable. Cruelly, they are almost exclusively diagnosed in young children, and they are deadly — without exception.
To combat DIPG, Michigan Medicine's newly established Pediatric Brain Tumor Research Initiative recently announced its second round of internal grants for faculty researchers. The ChadTough Foundation, in memory of 5-year-old Chad Carr, the grandson of former Michigan football coach Lloyd Carr, generously funded the grants.
"The incredible work of the ChadTough Foundation has opened doors and generated an unprecedented level of interest in pushing the limits of what we know about DIPG," says Valerie Opipari, M.D., a pediatric oncologist and the chair of the Department of Pediatrics at University of Michigan C.S. Mott Children's Hospital. "Chad and the kids we see here each day who are fighting this terrible disease are what's driving us to find cures."
"University of Michigan has always been known for taking on the toughest, most challenging problems," adds Eric Fearon, M.D., Ph.D., director of University of Michigan Comprehensive Cancer Center. "We have turned our attentions now to DIPG, and our faculty is doing incredible work in this area."
While the field of pediatric cancer research has seen a number of breakthroughs in recent years, DIPG has seen little progress. Fortunately, the search for cures is picking up steam thanks to advances in genomics, cellular therapy and immunotherapy, among other fields.
"We're in the business of pushing the boundaries and disrupting the field of childhood brain tumor treatment," says Opipari. "I have no doubt that the projects we've funded in this round will yield new understandings about this disease and how we can revolutionize treatment for DIPG."
Here's a summary of the six newly funded projects:
Analyzing DIPG tissue in real time
Until recently, doctors generally weren't able to biopsy a patient's DIPG tissue until after death.
"Our inability to adequately and consistently obtain biopsy tissue from these hard-to-reach cancers severely limited our ability to more effectively treat these children," says Rajen Mody, M.D., M.S., pictured above at left, a pediatric oncologist at C.S. Mott Children's Hospital.
To gain a more thorough understanding of DIPG's biology, U-M physicians have cautiously started to biopsy tumors in children with new diagnoses. This requires a complicated brain surgery with its own set of risks.
Intraoperative MRI, which allows pediatric neurosurgeons to perform the biopsies with greater precision and accuracy, has played a key role in the expansion of DIPG biopsy capabilities at U-M.
"Thanks to recent scientific advances in tumor genomics and tumor sequencing, the new reality may be that the pros of biopsy might outweigh the cons for these children," Mody says.
After the procedure, U-M scientists perform comprehensive DNA and RNA sequencing on both the child's tumor and normal tissue to guide treatment recommendations.
Individualized treatment plans, based on specific genetic markers found in each patient, are the goal. Treatment plans are built around the selection of targeted agents versus the one-size-fits-all therapeutic agents designed for adult brain tumors.
The team's work is already rewriting the book on DIPG. Preliminary results show that DIPG is not a homogeneous tumor and that the genetic composition shifts as the disease progresses.
"Without exception, we have broadened our general understanding of how this disease arises, grows and changes along its course with each child we've been able to biopsy and sequence," says Mody. "We are one step closer to cures with each biopsy."
Sequencing without surgery
Although surgical advances have made biopsy safer, it still requires open brain surgery. Carl Koschmann, M.D., and his lab are exploring whether genetic sequencing can be performed without tumor tissue.
"Evidence of tumor DNA has been found in cerebral spinal fluid in some adult brain tumor patients," says Koschmann, a pediatric neuro-oncologist. "Our goal is to be able to diagnose DIPG and create individualized treatment plans using spinal fluid, without the need for repeat biopsy."
Koschmann's lab is using ultra-sensitive technology to essentially multiply as little as a few copies of DIPG tumor DNA obtained from spinal fluid. Because the fluid collection is minimally invasive, they hope to molecularly fingerprint a tumor at diagnosis and at various points during treatment.
"The surveillance aspect of our sequencing plan is critical because it will allow us to observe how DIPG potentially develops genetic changes in response to therapy," says Koschmann, noting that this information will help them treat individual patients more effectively as well as shed light on more effective DIPG treatment as a whole.
In addition to testing whether it can perform a comparable level of sophisticated genomic profiling using spinal fluid, Koschmann's lab is also working to identify a screening panel for cerebrospinal fluid tumor DNA to quickly identify common genetic alterations in newly diagnosed DIPG.
Can we starve DIPG?
DIPG spreads quickly because of cell metabolism that allows the cancer cells to divide and multiply rapidly.
"Cancer cells in kids with DIPG are proliferating so fast, they're virtually unstoppable," says Sriram Venneti, M.D., Ph.D., pictured above with Koschmann, a pathologist at Michigan Medicine. Venneti and his team, in collaboration with colleagues at Stanford University, hope they can change that.
Research from the Venneti lab shows that the energy DIPG cells use to divide and grow comes from nutrients such as the amino acid glutamine.
"We think there may be a link between DIPG growth and the amount of glutamine present in this part of a child's brain at this stage of a child's development," Venneti says, noting that DIPG is most commonly diagnosed in young children during a phase of growth characterized by rapid brain development.
"Understanding the presence and function of glutamine in the brain could be critical to our ability to figure out how to 'starve' these tumors and stop their growth."
Venneti and his team are also working to alter the epigenetic state of DIPG cells — thereby attacking the cancer on two levels.
"We need to know that limiting access to glutamine will inhibit growth, and we need to know how and why," says Venneti. "This work could uncover a host of information about how these cells grow and what we can do to stop them in their tracks."
Probing mutations in DIPG cells
Recent advances have shown that more than 80 percent of children with DIPG have a specific genetic anomaly — the H3K27M mutation. It occurs in one of the proteins (histone H3) around which DNA is wrapped.
"There are a number of compelling signs that point to the histone H3K27M mutation being the key to finding better ways to treat DIPG," says Venneti.
Notably, the mutation is only found in cells in the midline of the brain, where the pons is situated.
"Why do we only see these mutations in this part of the brain, and how does the mutation affect other proteins?" asks Venneti. "There must be something other than just DNA organization at work here to cause this level of altered activity."
As suggested in his lab's work to reveal the role of glutamine metabolism in DIPG growth, Venneti and his team suspect there is a link between the rapid development normally occurring in this part of the brain and the mutations that occur in DIPG patients. This particular project is more discovery-based, designed to unearth clues scientists can use to design future tests and to identify existing drugs that can combat DIPG.
"We're using a proteomic approach — studying the role of proteins to see what other proteins the H3K27M mutant histone protein binds to," says Venneti. "Are they doing anything different or unusual, and does this relate in any way to early brain development? There's something about the H3K27M histone that's different. This research may help unearth these differences."
Cracking the blood-brain barrier
Under normal circumstances, a tightly packed cell wall surrounds blood vessels in the brain, protecting it from toxins and bacteria. This protective barrier can, however, complicate efforts to treat an inoperable brain tumor.
"Many therapies that seem like they have great potential to treat DIPG in laboratory studies have had disappointing results in patient care, in part due to failure to cross the blood-brain barrier and effectively reach the brain tumors themselves," says Daniel Lawrence, Ph.D., pictured above.
Options for crossing the blood-brain barrier are limited. The drug mannitol has shown promise, but the dose needed to be effective through IV delivery can be toxic, leaving delivery by way of open brain surgery the only other current option.
A better answer could come from outside the field of oncology.
Lawrence, a vascular biologist and researcher at University of Michigan Frankel Cardiovascular Center, has been studying a pathway through which a specific protein regulates the blood-brain barrier. The protein, tissue type plasminogen activator, regulates clotting and has a critical role in how physicians care for patients with ischemic stroke.
"In many cases, such as with stroke and traumatic brain injury, we've studied ways to block the activity of this pathway, working to seal the blood-brain barrier," Lawrence says. "If we can seal it, it stands to reason that from what we've learned about the signaling pathway, this could also lend insight about how to open the barrier."
His lab is testing whether administering tPA in combination with nontoxic doses of mannitol will allow physicians to open the blood-brain barrier in a precise and measured way, permitting more effective drug delivery to tumors on the other side of the blood-brain barrier — without invasive surgery.
Drugs would then be able to sensitize tumor tissue to radiation, allowing physicians to aggressively target DIPG as well as other inoperable brain cancers.
"If we can find a way to let drugs we already have access to more effectively attack DIPG," says Lawrence, "we have a better chance of not just slowing tumor growth but potentially killing the tumors completely."
New twists on old standards
A phase 2 clinical trial is set to open soon at U-M, with plans to expand to other sites shortly thereafter.
The work comes from Koschmann's lab, and targets the two most frequently found tumor mutations in DIPG patients with a set of drugs already in use for different conditions. Everolimus has previously been used in treating noncancerous brain tumors, and pazopanib has successfully treated leukemia and certain sarcomas.
The team hopes that a combination of these two drugs may be effective for children with DIPG that has returned after an initial relapse and who have the two genetic mutations his team has identified.
"Many therapies are failing today because we can't deliver the agent effectively into the central nervous system, or we don't have individualized information about that specific child's tumor biology to make better treatment recommendations with," says Koschmann, noting that often both aspects are problematic.
The work will build on his research evaluating cerebral spinal fluid for genetic tumor profiling, in that his team will use cerebral spinal fluid to evaluate how well the drugs are permeating the blood-brain barrier and how well the tumors are responding.
"With all the exciting work underway right now, we're seeing a multiplier effect in which what we're learning in one study is immediately factored into other work," Koschmann says. "Sharing this knowledge across our teams, our institutions, all in real time — this is how we're going to get across the finish line in the fight to cure DIPG."
Learn more about the Michigan Medicine Pediatric Brain Tumor Research Initiative.
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