For our cancer and blood diseases institute, limited thinking is off-limits
by Mary Silva
The only rule for outwitting childhood cancers, says Dr. John Perentesis, is that there are no rules. He encourages his team to stop at nothing in their search for answers.
There is something fundamentally wrong about a child having cancer. At least when cancer strikes in adulthood, we can often blame years of smoking, eating the wrong foods or generally indulging in ways we should not.
But for a child, there are no such explanations. Cancer in a child disrupts the order of the universe. Which might be why John Perentesis, MD, uses the word “disruptive” to describe the work of the Cancer and Blood Diseases Institute (CBDI).
Perentesis is head of the Division of Oncology and one of four co-directors of the Institute, which cares for several hundred children each year who are newly diagnosed with cancer. The Institute’s 100 faculty and nearly 400 support staff treat children who have cancers in their blood cells, bones, lymphatic system, kidneys, liver, eyes – you name it. Some of these cancers are more treatable than others; many are curable. But few are as little understood, or as impervious to treatment, as brain tumors.
Brain tumors, particularly the high-grade, incurable ones, are daunting, and Perentesis has assembled a powerful team to take them on. Maryam Fouladi, MD, heads the Brain Tumor Program; a team of researchers led by scientific director Qing Richard Lu, PhD, carry out the science. Neuroradiologists image the tumors; neurosurgeons perform the resections; pathologists interpret the biopsies. Many others provide an array of clinical support. Underlying it all is a tenet of close collaboration.
“One of our ethics is team science,” Perentesis says. “We spend a lot of resources to cover people’s time and effort so they can spend more time working as a team. And we fund high-risk research with transformational potential that would be hard to fund through traditional funding mechanisms.”
The results of this approach speak for themselves. Perentesis recites a litany of prestigious publications that have published findings of his scientific team. He calls an article published last summer by Lu in Nature Medicine a “tour de force.” Lu and his team discovered that an anti-depressant medication can combat medulloblastoma, an aggressive and often fatal brain tumor.
That discovery, Perentesis says, is a perfect example of the outside-the-norm thinking encouraged within the Institute.
“A lot of our internal resources go toward disruptive technologies and research,” Perentesis says, using that word again. “‘Disruptive’ is an important thing in these times. Science moves forward in two ways. One is incremental – methodically, carefully. The other is to pull in new ideas from different fields and to think in new and different ways.”
A NEW DIRECTION IN TREATMENT
Perentesis and his group lean heavily toward the latter approach. One of their new and different ways of approaching cancer treatment is currently under construction: a Proton Therapy Center at Cincinnati Children’s location in Liberty Township, Ohio. Perentesis considers proton therapy an essential tool for treating childhood cancers. And, he adds, this center will be the only one in the world with a dedicated research facility.
Along with the Proton Therapy Center, the Cancer Institute is expanding inpatient and outpatient services at the Liberty Campus. The Institute has enlisted faculty from the University of Cincinnati’s College of Design, Art, Architecture and Planning to work with families of children with cancer, to design a facility that truly meets their needs.
It only takes minutes for research assistant Otis Pinkard to run genetic information from tumors against tens of thousands of compounds to find the best match for treatment.
Perentesis’ own area of research is in drug discovery and development, where he takes advantage of the latest genomic technology to move science along. His laboratory today is a far cry from the early days of his career. “We would spend up to a year doing things that we can do in less than 10 minutes today in our sequencing lab.”
Now, just one flight of stairs down from his office, is a laboratory packed with $3 million worth of the latest gene sequencing equipment. The sequencers analyze each child’s tumor to see what makes it tick and researchers run the findings against tens of thousands of compounds in a matter of minutes to find the ideal match for treatment.
“We used to think about cancers as being a series of broken ‘on’ switches. And if you blocked those switches, you could cure the cancer,” Perentesis says. “It turns out to be much more specific than that. You have to do a designer solution for each type of cancer. And even the same cancers might react to a drug differently, depending on the child.”
At a time when pharmaceutical companies are not developing new drugs for pediatric cancers, the Institute’s research team has decided to take it on themselves. Yi Zheng, PhD, who heads the Institute’s Division of Experimental Hematology and Cancer Biology, is using information generated by our gene sequencing laboratories to understand the molecular underpinnings of certain cancers and to identify compounds that could revolutionize their treatment. One of his discoveries was published Nov. 20, 2014 in Chemistry & Biology – a compound that appears to block the Ras signaling pathway, implicated in a variety of diseases, including cancer.
Adopting promising therapies for pediatric use is a step Perentesis expedites through his role on the National Cancer Institute’s Investigational Drug Steering Committee, and as a member of the executive committee of the Children’s Oncology Group.
FOR EVERY CHILD, AN AVATAR
The Pediatric Avatar Program pairs each child with a mouse bearing a biopsied sample of his tumor. The mouse’s reaction to treatment helps predict response in the child.
Perentesis’ latest disruptive idea is adopting a “Pediatric Cancer Avatar Program.” Doctors sequence a biopsy of a child’s tumor to find what is driving the cancer. Tumor samples are then implanted into mouse “avatars” to grow and be treated with the same chemotherapies as the child. Researchers observe how the mouse model reacts to treatment and anticipate what the response might be in the child.
“Although this program is still in the research stages, the potential is here for next-generation advances for children with high-risk and relapsed cancers,” Perentesis says. “The goal is to develop curative and precise therapies individualized for a patient and his tumor. It is turning oncology on its side.”
Turning things on their side seems more than reasonable when your life’s work is treating children with a disease for which there is no explanation and all too frequently, little hope.
Perentesis feels fortunate to be part of an organization that understands the value of such thinking.
“We have here at Cincinnati Children’s an institutional culture and tolerance for risk – not risk with the patient, but with new ideas. And if it is a good idea, to put resources behind it,” Perentesis says.