Dr. Oren Becher, chief of the Jack Martin Fund Division of Pediatric Hematology-Oncology at the Mount Sinai Kravis Children’s Hospital, is at the forefront of research to find a cure for DIPG (diffuse intrinsic pontine glioma).
Dr. Becher was born in Israel, moved to the United States when he was 14, and now leads one of very few laboratories around the world that focuses solely on this type of pediatric brain cancer.
DIPG is a rare brain tumor that occurs in an area of the brainstem called the pons. The pons regulate the vital functions of the body like heart rate, blood pressure, and breathing.
DIPG is exclusively a pediatric cancer and affects approximately 300 children in the U.S. each year. Children are usually diagnosed between the ages of five and nine.
Due to its location in the brain, surgeons are unable to remove the tumor. The brainstem is a fragile area of the brain, so the most that surgeons can do is take a biopsy for analysis.
“Even that is controversial, because there is a small percent chance that you can actually have side effects from just doing a biopsy,’ Dr. Becher said. “It just highlights how delicate that area of the brain is – that even doing a biopsy is considered risky.”
Biopsies are not the standard of care because there is not enough research and data for doctors to know how to treat patients based on the results of the biopsy.
Dr. Becher did his pediatric residency at Children’s National Medical Center in Washington, DC. While training to become a general pediatrician, he met a pediatric oncologist, Dr. Tobey MacDonald, who was studying brain cancer. Dr. MacDonald mentored him and “nudged him” to pursue research for childhood cancers.
For his pediatric oncology training as a fellow, he treated patients with DIPG and discovered that “nobody was studying DIPG.”
“There were no models of DIPG,” he said. “I took care of children with DIPG…[and] I realized I wanted to focus on that tumor because it was incurable.”
Dr. Becher took care of patients while doing research in a cancer modeling lab led by brain surgeon, Dr. Eric Holland, that focused on adult gliomas (tumors). For a year and a half, he made models for medulloblastomas, a cancerous brain tumor that starts in the lower back part of the brain involved with muscle coordination, balance and movement.
“When I was taking care of children with DIPG and I realized there were no models with DIPG, I set out to make a model for DIPG.”
Under the mentorship of Dr. Eric Holland, along with other colleagues at the research laboratory, Dr. Becher made one of the first genetic mouse models of DIPG in 2010.
Based on the results of the genetic mouse models, Dr. Becher led two clinical trials testing the drug, perifosine. The results took about a decade to publish, but unfortunately, perifosine did not work and the results were negative.
“[Results] didn’t help the kids. It highlights the challenge of finding new treatments for this cancer,” he said. “A lot of these trials were initiated even before we knew about the histone mutation that was discovered in 2012.”
DIPG was the first cancer that was known to have a histone mutation. Histones are proteins inside the nucleus of the cell that package the genetic code (DNA). The mutation was in the Histone 3 (H3), which is part of the nucleosome. This new discovery highlighted how histones play an important role in determining what cell in the body should be a brain cell, skin cell, etc.
“This cancer is partly initiated… [when] the cell that’s supposed to become a brain cell becomes a primitive cell that can divide out of control.”
The histone mutation, H3K27M, is found in 90% of the DIPG tumors and was co-discovered by Suzanne Baker at St. Jude in Memphis, Nada Jabado at McGill in Montreal, and Cynthia Hawkins in Toronto.
“Those three should get the credit for discovering the histone mutation in DIPG,” he said. “Because [the histone mutation] is found in 90% of these tumors, because every cell in the tumor expresses that mutation – it is one of the main reasons why now [there’s] a really crowded field of researchers trying to find a cure for DIPG.”
In addition to the histone mutation, Dr. Becher was part of a group that identified that 25% of DIPGs have mutations in a gene called ACVR1. ACVR1 is a cell surface receptor. Dr. Becher says researchers are still testing inhibitors against the gene and that it is easier to target because it rests on the cell’s surface.
“It’s another target for therapy that people are exploring [and] is another hot area of research right now.”
As medical technology has evolved over the past 15 years, it has had a major impact on medicine and Dr. Becher’s research. CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is a new approach that allows researchers to “delete” genes from cells to see how it will affect cell growth.
The Nobel Prize was awarded to Jennifer Doudna and Emmanuelle Charpentier for their development of CRISPR. Their discovery and development was used by many other researchers and soon made CRISPR a common tool in labs around the world. Dr. Becher used DIPG cells from his mouse model and used CRISPR to conduct a genome screening.
“Our cells have about 19,000 genes, and there’s many we don’t fully understand [their function],” he said.
After deleting 19,000 genes in the individual cells in the mouse model, Dr. Becher and his team identified 1,000 genes that, if blocked, could slow the growth of DIPG cells.
“We’re now trying to look through this list –it’s a massive list of genes– to see if there’s a new gene target that we could go after to treat DIPG,” he said. “Any lab in the world can take any cell that they’re studying and then delete every gene and basically see, if I delete gene 1, does it make the cells grow slower or faster.”
With this newfound list of genes, researchers have been given more information that could lead to new therapies to treat DIPG. CRISPR is a new technology that has only been used in the past several years and has even been used outside of research. The ground-breaking technology can potentially be used as treatment and delete the gene that is causing cancer in a patient.
“I think it’s a hot new area that has a lot of promise,” Dr. Becher said.
Dr. Becher’s lab is collaborating with Dr. Joya Chandra in Texas to study a gene called LSD1. LSD1 is an enzyme that can modify histones as well, but it is uncertain if it is the right target for DIPG.
Most genes that are being studied are those that have already been researched. Fortunately, CRISPR allows for researchers to study all the genes, including those that are unknown, and prioritize which gene target is the right one to treat DIPG.
Currently, Dr. Becher’s lab has three areas of focus. The first is testing new cancer drugs in DIPG models, both the mouse models and patient-derived models. Researchers test the drugs in mice to see if they kill the tumor cells, how well they work, and if they are toxic.
The second area of focus at Dr. Becher’s lab is the immune system. Most progress in cancer treatment has been in turning the immune system against cancer. Treatment includes CAR T cell technology that can even be injected directly into the ventricles in the brain.
However, one of the reasons Dr. Becher says there has not been a cure for DIPG is because the tumor cells in the DIPG have other cells that turn off the immune system in the tumor. These other cells, called myeloid cells, are not tumor cells but immune cells that normally reside in the brain. When these cells are in the tumor, they turn off the immune system in the brain stem.
Dr. Becher is collaborating with neuroscientist Dr. Dolores Hambardzumyan at Mt. Sinai to find a way to reverse the function of the faulty immune cells that are in the tumors.
The final area of focus at Dr. Becher’s lab is opening the blood brain barrier, (BBB), an extra layer of protection to prevent the brain from exposure to chemicals or harmful substances. Dr. Becher is collaborating with pediatric neurologist, Dr. Praveen Raju at Mt. Sinai and Dr. Dan Heller at MSK, who is developing nanoparticles that can enter the brain with a drug that can infiltrate the tumor as a “novel approach.”
“This hasn’t been tested in kids yet. It’s kind of like a futuristic approach,” he said. The BBB, however, is delicate. When the BBB is opened, it disrupts homeostasis, inducing potential inflammation and damage to cells.
“Although it has protective functions, there’s even studies showing [that] if the blood brain barrier opens too much it can lead to neurodegenerative diseases… like Alzheimer’s,” he said.
There are several ways the BBB is opened: direct infusion into the tumor, disruption by a pulsed focus ultrasound (pFUS), and now, Dr. Becher and Dr. Raju’s approach with nanoparticles that is currently being researched. They were recently awarded a grant from the ChadTough Foundation for their research.
Another foundation that has supported DIPG research is the Cristian Rivera Foundation. Dr. Becher is also on its advisory board.
“John Rivera, Cristian’s dad, is extremely passionate about moving the field forward,” he said. “He’s a powerhouse in fundraising… and is very involved with patients with DIPG that are currently fighting, and he tries to help them get into clinical trials.”
Rivera has helped fund Dr. Becher’s researched for over a decade and is an integral part in the advocacy for this cancer that is incurable.
“I sometimes talk to families too, and I can see they’re shocked… like a deer in the headlights,” Dr. Becher said. “There’s like thirty trials and they don’t know which one is going to work.”
The diagnosis of DIPG is overwhelming. As DIPG has no cure, patients receive a different opinion from every doctor because there are many approaches to treatment and clinical trials.
“It’s the hardest thing I’ve ever had to do in my whole life – to tell families that the cancer their child has doesn’t have a cure yet,” he said. “It’s important to be honest. But you also want to give some hope that there’s some new approaches on the horizon that they can potentially try.”
In recent years, Dr. Becher has taken on an administrative role, mentoring doctors treating children with DIPG and focusing on the research for DIPG.
“There’s a very tight balance between giving hope to families and understanding the science well enough that it has a chance of working,” he said. At this point in time, the clinical trials have been unsuccessful.
The question, Dr. Becher says, is – do you want to start a new trial because a medicine may work? Or study the drugs in more detail to better understand how they work.
Dr. Becher’s research and passion is evident. Starting after his freshman year at the University of Pennsylvania , he worked at the research lab of Dr. George Cotsarelis, a dermatologist, who is studying to find a cure for hair baldness. Dr. Becher admired his passion and loved the idea of using science to help people.
“Someone that understands science and is also empathetic and compassionate and can take care of patients – that is the ultimate job,” he said. “That’s almost not a job.”
Dr. Becher’s advice for anyone interested in studying medicine or oncology, specifically, is simple.
“Find something that, for you, is not a job,” he said. “Whether it’s helping someone who is paralyzed to walk again or figuring out Alzheimer’s or I don’t know, going to Mars and colonizing Mars – it could be anything. You have to love it.”
For Dr. Becher, science is fun. Discovering something new, though those moments are rare, is worth the effort.
DIPG is a rare cancer in children and is devastating to the families because the kid’s life is “cut short so early.” Researchers need more resources to find a cure.
“Not because a famous person had it means that it’s more important,” he added. “But Neil Armstrong’s daughter had it. It can affect anyone…any insight on any cancer can be applied to other cancers in the brain or other diseases.
“We need to support these efforts…for these rare cancers in children so one day these cancers will be curable,” he said. Dr. Becher hopes a cure for DIPG will be found in our lifetime.
Dr. Becher earned his BA magna cum laude from the University of Pennsylvania, and MD Johns Hopkins School of Medicine. He completed his pediatric residency at Children’s National Medical Center in Washington, DC and fellowship in Pediatric Hematology-Oncology and Pediatric Neuro-Oncology at Memorial Sloan-Kettering Cancer Center in NYC. Dr. Becher served on the faculty at Duke University and Northwestern University prior to relocating at Mt. Sinai Kravis Children’s Hospital where he serves as the chief of the Jack Martin Fund Division of Pediatric Hematology-Oncology.
