How an innovative funding approach is advancing research and speeding treatments for patients whose complicated disorder can cause tumors on nerves all over the body. Every grant made by the Neurofibromatosis Therapeutic Acceleration Program, says neuro-oncologist Jaishri Blakeley, is bestowed with one question in mind: ‘How will this treatment get to clinic?’
Tamika and Laticia Robinson are as close as twins could possibly be. They have lived together for most of their 52 years, they tease and bicker and finish one another’s sentences, they feel one another’s joy and pain. And being identical twins, they of course share their unique genetic makeup — including a genetic disorder known as neurofibromatosis type 1, or NF1.
What the twins don’t share are some of the worst manifestations of this relatively rare but extremely complicated disorder that can cause a host of symptoms, including a variety of tumors that grow on nerve tissue throughout the body.
Though Laticia is definitely not symptom-free, her tumors have not yet required surgery, or morphed, as Tamika’s have, into an aggressive cancer that has required surgery three times over the past 32 years (plus chemo and radiation twice). Nor has she had breast cancer, as Tamika has, even though NF1 puts them both at higher risk. Nor has she endured the NF1-related scoliosis that has bent Tamika’s spine so severely that her left rib cage is now touching her pelvis, which required yet another major surgery this spring.
“I often wonder why all of this is happening to my sister — just that why question?” says Laticia, who lives with exquisitely painful but benign NF1-related glomus tumors in her fingertips, which produce nerve pain “like a lightning strike.” And she can feel other tumors in her body. “But it’s nothing compared to what my sister is going through,” she says.
Yet Tamika is philosophical about her condition. “When I get bad news, I tell God, ‘Hey, I don’t have that much body left. Come on!’” she says. “But I feel good for all I’ve been through. Mentally I’m okay with it, and at this point when things happen to me, I just look at it as an adventure.”
“You know why?” says Laticia. “It’s because we have a great team of doctors. No matter what, they have our backs. And they are working every day to find out more about NF1 so that down the road, there will be a cure.”
Chief among those doctors is neuro-oncologist Jaishri Blakeley, who since 2007 has led the interdisciplinary team at the Johns Hopkins Comprehensive Neurofibromatosis Center that cares for the Robinson sisters. Blakeley is also revolutionizing the NF1 research landscape as director of a radically collaborative, international grant-making project: the Neurofibromatosis Therapeutic Acceleration Program (NTAP). With generous support from Bloomberg Philanthropies and the Paula and Jerry Gottesman Family Supporting Foundation, NTAP (n-tap.org) has in little more than a decade rallied the academic and pharmaceutical research communities to substantially advance NF1 research — including supporting and expediting the process that led to FDA approval in 2020 of the first drug to treat NF1: selumetinib.
“In 2012, I was approached by two parents, who proposed a venture philanthropy initiative. Could we dramatically accelerate research leading to treatment for a rare disease like NF1 by investing money, time and effort into answering very specific questions? That’s how NTAP was born,” says Blakeley.
“NF1 is a very complex genetic condition that involves basically every organ of the body, and certainly all parts of the nervous system,” she says. “At NTAP, we chose to focus on two specific manifestations out of the many we could have chosen. And with this focus, some luck, contributions from many new and established collaborators, and lots of elbow grease, we’ve been able to make a remarkable impact.”
An Innovative Funding Strategy
Neurofibromatosis, or NF, actually includes multiple genetic disorders: NF1, NF2-schwannomatosis, and LZTR1, SMARB1 or 22q-related schwannomatosis, each with its own constellation of manifestations and symptoms. The Robinson sisters were born with NF1, the most common form, which affects an estimated one in 3,000 people worldwide. They both have the telltale café-au-lait spots on their skin, are short in stature, had to work hard to overcome learning disabilities, and live with a proliferation of skin and nerve tumors.
Plexiform (often deep nerve) and cutaneous (skin) tumors are NF1’s two most common tumor manifestations. Of these, cutaneous are the most common, affecting 99% of adults with NF1. They appear as rubbery bumps at the top of the skin and can be itchy or tender, but are perhaps the most psychologically devastating because they can be so disfiguring.
Plexiform tumors are the second most common manifestation, affecting as many as half of all people with NF1. They can grow anywhere in the body and tend to form around constellations of nerves. They have to be monitored because there is a 10% chance these tumors will turn into an aggressive cancer with a poor prognosis, known as malignant peripheral nerve sheath tumor (MPNST).
“My goal was to change the way medicine was practiced for NF1 tumors in five years, and to do that, you have to focus very narrowly,” says Blakeley, a member of the Johns Hopkins Kimmel Cancer Center. So she decided to zero in on plexiform tumors because there was already a promising research base, most notably the work of Brigitte Widemann, a pediatric oncologist who was conducting drug trials in children with plexiform neurofibromas at the National Cancer Institute.
“Brigitte is a brilliant, amazing, compassionate physician and researcher who had done the yeoman’s work of clinical research for plexiform neurofibromas,” says Blakeley.
Widemann’s first several drug trials didn’t show dramatic therapeutic benefit, but she was optimistic about an AstraZeneca drug called selumetinib that blocks MEK1 and MEK2 proteins. These proteins are in a pathway regulated by the master cell regulator RAS. When the NF1 gene is functional, it manages RAS activation and therefore cell activity. But when the NF1 gene is defective, RAS stays turned on all the time and drives uncontrolled cellular activity.
Concerned that access to selumetinib might be at risk after several studies failed to show it had the desired efficacy in treating common cancers, Blakeley offered NTAP’s help to speed up Widemann’s NF1 trial by funding patient recruitment at two participating sites — Children’s Hospital of Philadelphia and Cincinnati Children’s Hospital Medical Center — with the stipulation that enrollment be completed within six months.
The study achieved its enrollment and ultimately showed unprecedented results. In 2020, selumetinib was approved by the FDA for children with NF1 and symptomatic inoperable plexiform neurofibromas. For the first time, clinicians had a nonsurgical treatment to offer young patients that could shrink their tumors.
From the beginning, NTAP “was really thinking outside the box,” says Widemann. “Their funding process was different. Your grant could be approved for scientific merit, but it could also be approved for something just because it needs to be done to get to the goal.”
Blakeley sees NTAP’s role as figuring out how to remove obstacles researchers face in getting therapies into the hands of doctors and their patients. “Our goal is to complement rather than compete with the existing research infrastructure,” she says.
For example, Blakeley points to a natural history study Widemann had the foresight to launch 20 years ago for children with plexiform neurofibromas. Its funding was in danger of being cut, so NTAP jumped in to pay for a postdoctoral fellow to analyze and publish the data. It took about a year, but the data “told us something important we hadn’t known, that plexiform tumors grow the most from birth through the 20s, then slow and plateau,” Blakeley says. “The combination of this new data and the success of selumetinib enabled a new study that seeks to prevent symptoms caused by plexiform neurofibromas by treating kids early. It will be led by Dr. Andrea Gross in Brigitte’s group.”
Buoyed by the groundbreaking successes with plexiform neurofibromas, Blakeley and the NTAP team organized a symposium with researchers from around the world to tackle cutaneous neurofibromas. Several new projects were launched as a result, including a study in the works assessing whether another MEK inhibitor, mirdametinib, can shrink cutaneous neurofibromas. And last fall, thanks to a long-term commitment from NTAP funders, NTAP opened enrollment into an ambitious natural history study for cutaneous neurofibromas that will assess change in these tumors, over time, in people across all age groups and skin types.
The Power of Data
To date, NTAP has awarded 81 grants totaling $60 million to NF researchers all over the world. Some 80% of NTAP’s funding goes to scientists outside of Johns Hopkins. And every grant, made by a committee of experts with Blakeley at the helm, is bestowed with one idea in mind. “How will this treatment get to clinic?” Blakeley says. “In other words, even if they are only looking at drug concentrations in a cell culture, an investigator has to be able to plan the subsequent steps to get a treatment in front of the FDA. We always start with the goal in mind — a proven treatment we can offer our patients — and work backward.”
The other non-negotiable is that all grantees must share their data. NTAP will even fund the time it takes to properly annotate that data to make it easier to analyze in a larger data set. Blakeley says Annette Bakker, president of the Children’s Tumor Foundation, which has been supporting NF research since 1978, was her inspiration for the idea. In 2018, NTAP joined the Children’s Tumor Foundation and Sage Bionetworks in establishing an NF Data Portal for researchers.
Blakeley believes that sharing NF data could have enormous impact even beyond NF. “The way we structure our data for sharing could impact millions of people,” she says. “The NF1 gene underlies the condition NF1, but it is also mutated in several common cancers, and understanding how to treat NF1-driven tumors can impact millions of people with common cancers.” Plus, loss of NF1 is just one way RAS is dysregulated. There is a collection of conditions called RASopathies that overlap with NF1.
“A lot of what we discover in treating NF1 could matter for all RASopathies, many of which have neurodevelopment manifestations like autism,” she says. “I view it as my mission to make our data as interchangeable as possible so we can support therapies for all of these conditions.”
Justin McArthur, director of the Johns Hopkins Department of Neurology, who is internationally known for his work on HIV-associated cognitive disorders, says, “NTAP has been one of the most exciting projects I’ve seen in my 43 years at Hopkins, not just because of the generosity of the gifts that support it, but because of the energy and dynamism the Blakeley team, as I call them, have brought to bear.
“Prior to NTAP, there had been a number of centers around the country that were kind of doing their own thing. Really, really smart people. Physician-scientists committed to NF. But you can’t do anything today without collaborating because no one can do or know everything. You have to do it with team science,” McArthur says.
McArthur is also excited about the pathway NTAP has created for young clinician investigators. The Francis S. Collins Scholars Program in Neurofibromatosis Clinical and Translational Research — named in honor of the former director of the National Institutes of Health who co-discovered the gene mutation that underlies NF1 — provides mentorship, financial support and training for early clinician-scientists invested in revolutionizing NF1 care. Since NTAP launched the program in 2014, 16 scholars have been inducted and have rapidly created a community of exceptional clinician scientists leading NF1 research and clinical care around the world.
“This is critically important because it will lead to sustainability of our NF program,” McArthur says.
A Medical Home
Collaboration comes naturally to Blakeley, who studied theater and psychology at Barnard College, avoiding science classes as much as possible. Only later did she realize how much she loves clinical care and research, and finally embarked on her medical career. And Blakeley, who insists her patients and colleagues call her Jaishri — “It’s Jay and then Shree, or just call me Jay,” she says — sees her patients as her chief collaborators.
“I remember vividly the first person I met when I started in the Comprehensive NF Center as a fellow,” she says. “He was 6 and was of course with his mom, and she taught me most of what I know about NF1. I missed so many things, and she’d say, ‘No, no, you’re missing this, feel here.’ To this day, parents and patients tell me what I’m missing. I really value that partnership.”
The Comprehensive NF Center is one of just a few centers in the world that provide complete interdisciplinary care to both children and adults with NF. “Most rare diseases, especially genetic rare diseases, live in pediatric departments, and patients get great care until they become adults, and then they don’t have a medical home,” Blakeley says. “So our intention from the beginning was to create that medical home.”
Patients like Tamika and Laticia Robinson, who have been coming to the Comprehensive NF Center since 2010, helped build that home. “They embody why we are committed to the Comprehensive NF Center and NTAP,” Blakeley says. “They not only demonstrate the complexity of finding answers for NF1 manifestations — they have the exact same gene variant, the exact same epigenetics, yet totally different experiences — but are also full partners in thinking through and managing the things that come up with NF1. They are just amazing people, living with a condition that can be very challenging and scary, yet leading full lives with grace, passion and kindness. They will do anything to support other people with NF and are helping us build a vibrant NF community.”
The Robinson sisters say the care they get at the center gives them hope and helps them continue to live a normal life. Tamika has had a long career as a special education teacher, and Laticia has worked for many years in banking. They bought a house and travel together — despite the fact that their first doctor told their mother they’d never be able to live on their own. “We were lucky,” says Laticia. “We have a very determined mother.”
The sisters also love to engage with other people with NF. They’ve attended pizza get-togethers and related events at the Comprehensive NF Center, and even connect with NF patients on Facebook.
“For a long time, my sister was the only other person I knew with NF, and the team at Hopkins’ Comprehensive NF Center has introduced us to so many different people,” Tamika says. “I’ve learned we’re not the only ones living with this and that some people have it worse. If I had the cutaneous kind, with tumors all over my skin, I’d never leave the house. But we’ve met some inspiring people who live with it and smile through it every day.”
The same could be said of Tamika, says Shannon Langmead, who has worked with Blakeley as the Comprehensive NF Center’s senior adult nurse practitioner and clinic coordinator since 2011. “No matter what she is going through, Tamika always has a smile on her face,” Langmead says. “And she’s been a great support for other patients. Every time we reach out — about a new patient looking to connect with someone, or a new research project — she’s the first to volunteer.”
“When something new happens to me, I just say, ‘What’s the plan?’ and our medical team always has a plan,” says Tamika. Last year, for instance, her weight dropped from her normal 90 pounds to 78 pounds because her scoliosis was compressing her organs, including her stomach. “So they suggested a feeding tube, and I thought about it and decided to try it, and it’s worked great. I’ve gained back enough weight to be able to have the scoliosis surgery.”
Her Comprehensive NF Center team even closely followed her progress when she had breast cancer surgery, Tamika says. “They treat me like a queen.”
“We have a hard time letting go of control, Jaishri and I,” says Langmead. “When you take care of people for 12 years, you’re really invested, so we stay very actively involved.”
Langmead says she has found that patients actually look forward to NF clinic visits. “Many clinicians don’t know anything about NF, and patients are stuck having to teach them. Here, they don’t have to explain their condition, and we see them beyond their diagnosis.”
The Comprehensive NF Center has grown significantly over the past 12 years and today has a roster of more than 3,000 patients. “We were seeing eight to 10 patients a month in the beginning. Now we’re seeing twice that many in a week,” Langmead says.
Because NF has so many possible manifestations, the center’s team includes specialists from genetics, oncology, neurology and a host of other disciplines. “I can think of only three NF centers in the world that provide what we are providing — the sheer depth of the bench, some 50 people, all at the top of their various fields, completely dedicated to treating NF,” says the center’s neurosurgeon Allan Belzberg, director of peripheral nerve surgery.
“While you need all of these experts,” says Belzberg, “you are also dealing with the ego, and you need a leader who can bring these experts together while making sure that everybody is well-respected and participates in a healthy manner. Fortunately, Jaishri Blakeley is that kind of leader.”
Surgery was until recently the only way to treat NF, though surgeries are complicated because plexiform tumors are “big and ugly,” bleed a lot, and often impinge on vital vessels and organs, Belzberg says. It’s still the only option for malignancies, but the most troublesome plexiforms can sometimes now be treated with selumetinib, and there are other new treatments in the pipeline.
There is an ever-growing number of NTAP-funded clinical trials — investigating new drugs, laser therapies, injections and other novel ways to treat NF1-associated tumors, as well as early detection of cancer with biomarkers from a blood test, or using enhanced MRI, says Carlos Romo, a neuro-oncologist, NF expert and NTAP’s director of clinical research.
“NF is not terribly difficult to diagnose, but NF patients really need multidisciplinary care, and that’s what they struggle to find,” Romo says. In addition to providing Johns Hopkins NF patients with a rich array of experts, “I am able to offer them research projects not available elsewhere,” he says.
Looking back on 15 years of caring for NF patients and a decade of research progress, Blakeley says perhaps the most important thing she can offer her patients today is hope grounded in the work she does at NTAP.
She recently saw a new young patient with a large tumor burden. “Most of the inside of this child’s body is impacted by tumor,” she says. “But now I can say, ‘We have drugs to put you on, and we know that there is a good chance the drug will shrink some of these tumors, and it has a good chance of not letting the others grow.’
“Even when we see people with really bad problems, we can now say, ‘Wait, wait. We have so much cooking, we have so many ideas coming, and we’ve proven we can turn tumors around. Together, we will find a path.’”