The Neurofibromatosis Therapeutic Accelerations Program (NTAP) at Johns Hopkins launched a Challenge in mid-January which seeks creative ways to identify which plexiform neurofibroma tumors will undergo significant growth in individuals who have neurofibromatosis type 1 (a syndrome with a well-defined genetic cause but complex biology at the tissue level). We recently spoke with Dr. Jaishri Blakeley, Assistant Professor of Neurology, Neurosurgery and Oncology at the Johns Hopkins University School of Medicine and the Director of the Johns Hopkins Comprehensive Neurofibromatosis Center, about this important Challenge which is scheduled to run through February 13, 2013.
Hello Dr. Blakeley – thanks for joining us today. Could you help us understand more about neurofibromatosis type 1 (NF1) and its symptoms, causes, and current treatments?
NF1 is a common (prevalence 1:2700) autosomal dominant neurogenetic disorder caused by a mutation on chromosome 17q that results in reduced levels of neurofibromin. One well described role of neurofibromin is the regulation of the Ras pathway. It is thought that chronic activation of the Ras pathway in the absence of normal neurofibromin causes the symptoms of NF1. Clinically, NF1 presents with diverse clinical features ranging from mild skin markings to learning difficulties, brain tumors, peripheral tumors, bone abnormalities, and various forms of cancer.
The hallmark tumor of NF1 is the neurofibroma. These are tumors composed of nerve elements such as Schwann cells and neural tissue but also fibroblasts, mast cells, and pericytes. The most common form of neurofibroma is the cutaneous (skin) form that can number into the thousands in a given patient and can be disfiguring due to their appearance on the skin, but are not otherwise medically dangerous. Far more medically concerning are plexiform neurofibromas that occur along peripheral nerves throughout the body and can take over an entire body region. These tumors may compress vital structures such as the spinal cord or major vessels, cause neurologic dysfunction or pain, or lead to extensive regional disfigurement. Up to 50% of patients with NF1 have at least one plexiform neurofibroma. Plexiform neurofibromas also have a risk of transforming into malignant peripheral nerve sheath tumors, which are very aggressive sarcomas. The only established treatment for neurofibromas is surgery. Unfortunately, given that these tumors grow within the normal nerve structure, complete resection can result in major nerve damage, and with incomplete resection, the tumors simply continue to grow. Hence, we are in desperate need of additional treatments for plexiform neurofibromas. The trick is that in NF1, a patient may have four plexiform neurofibromas and three of them will never cause a problem, but that fourth one may cause terrible problems. We need a way to predict which tumor is going to be the “bad egg” before it starts.
Since January 2012, when NTAP was created to fast-track the development of therapies to treat tumors associated with NF1, what are some of the key accomplishments that can you point to?
NTAP was founded to focus research efforts entirely on creating and supporting opportunities that encourage the most thoughtful and efficient development of therapies for plexiform neurofibromas. The first step in this process was to perform an analysis of where the field was in order to allow identification of areas that needed the greatest attention and resources. We identified several key areas of need including cell culture models, a need to predict tumor behavior in order to allow prevention, clinical trial outcome measures, and natural history data pools. NTAP is supporting all of these initiatives in order to “fertilize the field” so that research across the board is developed to help patients with NF1 as quickly as possible. Thus far, we have fast tracked a cellular culture model initiative, partnered with the National Institutes of Health (NIH) to advance a natural history initiative, and are actively building collaborations to bridge the excellent scientists within the field of NF and those new to the syndrome. Our mission is to move good ideas into thoughtful research questions as quickly as possible so that the things with the best chance of helping patients get developed as rapidly as science will allow. This takes a broad outreach, a lot of partnership, high energy, and a willingness to take some risks with “out of the box” ideas.
As an Ideation Challenge with a guaranteed award for at least one submitted solution, what are some of the key attributes you’d like to see in a winning solution?
We are interested in seeing a broad range of ideas and feel that there will likely be many “right” answers. The most important aspect of an idea is that it recognizes that the behaviors of plexiform neurofibromas are variable and that we need a feasible technique to identify the “bad guy” early. Solutions that call on experience with other situations in which predication based on distinguishing features has been successful or that manipulate normal growth and development processes to be able to identify abnormal features are welcome. Ideas should also be at least theoretically safely applicable to children as we would need to predict which tumor is going to grow early in a patient’s life in order to successfully prevent that growth.
What was your primary motivation for crowdsourcing this Challenge to InnoCentive’s Solvers (versus using more “traditional” research avenues)?
We are eager to attract thinkers that have never known about NF1 or thought about plexiform neurofibromas before. NF1 is a fascinating, but vexing, syndrome. We know the mutation, but we cannot explain the heterogeneity we see in patients. The challenge of plexiform neurofibromas is similarly addicting. It is a “benign” tumor made up of the components in normal nerves, appears to have periods of natural senescence, but has resisted all therapies tried to date. There is a rich field of expert scientists invested in NF1 and we are hopeful that by crowdsourcing we can find new partners who will bring new energy, imagination, and expertise to collaborate and build upon the great work that is ongoing. Biomarkers to predict disease when it has not yet happened is a task that especially requires new and imaginative ideas. We thought a platform such as InnoCentive would attract just the kind of thinkers who patients with NF1 are counting on.
Do you have plans to further develop the viable solutions to this Challenge, either via additional Challenges (e.g., prototyping) or other means?
The ideas generated by this challenge will be used to craft a formal request for application to develop and test the biomarkers. Hence, the solutions offered will have direct (and rapid) applicability to further development plans.
Thanks for your time Dr. Blakeley. With a couple of weeks to go before your Challenge closes, do you have any final advice to Solvers?
Thank you, we are very excited to join this Solver community and learn from all of the innovative people out there. We invite all of those folks who have never heard of NF1 or a plexiform neurofibroma in particular to help us think about this problem. I promise you it will make a difference to many children who struggle every day with these tumors.