Adult and Pediatric Clinic Relocations Continue to Reap Benefits

A few months ago, we completed the relocation of our adult and pediatric NF Clinics to two distinct locations in the UAB Medical Center District; the adult clinic is located in the Kirklin Clinic at UAB, while the pediatric clinic is at the downtown Children’s Hospital of Alabama location. We’re finding that our patients continue to reap significant benefits from this change in terms of both convenience and improved integration of care with other medical specialties involved in the multidisciplinary care we provide. For example, our patients can have imaging, bloodwork, and consultations with other specialists, when needed, in the same location without having to walk down the street to another building, as they did prior to the clinic relocations. Also, our staff has become accustomed to the streamlined integration of care and the advantages it provides.  We continue to be pleased that the relocation has made our adult and pediatric clinics more efficient and patient-centered.

Headaches in NF1

Next, I’d like to briefly discuss the occurrence of headaches in individuals with NF1, which is fairly common in both adults and children.  Because NF1 is a condition that increases the risk of tumor development, a common concern is that headaches are a sign of a brain tumor. In most cases, however, headaches are not due to the presence of a tumor. The most common brain tumors that occur in people with NF1 are optic gliomas, which are tumors of the optic pathway. These tumors do not usually get large enough to cause increased pressure in the brain, which is the typical cause of headaches associated with brain tumors.  Other kinds of brain tumors can occur, and if they increase pressure in the brain they can cause headaches.  Usually these are severe, wake a person from sleep, and are associated with other neurological symptoms as well as nausea and vomiting.

While it is possible for some individuals with NF1 to develop malignant brain tumors, most headaches in people with NF are benign and are related to non-tumor causes. A common possibility is the presence of neurofibromas located on the scalp or neck that can be tender to touch or movement. These can serve as trigger points for pain that occurs on pressure, such as when brushing the hair or lying down. The pain can sometimes be interpreted as a headache. Also, migraine headaches are more common in people with NF than in the general population and can occur in children and adults. These are throbbing headaches that last several hours and often cause light sensitivity. Children with migraines can often experience stomach aches with or without nausea and even vomiting, which can often be the primary symptom.  Migraines in children can occur either infrequently or can happen often, sometimes interfering with daily living and resulting in missed school or work days, trouble with homework, and other problems. There are several approaches to management that can be helpful. Over-the-counter medications can be used and are often effective. If migraines are severe and frequent, prescription medications can be used when the headache presents, and other medications are also available that can help to prevent the development of migraines. While these medications can work remarkably well, not everyone needs to take a daily medication for the management of migraines.

Another condition that can be associated with headache is hydrocephalus, a condition of increased fluid pressure in the brain that is rare, but more common in people with NF than in the general population, and usually presents in childhood or young adulthood.  The headaches tend to be severe and might be associated with other symptoms, such as vomiting and other neurological signs.  In some other cases, headaches in association with NF1 can occur as a result of a problem called Chiari malformation.  This is defined as an extension of the lower part of the cerebellum of the brain below the foramen magnum, which is the opening at the base of the skull that marks the beginning of the spinal cord.  Chiari malformation appears to be more common in individuals with NF1 than in the general population, and can result in headaches, as well as other neurological signs, such as weakness or sensory changes in the upper part of the body.  Also, tension headaches, which are associated with emotional stress, can occur in individuals with NF1. Additionally, some individuals with NF1 have elevated blood pressure that can cause headaches.

Brain imaging studies usually aren’t performed right away in association with headache if an individual’s neurological examination is normal there are no neurological deficits. However, imaging is indicated if headaches are persistent and frequent or if other neurological signs are present in addition to headache. It’s also important to note that immediate evaluation is required for pain that awakens a person from sleep or causes persistent nausea and vomiting.

Continued Funding for NF Clinical Trials Consortium

As we begin a new year, I’m pleased to report that our application for a third cycle of funding for the NF Clinical Trials Consortium has been approved by the U.S. Department of Defense (DoD).  The Consortium is a collaborative group of 21 medical centers across the country and one in Australia dedicated to conducting clinical trials of the most promising drug therapies for all forms of NF.  As the coordinating center for the Consortium, UAB serves in several critical leadership and managerial roles during nearly every phase of the clinical trials.  Although protocols for the trials may be developed at other medical centers, UAB is responsible for coordinating Institutional Review Board (IRB) approvals, collecting and analyzing the data, and facilitating the preparation of results for publication. This is a significant role that we’ve held since the inception of the Consortium in 2006 and one that reinforces our commitment to accelerating the pace of NF research by providing the opportunity for patients to participate in clinical trials throughout the country. The DoD reviews were laudatory of the Consortium’s contributions to the NF community as a major source of hope for NF patients seeking new approaches to treatment. It is encouraging that critical funding for this important research initiative will continue.

Results of Clinical Trial Show Effectiveness of New Drug

Next, I’d like to highlight the results of a small clinical trial of a new drug, called Selumetinib, published last month in the New England Journal of Medicine (

The study results are significant because they represent the first time a medication has demonstrated clear potential as a treatment in a clinical trial for plexiform neurofibromas in NF1.  This was a small Phase I trial conducted at the National Cancer Institute of 24 patients.  After receiving Selumetinib twice daily for a 30-month period, more than 70% of participants in the trial experienced a reduction in the size of the plexiform tumor. Additionally, symptoms of pain and pressure related to the tumors were reduced.  It’s interesting to note that this trial was developed as a consequence of previous animal model testing conducted by scientists funded by the Children’s Tumor Foundation (CTF).

The medication acts as an inhibitor of the RAS/MAPK cellular signaling pathway that is hyperactive in people with NF1. The RAS/MAPK pathway achieves its signaling through a complex form of cell communication that is also implicated in other disease processes, including cancer.  During the cell signaling process, each cell receives an intricate combination of signals that triggers many different signaling pathways in a cascading-like effect.  Neurofibromatosis type 1 is caused by a genetic alteration in the gene that encodes for neurofibromin, a protein that regulates activity of the RAS/MAPK signaling pathway. When specific signaling pathways become altered as in NF1, cells respond with uncontrolled growth. Selumetinib is one of a family of drugs that has been developed to inhibit components of the RAS/MAPK signaling pathway implicated in the development of cancer and other diseases. Because we now understand that NF1 has underlying genetic alterations that occur in this signaling pathway, we can test this family of drugs for their effectiveness in treating NF. The results of this study are encouraging because they represent the first example of a notably positive trial of a medication to treat NF.

A larger clinical trial of the drug with a greater number of patients is underway. Selumetinib is currently considered an experimental drug and is not available clinically, although a similar drug, called Trametinib, is clinically available.  While these are not harsh chemotherapy drugs, they do have potentially significant side effects and are not for every NF patient. Because of the demonstrated potential of the drug in the clinical trial, we are optimistic that this family of drugs will play a role in the future treatment of NF.  Also, the NF Clinical Trials Consortium is conducting ongoing trials of other drugs that work by the same mechanism, and additional trials will be launched in the future. The positive results of the Selumetinib trial are both exciting and significant for the future of NF research.

Noteworthy Milestones of 2016

The end of 2016 provides a time to reflect on significant milestones for the UAB NF Program during the previous year and an opportunity to look ahead to new goals in the areas of patient care, education, and research for 2017.  A significant accomplishment achieved this year is the NF Clinic’s relocation to two distinct sites in the UAB Medical Center District, recently completed as part of a reorganization into adult and pediatric clinics located in the Kirklin Clinic at UAB and the downtown Children’s Hospital of Alabama, respectively. The clinics that have been held in the new locations thus far have gone smoothly, and patients have provided positive feedback about the improved facilities and logistics, particularly more convenient parking.  An important benefit for our patients is that the new locations allow more streamlined integration with the range of other medical specialties involved in the multidisciplinary care we provide and enable imaging, blood draws, and consultations with other specialists to occur in the same location. Our previous clinic space in the Hugh Kaul Human Genetics building has been closed and will be reconfigured for another purpose yet to be determined. We’re pleased that our patients are benefitting from the convenience and integration of care that the new clinic locations provide.

In the area of patient education and support, our program co-sponsored, with the Children’s Tumor Foundation (CTF), another highly successful NF Symposium on August 27th.  The event, also known as NF Family Day, was held for the first time at the Children’s Harbor Building at Children’s of Alabama and provided an opportunity for NF patients and families to hear a series of presentations on a range of NF-related topics presented by clinical experts. We were also pleased to again support the 3rd Annual Alabama NF Walk held on October 16th in Veteran’s Park in Hoover. The NF Walk is held in cities across the nation as an important fundraising event for the Children’s Tumor Foundation (CTF), the major source of patient advocacy and research support for all forms of NF in both children and adults. This year’s Alabama NF Walk, launched for the first time in our area only three years ago, raised more than $40,000 and registered more than 300 participants.

Our research program continued to advance robust basic and preclinical research as well as  clinical trials focused on finding and developing life-changing therapies for people with NF. Earlier this year, our NF Program Genetics Counselor, Ashley Cannon, MS, PhD, CGC, was named a 2016 recipient of the prestigious Francis S. Collins Scholars Program Award, which is designed to attract the highest level of talent to the field of NF research by providing salary and research support to advance a clinical translational research study that will lead to improved treatment options for NF1.  The first individual in our program to have received this significant honor, Ashley has been working on a clinical study for cutaneous neurofibromas utilizing eight years of patient data, representing the largest existing data set of cutaneous neurofibromas. The results of the study are in the final stages of review and will be submitted for publication in the near future. Our entire NF clinic team is proud of Ashley for receiving the Collins Scholar distinction and her outstanding work in NF research.

The capabilities of our renowned and dedicated research team were further enhanced with the addition of two new faculty members this year.  Deeann Wallis, PhD, joined our drug discovery initiative to identify compounds that may lead to effective therapies for NF. Her research involves developing assays that are used to test cultured cells with compounds that could restore function of the NF gene using the RAS pathway. Our program’s partnership with Southern Research Institute provides access to a vast chemical compound library and the use of high-throughput screening, an important drug discovery method that uses robotic automation to quickly evaluate the biochemical activity of a large number of compounds that may have potential in restoring gene function.  Additionally, Dr. Wallis is testing the effectiveness of potential new drug therapies for NF1 using induced pluripotent stem (iPS) cells derived from individuals with the NF1 gene mutation. These specialized types of cells are reprogrammed from an adult cell and can develop into virtually any type of cell in the body, allowing the creation of disease-specific stem cells that can be used to test drug effectiveness. Also, computational biologist Andre Leier, PhD, joined our research team this year with a focus on developing mathematical models of the RAS signaling process. Dr. Leier’s efforts will further our understanding of the genetic mechanisms involved in NF so that drug therapies can be developed to restore function to mutated genes.

In other research initiatives this year, our efforts to produce mouse models of specific types of NF mutations continues to progress. These models are useful in allowing our genetic scientists to study the NF disease process as well as the effectiveness of new drug treatments.  Animal model development represents an area of significant commitment in our research program that will continue to expand in 2017 and beyond. In the area of clinical trials, we are hoping to launch a clinical trial for cutaneous neurofibromas in the upcoming year.

New Goals for the Year Ahead

Our commitment to supporting clinical trials continues with our role as the coordinating center for the NF Clinical Trials Consortium, a collaborative group of 18 medical centers across the country and in Australia dedicated to conducting clinical trials of the most promising drug therapies for all forms of NF. We have submitted a five-year funding renewal request to the U.S. Department of Defense and are hopeful that funding will be renewed. During our recent Consortium steering committee meeting, several new clinical trials were proposed for the upcoming year. There are two clinical trials for next year that are not dependent on Consortium funding, including a cutaneous neurofibroma trial that will be launched in early 2017.

We also plan to continue our preclinical research efforts in the coming year. Several members of our NF clinic team attended a meeting in Detroit recently with scientific leaders from all over the world representing many genetic conditions, including cystic fibrosis and muscular dystrophy. We discussed drug development efforts aimed at restoring function to mutated genes and have developed collaborations with many of these leaders so that we can adapt these approaches to NF research.  Also, we continue to support NF research efforts beyond those of our program. In my role this year as chair of the strategic planning committee for the Children’s Tumor Foundation (CTF), I recently chaired a retreat in Virginia focused on planning future CTF research goals. 

In the area of patient education and support, an important goal for our clinic in the upcoming year is to increase patient engagement. We are working with a group at UAB to develop a smart phone app that will allow patients to become more involved in several aspects of their care as well as enhance their interaction and experience with the clinic.  We are also actively planning the next NF Symposium, or NF Family Day, scheduled for August of 2017.  In conjunction with Children’s Harbor, we’re exploring the possibility of using an off-campus location for an overnight retreat with our NF families.  Also, we’re looking forward to supporting another successful Alabama NF Walk in October as part of CTF’s ongoing efforts to raise funds for critical research aimed at finding and developing effective treatments for NF.