Director's Blog
Highlights of the 2017 NF Conference, NF Clinical Trials Consortium Update, and Frequently Asked Questions about Clinical Trials
Last month, nearly a dozen colleagues from UAB attended the 2017 NF Conference in Washington, DC. This international conference, organized by the Children’s Tumor Foundation, began in the 1980s with the original purpose of promoting the sharing of data to assist in mapping and the ultimate identification of the NF genes. When these goals were accomplished for NF1 and NF2, the meeting gradually evolved to an annual international research conference. The event now serves as the global flagship scientific forum where more than 300 participants from a range of scientific and clinical backgrounds gather annually to build consensus and foster collaboration for advancing basic, translational, and clinical research focused on improving outcomes for all forms of NF. The four-day conference features a series of poster presentations summarizing research, invited lectures, and platform presentations. Many of the speakers are from outside the NF field, broadening the scientific input into the study of NF.
While I’m not certain whether our UAB group was the largest contingent at the meeting, we were certainly among the largest groups in attendance. Several of us from UAB gave talks from the platform and most had poster presentations. A poster developed by Bob Kesterson, PhD, a professor of genetics and research scientist in our program, won the prize for best poster at the conference. Dr. Kesterson’s poster demonstrated how complementary DNA (cDNA) is now being used to provide a tool for assessing whether a mutation affects the function of the NF1 gene. This approach will be useful in determining whether some variants of unknown significance in the NF1 gene are actually disease-causing. It will also be used to determine whether skipping some part of the gene that contains a mutation will be tolerated (see last month’s blog on exon skipping). Dr. Kesterson was invited to give a brief talk on his research, and his award and recognition was an honor for him and our program. As I discussed in last month’s blog, there is an increasing focus within the NF scientific community on the development of genomic-guided therapies that will restore function to mutated genes. While this approach is already being used to develop potential treatments for other diseases such as cystic fibrosis and muscular dystrophy, it is receiving greater focus and attention from other scientific communities, including NF. We at UAB are recognized as the pioneering group in genomic-guided therapeutics within the context of NF, and we look forward to continuing our role as a leader in developing initiatives that will advance this promising avenue of potential treatment for NF.
NF Clinical Trials Consortium and Commonly asked Questions
Every six months, the NF Clinical Trials Consortium Steering Committee meets to discuss plans for upcoming clinical trials. Our most recent meeting was held in December in Baltimore with staff members from the Department of Defense (DoD) in attendance. This was the first steering committee meeting held since we learned of renewed funding, and we are preparing to launch the next round of clinical trials. Persons with NF often inquire about which clinical trials are available and if they can participate. Sponsored by the US government, the Web site www.clinicaltrials.gov provides information about all clinical trials categorized by condition. The federal government requires trials to be registered and to include detailed information on the site about eligibility criteria, site location, primary outcome measures, and other information.
In the past, clinical trials were not always forthcoming about outcome information, especially if the trial did not prove to be effective. Now it is mandated that outcome information be posted on the site for trials that have been completed.
We also receive occasional questions regarding the preliminary outcome of a clinical trial that is ongoing. We’re unable to provide any information about the preliminary findings of a clinical trial until the final data have been received. Typically, the investigators are not privy to the data because there is concern about possibly biasing the study. We therefore can’t answer the question of “What are you seeing so far?” A Data Safety Monitoring Board appointed to oversee a trial reviews the data for the ongoing study. In some cases, the trial is so effective that it is discontinued early. In other cases, the board may have data to indicate that the trial is not working or that side effects are too serious, and they will stop the trial. Another frequent question from patients is whether they can participate in a trial at a distance, or even from outside the country, instead of at the site where the trial is being conducted. Depending on the trial design, sometimes this is possible, though most times challenges exist that may not make it possible. If a medication is part of a trial, it is required that participants receive the medication at the site of the trial. Also, there are often routine screening tests that must be performed on site. Because it is sometimes possible to participate in a clinical trial from another location, it’s best to contact the staff conducting a particular trial to learn about participation requirements. Contact information is provided on clinicaltrials.gov.
Development of Genome-Guided Therapeutics for NF Based on Genetic Mutation Subsets
Neurofibromatosis type 1 is caused by a change in the genetic sequence in the NF1 gene, a large and complicated gene that contains a code for making a protein called neurofibromin. All individuals have two copies of this gene, one inherited from each parent. In people with NF1, one copy of the NF1 gene is altered due to either inheriting the altered gene from a parent, or acquiring a new genetic mutation that occurs in the egg or sperm prior to conception, or from a mutation that occurs early in embryonic development (this results in segmental NF). For someone to develop NF1, a random genetic mutation must occur to the second copy of the NF1 gene in the tissue that will become the neurofibroma, café-au-lait spot, or other lesion. This is referred to as the “second hit” mutation. All individuals – with or without NF1 -- probably have some acquired mutations, which are random errors, that result in a few cells containing an NF1 gene alteration. These cells will not become neurofibromas, however, if only one NF1 gene copy is altered. The problem for individuals with NF1, however, is that this “backup copy” of the NF1 gene is already altered, which is why a neurofibroma will develop. Genes function in the cell to direct the production of proteins. The key question is whether we can find a way to restore function to an NF1 gene that has been damaged by mutation, or perhaps restore function to the abnormal neurofibromin that in some cases is produced.
Therapies Focused on Blocking the Ras/MAPK Signaling Pathway
The majority of therapeutics developed so far for NF1 has focused on blocking the Ras/MAPK signaling pathway that is hyperactive in cells in which both copies of the NF1 gene have been impaired. Neurofibromin regulates the activity of the Ras/MAPK cellular signaling pathway that helps to control cell growth and division. This pathway is also implicated in other diseases, such as cancer. Several drugs have been developed that have shown promise in inhibiting components of the Ras/MAPK signaling pathway implicated in NF1 and other diseases. For example, selumetinib is one of a family drugs that has been developed as an inhibitor of one of the components of the pathway and has been shown to have efficacy in reducing the size of plexiform neurofibromas. The development of therapies that inhibit the over-activated Ras/MAPK pathway and other Ras-connected pathways opens new opportunities for treatment for NF1, cancer, and other disorders that share a similar mechanism.
Development of Genome-Guided Therapies Based on Genetic Mutations
While the development of therapies that target Ras signaling is an important approach to developing potential treatments for NF, the possibility of restoring function to mutated genes using genome-guided therapies has gained increasing attention from the NF scientific community and represents an area of focus for the UAB NF Research Program. An advantage of this approach is that restoring function to the mutated gene might result in fewer side effects than with drug treatments that block Ras signaling. On the other hand, Ras signaling seems integral to the mechanism of disease in all patients with NF1, whereas genome-guided treatments are based on the specific type of genetic mutation causing an individual’s NF1, and therefore one treatment will not work for all patients. There are thousands of different mutations in different patients with NF1. These mutations are distributed across the gene with no specific mutation predominating. There are, however, subsets of mutations that can be identified through genetic testing, which enable the development of specific approaches to restore function to specific types of mutated genes. In this way, rather than require development of thousands of drugs, one for each mutation, it may be possible to develop a handful, each of which targets a specific type of mutation.
Mutation Subsets
The thousands of mutations can be classified into a number of types. A deletion mutation results in the total loss, or deletion, of the entire gene and usually produces a severe form of NF. Approximately 3% - 5% of NF mutations are of this type. There are currently no effective methods for replacing large genes, such as the NF1 gene, although this capability may be developed at some future point.
Another type of mutation, called a truncating mutation, causes a blockage or interruption in the formation of a protein. Neurofibromin is comprised of a chain of 3,818 amino acids strung together in a unique sequence. One type of truncating mutation, called a premature stop mutation (or nonsense mutation), inserts a signal that tells the protein production machinery in the cell to cease production of neurofibromin before the complete protein is made. Drug therapies currently in development have shown potential effectiveness in overcoming the effects of premature stop mutations. The UAB NF Research Program is currently testing drug compounds that read through the premature stop signals caused by these mutations, with the goal of allowing cells to produce a full-length, functional protein.
A frameshift mutation is caused by insertions or deletions of a number of nucleotides in a DNA sequence that is not divisible by three. When DNA is used by the cell to produce protein, the genetic information is read out in groups of three DNA elements, called “bases.” Hence a specific building block of a protein (an amino acid) is inserted into the protein because of the presence of a specific three-letter base sequence in the gene. If there is a loss or gain of one or two bases in the DNA sequence for that gene, the reading of the three-letter “words” is confused. This results in the sequence of amino acids being significantly altered, and at some point there will be a premature stop in the sequence. These types of mutations may be hard to correct, but we are exploring an approach that would jump over the segment of a gene that contains a frameshift when the gene is being processed for reading the sequence and producing the protein.
Splice-site mutations also result in a meaningless sequence that causes the production of a nonfunctional protein. A gene is encoded in segments, called exons, which code for the amino acids of a protein, separated by introns, which are intervening sequences. The genetic code in the DNA of a gene is first copied into a molecule called RNA, which is then read out to instruct the production of a protein. Initially, both the exons and introns are copied into the RNA, but then the introns are cut out and the exons spliced together to make the final “messenger RNA.” The process of splicing is precisely controlled by the base sequence of the gene, and some mutations occur at the sites that control this process, and therefore disrupt splicing. It may be possible to restore the normal splicing pattern using medications that interact with the splicing system. This may restore function to a gene disrupted by a splicing mutation; it is also the same method that might be used to jump over a segment with a frameshift mentioned above – this is called “exon skipping.”
Lastly, missense mutations result in the production of a full protein, although one amino acid in the sequence is incorrect. With some sequences, this error won’t cause a problem; however, if the error is related to the production of a critical part of a protein it may disrupt function. We’re currently working to develop compounds that that interact with protein to restore its function, at least partially. This has been a useful approach to therapeutics in the treatment of conditions such as cystic fibrosis. The exon skipping approach also might be useful here.
Gene Editing or Replacement
A final possibility is to try to get into the cell and actually correct the gene mutation, or perhaps even to replace the mutated gene entirely. There has been a lot of interest in these kinds of possibilities, especially recently with the advent of the CRISPR/Cas9 system. This system was developed based on a natural mechanism discovered in bacteria that protects bacterial cells from infection by viruses. It has been modified to permit editing of DNA sequences, including potentially correction of gene mutations. Our lab, and many around the world, are using CRISPR/Cas9 as an approach to creation of model systems that require producing a specific mutation of interest. Applying this to the treatment of a genetic disorder is much more complicated, especially one like NF1 that affects a very large number of cells in the body. This is, however, a new area of research, and one where we may see significant progress in the years to come.
Conclusion
We are beginning to see benefits from small molecule treatments that target Ras signaling, but in the long run we are likely to need many parallel approaches to effectively treat NF1. Our group, and many others, are pursuing such approaches, including the development of genome-guided therapeutics. It is likely that the eventual treatments of NF1 will require combinations of different approaches that will synergize with one another to control the symptoms of the disorder.
Current and Future Research Initiatives for the Treatment of Cutaneous Neurofibromas
I’d like to focus this month’s blog post on a discussion of cutaneous neurofibromas, which are benign tumors that can grow on nerves throughout the body in some individuals with NF1. Typically beginning around the time of puberty, these tumors grow from small nerves either in or under the skin and appear as small bumps on the surface of the skin or as purplish spots when the tumors occur underneath the skin. Although these tumors are sometimes also referred to as “dermal neurofibromas,” NF clinicians and scientists at a recent meeting of the Neurofibromatosis Therapeutic Acceleration Program (NATP) emphasized the need to move away from using this term in favor of the term “cutaneous neurofibromas.” The dermis is actually not the layer of the skin from which neurofibromas originate, while “cutaneous” is a general term referring to the skin and is therefore a more accurate term for these tumors.
In the past, we have found that obtaining funding for clinical trials of cutaneous neurofibromas has been somewhat difficult. Because these tumors are non-malignant and not life-threatening, the question often posed is: Why is it necessary to treat cutaneous neurofibromas? Conversely, plexiform neurofibromas are much more serious and sometimes life-threatening due the risk of malignancy and the possibility of compression of the airway or the spine. However, it is also true that cutaneous neurofibromas may be unfairly trivialized in their impact on the lives of individuals with NF. We receive numerous inquiries asking why cutaneous neurofibromas are not the subject of clinical trials. Data indicate that quality of life for people with cutaneous neurofibromas can be significantly impaired. There are sometimes cosmetic concerns in a major sense, as these tumors may be quite disfiguring. Also, the tumors may itch, can sometimes bleed, and even cause pain.
Research Focused on Cutaneous Neurofibromas
A longitudinal study has been in progress at UAB for the past several years focused on understanding how cutaneous neurofibromas grow and change over time. As part of the study, 22 participants have had their neurofibromas counted and measured every three months. Our NF Program Genetics Counselor, Ashley Cannon, MS, PhD, CGC, assumed the principal investigative role in the study when she joined our program in 2015 and has now completed an analysis of eight years of quantitative data on many of the original study participants. Dr. Cannon recently presented the study findings at the conference of the American College of Medical Genetics and Genomics (ACMG) in Phoenix and is preparing the results for upcoming publication.
These findings will also serve as the basis of an upcoming clinical trial at UAB that will test the effectiveness of a systemic treatment for cutaneous neurofibromas administered in the form of a pill. While development of a topical treatment was considered, it can be difficult to formulate a compound that permeates the skin layer. Also, for some people, cutaneous neurofibromas are too widespread on the body for a topical treatment to be effective. Additional information about the trial and details about upcoming recruitment can be found at www.clinicaltrials.gov.
In other research for cutaneous neurofibromas, we are exploring other potential treatments for future clinical trials of cutaneous neurofibromas. We’re also working to find ways to restore function to mutated genes or gene products, which could provide new ways of treating these tumors. Researchers at UAB are currently studying the more than 3,000 NF mutations contained in the library of the UAB Medical Genomics Laboratory to determine whether particular mutations increase the likelihood for cutaneous neurofibromas to occur. We know of two mutations that do not produce neurofibromas of any type. There are other mutations that don’t produce cutaneous neurofibromas but do produce neurofibromas deep inside the body (plexiform neurofibromas). We are currently developing animal models and other types of model systems to understand the characteristics of specific mutations with the goal of developing new treatments for cutaneous neurofibromas.
Highlights of UAB Rare Disease Genomics Symposium and a Discussion of Visual Screening in Children with NF1
I am completing this blog post just hours after finishing the New York City half marathon with a team from the Children’s Tumor Foundation. It was a cold start, but otherwise a beautiful day – a lot nicer than the rain/snow mix the day before. We were raising funds for the Children’s Tumor Foundation and it’s not too late to add to the dollars contributed. My fundraising page is at: https://join.ctf.org/fundraise?fcid=674407. Any help in reaching my goal would be greatly appreciated!
UAB Rare Disease Genomics Symposium Advances Role of Genomics in Everyday Medicine
The fourth annual Rare Disease Genomics Symposium, held March 3rd at UAB, was a successful and well-attended event designed to share information about the role of genomics in the diagnosis and treatment of rare diseases with healthcare practitioners who are non-genetic specialists. As a rare disorder, NF1 is a condition that benefits from diagnostic and therapeutic approaches used in the management of other rare disorders. Titled Genetics and Genomics in Day to Day Medical Practice, this one-day seminar covered a range of topics on the application of genomics in medicine. The Symposium featured a panel discussion led by parents of children with rare diseases that provided insight into the challenges and emotional needs of families of children with a genetic condition. One of the parents on the panel was the newly appointed director of the UAB Hugh Kaul Personalized Medicine Institute, Matthew Might, Ph.D., who provided a personal perspective of the potential of genomic medicine, as his son was diagnosed with a rare genetic disorder in 2012. The Symposium serves as an important forum for presenting topics to faculty and clinicians at UAB and in the community that demonstrates the increasingly important role of genomic medicine in the diagnosis and management of rare disorders.
Visual Screening in Children with NF1
I’d next like to discuss the issue of visual screening in children with NF1. As I’ve mentioned previously, the primary concern regarding visual problems is the development of an optic glioma, a tumor of the optic pathway, which occurs in approximately 15% of children with NF1. Most of the time, these tumors occur early in life, usually between the ages of 18 to 24 months. More than half of patients with optic gliomas have no symptoms. The most common presentation in patients who show symptoms is loss of visual acuity, and/or loss of peripheral vision, although other symptoms may include proptosis, or bulging of the eye; swelling, retraction, or drooping of the eyelid; and the onset of early puberty, which results in abnormally short stature in adulthood.
Although optic gliomas are fairly common in NF1, the majority do not require treatment. Fewer than half of optic gliomas in children with NF1 do progress and require treatment with chemotherapy. An important question for clinicians is how to identify those patients with optic gliomas who need treatment.
The current consensus recommendation for identifying NF1 patients with optic gliomas is to perform a comprehensive ophthalmologic assessment one time per year beginning at the age of diagnosis until late childhood, as the greatest risk for development of these tumors is through approximately the first six years of life. Ophthalmologic exams – which include tests for visual acuity, peripheral vision, and optic nerve health – are often difficult to perform in young children. For this reason, some ophthalmologists are testing advanced tools for administering exams in these patients. Sometimes, parents ask whether a school eye exam will suffice, and the answer is that it will not. Appropriate screening for optic glioma and other vision problems in children with NF1 requires a comprehensive eye exam administered by an experienced ophthalmologist.
If concerns arise based on the ophthalmologic exam, a brain MRI scan would be performed. If an optic pathway tumor is found, this may lead to more closely following the child’s visual function and monitoring growth of the tumor using MRI. If there is radiographic evidence of tumor growth but no symptoms are present, often it is possible to continue close clinical and radiographic follow-up without initiation of treatment. Some of these tumors grow for a period of time and then stop, and in rare cases may even regress. Because of this, if a tumor does not cause symptoms, treatment may not be necessary. Some clinicians prefer to obtain a baseline MRI scan of the brain in all children with NF1. I do not tend to do this, since identifying an optic glioma in a child with NF1 using MRI is not in itself an indication to begin treatment if there are no symptoms of tumor growth. We may be missing some optic gliomas by not using MRI as a screening tool, but if we’re not going to treat unless we see symptoms, the value of using an MRI to identify one in an asymptomatic child is unclear. This is consistent with current consensus recommendations for screening for optic glioma.
In the area of research for optic gliomas, there is an ongoing natural history study that is collecting data on NF patients with optic gliomas to help identify risk factors to predict those who will need treatment and those who will not (http://www.ctf.org/news/the-ctf-and-gilbert-family-nf-institute-opg-consortium-is-underway). Also, because the UAB Medical Genomics Laboratory performs the highest volume of NF genetic testing of any laboratory in the world, we have some limited data on patients with optic gliomas that may be used to identify gene mutations that might be associated with these tumors. Lastly, our program is exploring the development of more advanced ophthalmologic assessment tools for use in children with NF1.
Continued Benefits of NF Clinic Relocations and a Discussion of Headaches in Individuals with NF1
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.
Renewed Grant for the NF Clinical Trials Consortium and a Promising New Drug for the Treatment of NF1
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 (www.nejm.org/doi/full/10.1056/NEJMoa1605943).
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.
Highlights of a Successful Year and a Look Ahead to New Goals for 2017
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.
Successful Relocation of Adult and Pediatric NF Clinics and a Discussion of Increased Breast Cancer Risk in Women with NF1
Relocation of Adult and Pediatric NF Clinics
I’d like to provide an update of a development mentioned in a previous blog regarding the NF Clinic’s relocation to two distinct sites in the UAB Medical Center District. The relocation, which has recently been completed, originated earlier this year with the reorganization of the NF Clinic into adult and pediatric clinics. 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. Both of these facilities provide our patients with more convenient parking than our previous NF Clinic location in the Hugh Kaul Human Genetics building. Also, the new locations will enable improved integration with the range of other medical specialties involved in the multidisciplinary care we provide while allowing our patients to remain in one physical location for blood draws, imaging, or consultations with other specialists. Although our previous clinic location allowed us to see adults and children in the same visit, we now see adults at the Kirklin Clinic location on Mondays and children at the Children’s Hospital facility on Thursdays; at the Kirklin location, patients must be 16 or older, while patients in the children’s clinic must be 18 or younger. Because we understand that these split clinic days could be an inconvenience for some patients, we can certainly arrange to see members of the same family on the same day if needed, by prior request on a case-by-case basis. Overall, we believe that our patients and families will benefit from the convenience and integration of care that our adult and pediatric clinics provide.
Increased Breast Cancer Risk in Women with NF1
Next, I want to review information concerning the increased risk of breast cancer in women with NF1. In recent years, it has become clear that women with NF1 are at an increased risk for breast cancer, with the risk being two to three time higher in women with NF1 than in those in the general population. Also, these cancers occur at a younger age and tend to be more aggressive in women with NF1 than those that occur in women in the general population. The nature and composition of the cancers, however, are not different.
In many women who have been diagnosed with breast cancer, a genetic panel of tests is performed to detect mutations that might be associated with the cancer. The NF1 gene is now being tested as part of this panel, as well as other genes including BRCA1 and BRCA2. However, it’s important to note that the increased risk of breast cancer in women with NF1 is not associated with mutations in the BRCA1 or BRCA2 genes.
The reason for the increased risk of breast cancer in women with NF1 is not completely understood. We know that cancer is the result of the accumulation of genetic alterations that cause cells to behave abnormally. The NF1 gene has been shown to have mutated in many common cancers, which might indicate that the NF1 mutation puts an individual one step closer to developing other cancers.
Some women diagnosed with breast cancer have been referred to our clinic because of an unexpected NF1 mutation detected in the genetic testing panel. There are a few possible explanations for this finding, including that the individual has NF1 and was never diagnosed because the clinical features went unnoticed. Another possibility is that the individual has a mosaic form of NF1 that is detected in the blood but may not be clinically evident. Lastly, genetic variants are sometimes found in testing that are different from the normal gene variations. These are known as variants of unknown significance, and it can be a challenge to know what to do with this information. Often, when these patients are evaluated, they are not found to have NF1.
Breast Cancer Screening Recommendations
The increased risk of breast cancer in women with NF1 raises questions about screening recommendations. The National Comprehensive Cancer Network (NCCN), an organization that issues screening guidelines for various cancers, recommends that women with NF1 should be screened for breast cancer at an earlier age than the general population, beginning at age 30. In addition, the NCCN states that some consideration should be given to the use of breast MRI from age 30 to age 50. After this, the guidelines shift back to that of the general population. We are now recommending these screening standards to the patients we see in our clinic with the goal of achieving an early diagnosis for improved outcomes.
Some patients are concerned that neurofibromas in the breast may be confused with breast tumors during imaging. Although neurofibromas can develop in the skin of the breast, they are clinically distinguishable from tumors in breast tissue. However, it is important for radiologists to know the NF history when reading imaging results for these patients.
A Successful 3rd Annual Alabama NF Walk and a Discussion of Developmental Issues and Cognitive Function in NF1
The 3rd annual Alabama NF Walk, held on October 16th in Veteran’s Park in Hoover, proved to be another highly successful event that raised both awareness of NF in our community and critical funds for NF-related research. Held in cities across the nation, the NF Walk is 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. Launched only three years ago in our local area, this year’s Alabama NF Walk raised more than $40,000 and registered more than 300 participants. In addition to raising awareness of NF among people in our community, the event also provided an opportunity for NF patients and families to enroll in the NF Registry, established by CTF in 2012; the purpose of the NF Registry is to notify NF patients who may be eligible for clinical trials or other research studies and to determine the frequency of NF characteristics. Several newly diagnosed patients and their families in attendance expressed their gratitude for the hope and support they received as a result of coming together as an NF community, which is an important and meaningful benefit of this special fundraising event.
Cognitive Function and Learning Difficulties
I’d like to focus our discussion this month on developmental issues and cognitive function in individuals with NF. Neurofibromatosis type 1 is associated with an increased risk of learning disabilities as well as a constellation of other symptoms that can impede school performance, including attention-deficit/hyperactivity disorder (ADHD), delayed language development, immature behavior, and low muscle tone. Sometimes cognitive problems are severe and evident early in life; however, sometimes these problems don’t appear until children have reached school age. It is estimated that 50% of children with NF1 have some type of learning problem, although this statistic may be an underestimate of the prevalence of learning issues in children with NF1. I find that the more one looks for learning problems in children with NF, the more these problems are identified.
We therefore keep a watchful eye out for learning difficulties among children with NF1. Although we don’t always perform formal developmental assessments, we do focus on developmental issues and evaluate whether a child’s development is in the normal range of what is expected for his or her age. Also, we educate families about the prevalence of learning disabilities in children with NF1 and arrange an evaluation with a neuropsychologist for a formal developmental assessment if needed. Some parents have found that developmental assessments administered by schools can be difficult to obtain. Families considering formal evaluations for their child with NF should seek out an experienced professional, usually a neuropsychologist with experience in administering developmental assessments, who is familiar with resources in the community and can also advocate effectively for their child.
It’s important to note that learning problems are also common among the general population. Because there is not a specific profile of learning issues unique to NF, there is not a specific management plan that is unique for those with NF1. Learning problems are managed using the same methods as for individuals who don’t have NF. Effective management of learning difficulties involves providing a supportive educational environment with a focus on early intervention to address specific issues such as delayed language development. The same management approach applies to children with ADHD, although these children may also benefit from the use of stimulant medication to help control symptoms.
Regarding other developmental issues in children with NF1, the low muscle tone that occurs in some children tends to improve over time. It may, however, evolve into less overall coordination in adolescence and adulthood. The lax muscle tone may cause some children with NF, even those of normal weight, to have a protuberant belly. This is a common occurrence, however, and not a cause for concern.
Questions sometimes arise as to whether parents should tell a teacher that their child has NF. The concern is that providing this information may cause a teacher to assume that the child has a learning disability. If learning issues are occurring, however, early intervention and support can lead to better outcomes for the child. Without this critical support, children are at risk for performing below their academic capabilities, which may lead to more limited opportunities in adulthood. Another consideration is that when parents don’t inform the teacher that their child has NF they are not in control of the information acquired and assumptions the teacher may form about their child. Most parents find that sharing information and recruiting the teacher as an ally is a helpful step in ensuring their child’s academic success. The Children’s Tumor Foundation offers a brochure designed specifically for educators that can be helpful in sharing information about NF (www.ctf.org or 1-800-323-7938).
While there are no medications that are effective in improving learning disabilities, there was hope that statin drugs may improve learning based on studies a few years ago using mouse models. However, three subsequent clinical trials showed no beneficial effect of statin drugs on learning. Possible reasons that statins showed improved learning in mice but not humans include the fact that mice are inherently different than humans and the measures for learning are also different. Also, the dosage administered to mice in the studies may have been higher than is safe for humans. Based on the findings of the clinical trials and the risks associated with statins, the use of these medications for learning disabilities is not a recommended approach to treatment.
Highlights of NF Symposium, Plans for 3rd Annual NF Walk, Discussion of Mosaic NF1, and a Review of the NF Neurologic Exam
Last month saw another successful annual NF Symposium, held for the first time at the Children’s Harbor Building at Children’s of Alabama on Saturday, August 27th. Co-sponsored by UAB and Children’s Tumor Foundation (CTF), this half-day, free event, also known as NF Family Day, provided an invaluable opportunity for NF patients and families to hear a series of presentations on a range of NF-related topics presented by clinical experts. A special program of activities was provided for the children in attendance, and our NF families also had an opportunity to learn about the range of services available at Children’s Harbor, a non-profit organization that supports seriously ill children and their families through education and counseling services. I opened the Symposium with an introduction to the features of NF as well as an overview of our research initiatives in the NF Program. UAB Professor of Pediatrics and Director of Neuro-Oncology Alyssa Reddy, MD, provided an update of NF-related clinical trials currently in progress, and UAB Assistant Professor of Pediatrics Critical Care Michele Kong, MD, gave an interesting and informative talk on developmental issues in children (not just those with NF). Also, our NF Program Genetic Counselor Ashley Cannon, MS, PhD, CGC, presented the natural history of dermal neurofibromas, followed by Birmingham patient advocate Renie Moss’ review of advocacy, fundraising, and upcoming events. In addition to providing an opportunity for NF patients and families to gain important information about NF, it’s also rewarding to know that this annual event facilitates connections among patients and families that allow them to share their unique challenges, experiences, and concerns.
I also want to mention that plans are underway for another important NF event, the 3rd Annual Alabama NF Walk, which is scheduled for Sunday, October 16th, at 1 p.m. in Veteran’s Park in Hoover. The purpose of the event is to raise funds 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. Last year’s event raised more than $73,000 and registered more than 400 participants, which was a significant accomplishment for an event that was launched in our local area only two years ago. We’re pleased that the NF Walk has continued to generate increased interest each year and has become a significant means of raising critical funds to support NF research focused on the development of breakthrough treatments. To learn more about the Alabama NF Walk or to register, visit www.nfwalk.org.
Brief Review of Mosaic NF1
In previous blogs, I’ve referred to the fact that some people have features of NF that are confined to a certain region or segment of the body. A possible explanation for the occurrence of isolated NF features in some individuals is mosaicism, caused by a genetic mutation of the NF1 gene that arises after conception and during early embryonic development. As a result, some cells in the body have the mutation while other cells do not. The area of the body affected may be a cluster of cells in one region, such as an arm or leg, resulting in café-au-lait spots or a cluster of neurofibromas in one region of the body. Because genetic testing for NF1 using blood doesn’t always detect the mutation in people with mosaicism, the best method of diagnosing this form of NF is to perform genetic testing using a biopsy of affected tissues, either neurofibromas or café-au-lait spots.
A question that often arises related to mosaicism is whether there may be features of NF present in the body that are not visible on the surface. In the majority of people with mosaicism, the outward manifestation is the only NF feature that is present, but we do remain vigilant for other manifestations that may occur internally. Unless specific symptoms are present, there is usually no need for imaging to detect tumors.
Another important question related to mosaic NF1 is whether it can be passed to a child at conception. An individual with mosaic N1 cannot have a child with the mosaic form of NF1. However, it is possible for someone with mosaicism to have a child with generalized NF1, in which every cell in the body has the NF1 mutation. If we know an individual has a mosaic form of NF, we can offer prenatal counseling and genetic testing to assist in pre-conception planning.
Neurologic Exam
Continuing our discussion from last month’s blog about what to expect during an NF exam, I’d like to briefly review the components of the neurologic exam. First, mental status is evaluated by determining if the patient is awake and alert and able to understand and speak. For a child, this part of the exam involves an evaluation of developmental status, including a determination of whether the child can talk and follow basic commands in accordance with his or her age level. In addition, we evaluate the function of the 12 cranial nerves, which originate from the brain and brain stem and affect the head and neck. Each nerve has a specific sensory or motor function. For example, the 3rd, 4th, and 6th cranial nerves are responsible for eye movements and could be affected either by neurofibromas or problems in the brainstem related to NF. We also perform a visual assessment to evaluate functioning of the 2nd cranial nerve, the optic nerve, which carries visual information from the retina to the brain. People with NF may develop tumors on the optic nerve, called optic gliomas, that can cause loss of vision and can also affect hormone secretion in the pituitary gland that may lead to early onset of puberty. It’s important for children with NF to have a comprehensive eye exam yearly to check for symptoms of optic glioma.
Also as part of the neurologic exam, we evaluate the strength of the facial and jaw muscles, the tongue, and the neck and shoulders; muscle weakness in these areas may indicate a problem in the brain stem or a tumor on the nerve itself. Next, we evaluate the peripheral nervous system, which involves an assessment of overall muscle strength as well as reflexes and coordination. We look closely for asymmetry of motor strength, which could indicate the presence of a neurofibroma on the nerve as it exists the spine. Abnormal reflexes provide a possible indication that a tumor may be compressing the nerve or the spinal cord. The last component of the exam is the sensory evaluation. Some individuals with NF have symptoms of neuropathy, or peripheral nerve damage, which may include numbness, tingling, or burning sensations usually in the feet and hands.
