Measurement Technique for Dermal Neurofibromas Validated at UAB Expands Possibilities for Clinical Trials

In continuing our discussion from the previous blog regarding how the focus of a clinical trial is determined, I’d like to address the treatment and research of two distinctive features of NF that are of significant concern to patients – dermal neurofibromas and plexiform neurofibromas.  A frequent question from patients related to neurofibromas is:  Why do clinical trials focus on plexiform neurofibromas, while there are no clinical trials in progress for dermal neurofibromas? Many patients feel that dermal neurofibromas are an underappreciated feature of NF.  

The basis for focusing on plexiform neurofibromas thus far in clinical trials centers on three issues: first, complications of plexiforms are often more serious than for dermal neurofibromas and can sometimes be life-threatening; second, the several mouse models for testing drug effectiveness in plexiform neurofibromas are better established than the model currently available for dermal neurofibromas; and the technology for measuring dermal neurofibromas is not as advanced as for plexiforms, making it more difficult to determine the effectiveness of a specific drug on tumor growth.  The good news is that the UAB NF Program has worked with collaborators recently to establish the validity of a measurement technique for dermal neurofibromas, and this method will enable the development of future clinical trials focused on testing the effectiveness of drugs in slowing or reversing the growth of these types of tumors.

In providing a more thorough explanation about the future of clinical trials for dermal neurofibromas, it’s first helpful to understand the significant differences between dermal and plexiform neurofibromas.  Dermal neurofibromas are soft, benign tumors that develop under the skin.  These tumors typically appear after puberty and grow slowly over a period of time. While they are variable in size and number, dermal neurofibromas can be disfiguring in some patients, causing embarrassment and problems with self-esteem.  In fact, the unpredictability of dermal neurofibromas can be the most daunting aspect of this NF feature; some individuals have few or none, while others’ bodies may be completely covered.   Many women with NF1 experience increased growth of neurofibromas during pregnancy, suggesting that hormonal changes may be related to their development. 

The treatment approach for dermal neurofibromas is dependent on the number and location of tumors, although the most common approach is to leave them alone due to their benign nature and the low risk of medical problems. The most common treatment is surgical removal of individual tumors using either conventional plastic surgery, laser treatment, or a procedure called electrodessication that uses an electrical current to remove a large number of tumors at one time.   While these treatments can be effective, each can leave scarring and none of the options prevents additional tumor development.  

Plexiform neurofibromas are congenital tumors that often first appear in infancy or early childhood as a soft swelling under the skin.  Affecting about 50% of people with NF1, these tumors are frequently larger and usually involve multiple branches of large nerves.  Depending on their location, plexiform neurofibromas can lead to abnormal bone growth or pressure on nerves, blood vessels, or organs. For example, plexiform neurofibromas along the spine can compress the spinal cord, leading to weakness, pain, and sometimes paralysis.  Surgical removal can reduce the overall size of the tumor, although it will not stop the tumor from growing.

Because the symptoms of plexiforms can be urgent and potentially life-threatening, this feature has been given greater priority over dermal neurofibromas in clinical trials.  Plexiform and dermal neurofibromas are similar at the cellular level, however, so the hope is that some treatments for plexiforms may also be effective for dermal neurofibromas.

Until recently, the challenge in testing the effectiveness of specific drugs for the treatment of dermal neurofibromas has centered on the difficulty of obtaining accurate measurements of these tumors. Unlike plexiforms that grow quickly and can be measured relatively easily with imaging studies, the slower growth rate and configuration of dermal neurofibromas make them difficult to measure accurately.

In collaboration with a research group in Brazil, scientists in the UAB NF Program have tested a measurement method over the past several years that recently has been validated as providing an accurate estimate of dermal neurofibromas (Publication). Using adhesive paper frames with a 10 cm x 10 cm window cut-out, a group of patients’ dermal tumors were documented and measured by attaching the paper frame to a specific region identified by a physical landmark that was photographed; this procedure allowed us to measure growth of dermal neurofibromas over a period of time.

This recently validated measurement technique for dermal neurofibromas has opened the door to conducting clinical trials focused on testing medications to treat this feature that is problematic for so many NF patients.  We are now exploring the possibility of conducting a small, independent pilot trial to determine the effectiveness of a treatment for dermal neurofibromas.  Also, we have plans to design a secondary arm of a clinical trial for plexiform neurofibromas that would test the effectiveness of the medication on dermal neurofibromas.  As a secondary endpoint within this trial, individuals with plexiform neurofibromas would undergo measurements of dermal neurofibromas over a period of time to determine if the medication has had an effect on slowing the growth.

We still do not know when there will be effective treatments for the various aspects of neurofibromatosis.  Those with dermal neurofibromas should know that this aspect of the condition is not being ignored, and I am hopeful that clinical trials for dermal tumors will become a reality soon. 

Birmingham Family Affected by NF Recognized at CTF BeNeFit II Gala in Detroit, and Frequently Asked Patient Questions Regarding NF Clinical Trials

The previous year drew to a close with the recognition of an inspirational family affected by NF who has shown unique courage, determination, and leadership in facing the challenges so familiar to other NF families.  On November 22, 2014, a well-known Birmingham family in the NF community – Renie and Philip Moss and their children, Philip and Helen – received the prestigious Strength and Honor Award at the Children’s Tumor Foundation (CTF) BeNeFit II in Detroit, Michigan.  The well-deserved recognition of this special family is based on their leadership role in establishing the Alabama chapter of CTF and their ongoing, tireless dedication to NF-related education, fundraising, and outreach. With more than 1,100 people in attendance, the superhero-themed gala raised approximately $3 million for CTF, the major source of patient advocacy and research support for all forms of NF in both adults and children. A brief video of the Moss family’s story and Renie’s and Philip’s reflections of the gala and the Strength and Honor Award can be found on the CTF web site

As a new year begins, we at UAB continue our commitment to advancing and facilitating research for all forms of neurofibromatosis. In support of this commitment, UAB serves as the national coordinating center for the NF Clinical Trials Consortium, a collaborative group of 17 medical centers across the country (and one in Australia) dedicated to conducting clinical trials of the most promising drug therapies for all forms of neurofibromatosis. During the NF Clinical Trials Consortium steering committee meeting held last month in Baltimore, discussions were held regarding selection criteria for topics of upcoming clinical trials.  Frequently, two specific questions that arise from NF patients regarding clinical trials are:  Why are the entry criteria for clinical trials so strict?; and Why aren’t more clinical trials conducted for more features of NF?

Regarding the first question, it is understandable that many NF patients are interested in participating in clinical trials to assist in advancing research and to receive drug therapies that might be beneficial in treating a specific feature of NF.  The purpose of a clinical trial is to conduct a test of a specific medication to determine if it has a potential benefit.  It’s important to understand that clinical trials must be conducted according to strict protocols, and in the case of new drugs, the trials are monitored by the FDA.  Also, data have to be collected with strict adherence to the protocols to ensure that results are valid and usable.  If a trial proves to be effective, a specific drug could be made available to a wide number of people, instead of just the few individuals who participated in a specific trial.  Strict entry criteria must be maintained to ensure the validity and reliability of the clinical trial, which in the long run benefits the entire NF community.  These criteria include:  A confirmed diagnosis of NF; the confirmed presence of the NF characteristic(s) being investigated in the trial; and the absence of a prohibitive medical history, such as reduced kidney or liver function or other medical conditions that could compromise the study results or endanger the study participant.  Because of these strict entry criteria, some NF patients are not eligible for a certain clinical trial.  While this can be disappointing for these patients, it is important to remember that accepting only those patients into the trial who fit the specific criteria ensures the reliability of the trial and safeguards the potential of making a specific beneficial drug available to larger number of NF patients.

Some NF patients find it frustrating that the complications they are experiencing may not be the subject of a clinical trial and often ask how the focus of a clinical trial is determined.  This is an important question, and it should be emphasized that we are interested in conducting clinical trials for all forms of NF. Because financial resources for conducting clinical trials are limited, with the minimum average cost of a trial in the hundreds of thousands of dollars, decisions regarding the focus of a clinical trial are made according to specific criteria.  We are also mindful of the fact that the NF patient community is relatively small, and we want to make sure that clinical trials are done for the most promising treatments, so that we don’t overwhelm the community with trials that have little chance of working.  Generally, features that are potentially life-threatening are given greater priority, such as plexiform neurofibromas and malignancies.  The NF Clinical Trials Consortium Steering Committee determines the focus of a clinical trial based on the following criteria:  The degree to which a specific feature of NF is problematic or life-threatening; the availability of a drug that might be effective (based on previous animal model studies); and the prevalence and availability of patients with the NF feature.  The recommendations of the Steering Committee are then reviewed by an external scientific review panel and also by an external oversight committee appointed by the Department of Defense, which is the sponsor for the Consortium.

In using specific definable criteria for selecting the focus of clinical trials and the participants to whom drug therapies are administered, we’re ensuring that the results of these important studies are valid, reliable, and can ultimately be used to identify the most promising drug therapies for all forms of neurofibromatosis.   

Highlights of NF Family Day and Encouraging Developments from an International NF Meeting

I’m pleased to report another successful Neurofibromatosis Symposium was held at the UAB Hugh Kaul Genetics Building on September 27th.  Entitled “NF Family Day 2014:  Learning & Thriving Together,” this half-day, free event was co-sponsored by UAB and the Children’s Tumor Foundation (CTF).  The focus of the event – also known as NF Family Day – was to provide NF patients and their families with a range of information about NF through a series of brief presentations, including an overview of neurofibromatosis, an update on clinical trials and research advances, and patient advocacy.   Also, a well-known patient advocate in the Birmingham NF community, Renie Moss, and Kristen Stanley from CTF gave presentations about the work of CTF and also the NF registry.  The NF registry (https://nfregistry.patientcrossroads.org) was established by CTF in 2012; its purpose is to help notify NF patients who may be eligible for clinical trials or other research studies and to determine the frequency of specific NF characteristics.  A highlight of this year’s NF Family Day was the opportunity for patients and their families to tour two UAB laboratories involved in NF-related research – the Medical Genomics Laboratory, which has performed the largest number of NF mutation tests of any laboratory in the world, and another laboratory developing animal models of NF1 mutations. These tours gave patients and families a firsthand, “insider” look at the promising research initiatives being conducted at UAB with the overall goal of finding and testing effective treatments for NF.

In addition to providing patients and families with important information about NF, a primary purpose of this event is to give families an opportunity to meet and interact with one another. Many of these families haven’t previously had the chance to speak with other families affected by NF, and it’s very meaningful for them to be able to talk to and learn from others with similar experiences and challenges.  Many NF families attending the Symposium find that having the opportunity to meet other families in our community affected by NF is one of the most helpful aspects of the event.  It’s rewarding to know that the annual NF Family Day can help to facilitate these important, supportive connections among NF families. 

In early September, two UAB colleagues and I attended the 16th European Neurofibromatosis Meeting in Barcelona, Spain. Held every two years, this meeting assembles more than 100 international clinicians and researchers in the field of neurofibromatosis to present the most current research and clinical advances.  Dr. Ludwine Messiaen, director of the UAB Medical Genomics Laboratory, chaired a session at the meeting and presented an overview of her NF-related research involving the pursuit of genotype-phenotype correlations and identification of novel disease-predisposing genes. Visiting UAB professor and clinician Dr. Xioajie Hu from Shanghai, China, also attended.  Dr. Hu, a plastic surgeon, has been working with us since April with the goal of establishing an NF clinic and research program upon his return to Shanghai in a few months.

During the meeting, I was honored to chair a session on quality of life issues in NF and to give an overview of our UAB NF research program, including current clinical trials of promising NF medications and the development of mouse models of actual human NF1 mutations with the goal of testing medications that may restore function to the mutated gene or gene product.  Overall, the meeting underscored the robust international efforts currently in progress to generate new research initiatives focused on indentifying effective NF treatments. It was encouraging to be a part of this global, collaborative effort that promotes and fosters an exchange of ideas among members of the NF scientific community.