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Survival rates following childhood cancer are now over 80%, but closer analysis shows the majority of success in the past 10 years has been in improved treatment of blood disorders such as leukemias. In contrast, solid tumors have remained the most challenging, and survival rates have not changed in the past 10-20 years. Though only a small proportion of NF-related tumors will be cancer (malignancy), it is important for us to see what we can learn from this finding, to ensure we advance as fast as possible with treatments for the benign tumors that can affect kids with NF1. 

So what is the reason? Thursday’s Wall Street Journal Health Blog discussed this with Eugenie Kleinerman, professor and head of pediatrics at M.D. Anderson Cancer Center. The reasons are those that we face with trying to find treatments for NF tumors: need to understand biology and test the right drug candidates; the small numbers of patients for each type of tumor makes it hard to do a proper study coordination with other centers is key; and the difficulties that can be faced in trying to bring an adult-approved drug to children (bevacizumab/Avastin for example was controversial for kids in case it stunted growth, leading to a 10-year delay in this drug being used in children). 

So what is most needed? Not surprisingly Dr. Kleinerman highlights the need for funding into childhood cancer studies and trials. He cites an example that from an NCI annual budget of $4.8 billion, only $173 million went to pediatric cancer. Hopefully this will change as the biology is unraveled, drugs are selected, and more pediatrics studies are designed and submitted to NIH for funding.

Since its introduction, the use of the auditory brainstem implant (ABI) for hearing restoration in NF2 has grown in popularity.  Over the last 10 years, ABI use has also been extended to adults and children without tumor conditions but with those with cochlear or cochlear nerve malfunctions but did not benefit from a cochlear implant. However currently, ABI transplants can only be done by a very limited number of medical centers, which restrict access to ABIs for many individuals who could benefit, including those with NF2.   ABIs have been shown to be effective in individual cases, but can their use be expanded to more medical centers to benefit more patients? A new report* does a retrospective analysis of 114 individual ABI surgeries (83 adults and 31 children) performed between 1997 and 2008. 36 cases were persons with NF2, and 78 persons had non-tumor related cochlear and cochlear nerve disorders.

Overall ABI surgery has had a very low rate of major complications, particularly in non-NF2 patients. Minor complications were easily controlled and resolved in all cases.  The complication rates in the non-tumor cases were comparable to those of cochlear implant surgery in both adults and children. Overall this analysis is favorable of ABI use, a safe procedure when performed by an experienced surgical and rehabilitation team. Looking ahead it is hoped the benefits of the ABI can be extended to a larger population of hearing-impaired patients.

Welcome to the eighth and final in a series of "NF Bites" - providing snapshots of individual areas of neurofibromatosis research and how the Children's Tumor Foundation is advancing this. Today: where are we with optic pathway glioma research progress?

Optic pathway gliomas (OPGs) can occur in a small percentage of children with NF1, but these tumors can require surgical removal often leading to sight loss.   Additional impact of these tumors in the brain can extend to impacting hormone fluctuations and precocious puberty. Most commonly OPGs have been managed through surgery. Treatment with chemotherapy and radiation are also used though these have been somewhat controversial. Like the majority of NF1 tumors, OPGs are benign and the concern is that many chemotherapy approaches might be too harsh and that radiation might trigger advancement to malignancy.  

The good news is that researchers now understand quite a bit about OPG biology and this is helping to inform the selection and testing of candidate drug regimes in mice that might be advanced to humans.

·         Through the CTF NF Preclinical Consortium, a $4M multi-year initiative to accelerate the most promising candidate drugs to the clinic, the laboratory of David Gutmann (Harvard/ Brigham & Women’s Hospital) is testing candidate drugs in genetically-engineered mouse models of OPG, including through a collaboration with Genentech.

·         Joshua Rubin (Washington University School of Medicine) has received two Drug Discovery Initiative Awards – one, our only Advanced DDI Award (a special $50,000 Award for most promising DDI projects) to date, highlighting the importance of this research.  Based on understanding the biology of cells during OPG growth, Dr Rubin has used a mouse model to evaluate the use of the anti—inflammatory drug Rolipram as a co-therapy for treatment of optic pathway tumors. The goal of this research is to be able to reduce the amount of temozolomide that needs to be used to treat these tumors, and to take this forward to a clinical trial.

·         Young Investigator Awardee Sutapa Banerjee (Washington University School of Medicine) is examining the cell signaling element mTOR in regulating growth of optic pathway glioma tumors and in 2009 published early findings in the International Journal of Cancer.  Dr. Banerjee also published a paper in early 2010 in Cancer Research highlighting a new candidate drug target, called STAT3, for treating OPG.

·         Outside of CTF funding, an optic pathway clinical trial of Everolimus will commence in 2010 through the CDMRP NFRP Phase II Clinical Trials Consortium.

Thank you for your enthusiastic responses to the NF Bites series. Look for an updated series in the future!

Welcome to the seventh in a series of "NF Bites" - providing snapshots of individual areas of neurofibromatosis research and how the Children's Tumor Foundation is advancing this. Over the coming days and weeks we will focus on different aspects of neurofibromatosis research. Today: in Part 2 on where are we with research progress in NF2, we focus on advances in preclinical drug testing and clinical trials.

NF2 research activity, especially in the area of testing candidate drug treatments has increased significantly in the past several years. This has been driven in part by our publication in 2009 of consensus documents on NF2 clinical trials and drug pipeline in Clinical Cancer Research, based on an expert workshop convened by the Foundation. We currently fund a significant amount of NF2 research ‘from bench to bedside’ – an indicator of the exciting progress made in NF2 recently in understanding the underlying biology and then applying this to finding effective drug therapies. Importantly CTF is hosting an expert workshop in May 2010 to evaluate progress to date in NF2 clinical trials and how these can be further accelerated.

·         The Foundation was a co-supporter of the groundbreaking pilot Phase II trial of Bevacizumab (Avastin) which caused vestibular tumor shrinkage, restored hearing and was published in New England Journal of Medicine in July 2009.

·         One of our first Clinical Trial Award recipients in 2009 was Jaishri Blakeley (Johns Hopkins University), receiving $125,000 to do a Phase Zero NF2 clinical trial of the drug Lapatinib, currently in progress.

·         Outside of CTF funding, a Phase II NF2 trial of note is underway at Massachusetts General Hospital to assess drug PTC-299 in patients. This trial is co-supported by CDMRP NFRP and PTC Therapeutics. 

·         Through the Foundation’s NF Preclinical Consortium, a $4M multi-year initiative to accelerate promising candidate drugs to the clinic, the laboratories of Andrea McClatchey (Harvard/ Massachusetts General Hospital) and Marco Giovannini (House Ear Institute) are testing a pipeline of NF2 drugs, in collaboration with Novartis, Genentech and Avila Therapeutics.

·         In one of our first Drug Discovery Initiative Awards, in 2006, Oliver Hanemann (University of Plymouth) received $11,000 to test the drug Sorafenib on human NF2 schwannoma cells in culture. Positive data emerging from this study has led to planning of a Phase II European clinical trial.

Look for the final instalments of NF Bites next week!

Welcome to the sixth in a series of "NF Bites" - providing snapshots of individual areas of neurofibromatosis research and how the Children's Tumor Foundation is advancing this. Over the coming days and weeks we will focus on different aspects of neurofibromatosis research. Today: where are we with research progress in NF1 learning disabilities?

Our understanding of NF1 learning disabilities has opened up significantly in the past few years in terms of understanding their basis and developing treatment strategies – but we still have much more to learn and CTF is supporting this area.

·         In 2005 Dr. Alcino Silva and his team at UCLA published a landmark finding. They showed that the cholesterol-modifying drug Lovastatin when given to a genetic mouse model of NF1 learning disabilities could reverse these deficits. Mice given Lovastatin had improved ability to respond in a test system called a water maze.

·         Dr. Silva’s findings advanced rapidly to the clinic and Lovastatin trials are now well underway around the world through the CDMRP NFRP Phase II Clinical Trials Consortium as well as other independent clinical trials. Lovastatin offers the first hopeful drug for those with NF1 learning disabilities, but has also advanced other areas of NF, for example Lovastatin also show promise as a treatment for bone dysplasia (reported in an earlier NF Bites’).

·           CTF Young Investigator Awardee Ana Oliveira (Duke University Medical Center) is examining the underlying changes that occur in brain cell in NF1 related learning & memory disabilities.  She has found that cells in the brains of individuals with NF1 are actually different in their appearance and function. 

·         CTF Young Investigator Awardee Weidong Li (UCLA) is assessing Ritalin in mice as a candidate treatment for NF1 cognitive defects. 

·         CTF Young Investigator Awardee Linnea Vose (New York Medical College) is testing learning disabilities candidate drug treatments including rapamycin and rolipram in NF1 fly models. 

·         One of the challenged of early clinical trials was how to measure a drug’s effectiveness on NF1 learning disabilities. To more quickly advance discoveries from mouse to human, Dr. Nicole Ullrich and her colleagues at Children’s Hospital Boston have developed a ‘humanized’ water maze which is a computerized test. It is anticipated this ‘Arena Maze’ will be able to quickly determine if a drug is improving NF1 learning disabilities.

·         In 2006 and 2007, CTF organized NF1 Learning Disabilities workshops to bring basic and clinical researchers in this area together. This helped in the planning of the ongoing Lovastatin clinical trials. Looking ahead we hope to again convene this community in 2011 to plan next steps. Of particular interest is the growing link between learning disabilities seen in NF1 and other genetic conditions. A next step is therefore to build on this common links and share data and ideas so that advancements can benefit not only those with learning disabilities in NF1 but also in the context of other genetic conditions.

Look for more NF Bites in the coming days!