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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!

 

 

 

 

Welcome to the fifth 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 malignancies?

Malignant tumors are estimated to occur in up to 15% of persons with NF1 and may occur in plexiform neurofibromas or other cell type. However it is not readily predictable when and where malignancy will occur; therefore it is critical to understand how and why malignant transformation occurs and how malignant tumors might be treated or even prevented.  The Children’s Tumor Foundation funds a number of studies to unravel what causes a tumor to transform from benign plexiform neurofibroma to malignancy and to assess candidate drug treatments for MPNSTs.

• Through the CTF NF Preclinical Consortium, a $4M multi-year initiative to accelerate the most promising candidate drugs to the clinic, the laboratory of Karen Cichowski (Harvard/ Brigham & Women’s Hospital) is testing a pipeline of candidate MPNST drugs in collaboration with Novartis and Genentech.
   
• David Wiemer(University of Iowa) received two Drug Discovery Initiative Awards to develop candidate MPNST treatments called schweinfurthins; these studies led to two publications in the Journal of Organic Chemistry and the schweinfurthins are now being commercialized through startup biotech Terpinoid Therapeutics.
   
• Mark Philips (New York University Langone Medical Center) has a Drug Discovery Initiative Award to test new drug entities called Icmt inhibitors on MPNST cells to see if they halt growth. This work is in progress.
   
• Among our Young Investigator Awardees, Jody Fromm (Harvard/Brigham and Women’s Hospital) is currently testing combined drugs Sunitinib and Rapamycin in mice with MPNSTs. Young Investigator Awardee Johanna Buchstaller (University of Michigan) is looking for those cells within a plexiform neurofibroma that drive tumors from benign to malignant and has identified a gene, Hmga2 that may be involved.
   

Look for more NF Bites in the coming days and weeks!

We have recently reported updates on the underpinnings of merlin, the protein encoded by the NF2 gene. Understanding merlin’s normal function, and how this is disrupted in individuals with NF2, is important in order to figure out what drugs might be effective in treating NF2.  Now a new study* done if fruit flies shows that inside the cell merlin moves up and down on structures call microtubules, which form a scaffolding framework that controls changes in cell shape as well as function.  In a stunning finding the study shows that a single amino acid change – the tiniest substitution in how merlin is encoded – markedly inhibits this movement, apparently by interfering with phosphorylation of merlin. In addition when present, this dysfunctional protein also prevented healthy merlin protein from moving around.  It has been an interesting year already in reports on merlin function and we are delighted to have a session of the NF Conference focused on this topic – we look forward to some lively debate.

Welcome to the fourth 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: the first of a two-part blog: where are we with NF2 research progress?

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.

Among our Young Investigator Awardees, Wei Li (Memorial Sloan-Kettering Cancer Center) has shown that merlin, the protein product of the NF2 gene, has a unique role in the cell nucleus. This work is published in leading journal Cell in February 2010 and will inform future NF2 drug design. Young Investigator Awardee Timmy Mani (University of Cincinnati) is examining a cell element called PIP2 as a candidate NF2 drug target. His promising data published in Molecular and Cell Biology in early 2010.   Young Investigator Awardee Chunling Yi (The Wistar Institute) is developing candidate treatment approaches for NF2 tumors focused on targeting merlin signaling as well as function of a protein called angiomotin; this is in progress.

• Andrea McClatchey (Harvard/Massachusetts General Hospital) and Marco Giovannini (House Ear Institute) have received funding through the Foundation’s Drug Discovery Initiative Awards to test pan-erbB inhibitor CNX-222 from Avila Therapeutics in NF2 genetic mouse models and human xenograft models; and to test NXD30001, a novel Hsp90 inhibitor from Nexgenix Pharmaceuticals in mouse models of human NF2 vestibular tumor xenografts.  This work is underway.
  
• Abraham Jacob (Ohio State University) received a Drug Discovery Initiative Award to test Akt inhibitor drug OSU-03012 in an NF2 vestibular schwannoma xenograft model. The drug showed promising data, inhibiting tumor cell growth. This data was published in the European Journal of Cancer and the drug is now in commercial development as AR-12 by Arno Therapeutics. 
  
• Joseph Kissil (The Wistar Institute) received a Drug Discovery Initiative Award to optimize NF2–targeting Pak inhibitors building on information as to how drug binds to receptor. 
  
• Marianne James (Harvard /Massachusetts General Hospital) has received a Drug Discovery Initiative Award to test mTOR inhibitors rapamycin, Torin1 and PI-103 on NF2 meningioma cells as candidate drug therapies.  

Look for more NF Bites in the coming days and weeks!

 

Welcome to the third 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 NF1 bone dysplasia research progress? 

Children with NF1 are at risk of developing bone abnormalities, most commonly affecting long bone growth and maturation. Fundamentally, bones can fail to heal after breakage and become a chronic health problem that may require amputation. Research into understanding bone dysplasias in NF1 has made significant progress in the last few years and interventional clinical trials though no currently ongoing are certainly on the horizon. 

To accelerate collaboration and progress this area, in 2009 the Children’s Tumor Foundation published a consensus paper in American Journal of Medical Genetics that provided an overview of expert recommendations from a Foundation-convened workshop on management & therapeutic development for NF1 bone abnormalities.  The Foundation is also supporting model development and preclinical drug screening in this area:

·         Foundation Drug Discovery Initiative Awardee Florent Elefteriou (Vanderbilt University) utilized a mouse model of NF1 long bone dysplasia to test Lovastatin as a drug therapy to promote bone healing after break.  This research has advanced to developing a nanoparticle delivery approach so that drug can be delivered to the fracture as efficiently as possible, and was recently published in Journal of Bone and Mineral Research.

·         Foundation Young Investigator Awardee Aaron Schindeler (The Children’s Hospital at Westmead, Sydney, Australia) has developed another unique mouse model on NF1 long bone abnormalities and is also utilizing this to test candidate drug treatments.

Excitingly, planning is now underway for the first therapeutic clinical trials focused on NF1 bone dysplasia and will no doubt be a point of discussion at June's 2010 NF Conference.

Look for more NF Bites in the coming days and weeks!

 

 

Mouse models of a particular condition such as cancer are often the test subjects for drug therapies long before clinical trials begin. However the question of whether or not mouse results are meaningful in the search for effective drugs is still hotly debated in scientific research, both in universities and industry. Some camps believe that yes, mice with genetically engineered features of a particular diseases or condition are valuable in narrowing down drugs to proceed to human clinical trials; other camps believe that no matter how sophisticated a mouse model of a particular disease is it will never replicate the human condition and therefore using these to test drug treatments is not helpful. Now the Boston Globe reports that Dr. Pier Paolo Pandolfi of Beth Israel Deaconess Medical Center in Boston has leveled the playing field in a research study that gives drugs to humans and mice at the same time. The goal is to better integrate what is learned about a new drug from the mouse with what is learned from the human.  Dr. Pandolfi first used this strategy successfully 15 years ago to develop treatments for then untreatable rare acute promyelocytic leukemia. The value of the ‘co-clinical trial’ approach is that it allows many more drugs to advance through testing at once, particularly combinations of drugs. And by using mice with different genetic mutations, researchers might predict which drugs should work in which patients.

Cheryl Marks, associate director in the division of cancer biology at the National Cancer Institute is quoted as saying “our traditional clinical trial structure . . . is simply not serving us very well.’’ Supporting this new approach is certainly an exciting way of implementing change; and Dr. Pandolfi received a $4.2 million National Cancer Institute grant through economic stimulus (ARRA) funding last year and a further five-year, $3.75 million grant.

Neurofibromatosis research too has the advantage of having a roster of very well developed genetic mouse models replicating all aspects of NF from bone dysplasia, learning disabilities to individual tumor types.  The philosophy of testing drugs in more than one mouse model at a time is one utilized in the Children’s Tumor Foundation NF Preclinical Consortium in which drugs can assessed in up to six tumors of NF1 and NF2 in parallel making sure each drug receives as thorough an assessment as possible. It is an exciting prospect that we might utilize these models as a partner for future clinical trials.

Welcome to the second 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 NF1 and NF2 research. Today: where are we with NF1 plexiform neurofibroma research progress? 

 

The Children’s Tumor Foundation is currently investing in both traditional and highly novel approaches to developing drug treatments for NF1 plexiform neurofibromas. These are the most common tumor type seen in NF1, and can cause devastating health issues. However researchers now have a reasonable understanding of their biology and are applying this information in developing clinical treatments; and plexiform tumors have been the first NF1 tumor type to advance into a number of ongoing clinical trials.

·         Bruce Korf (University of Alabama at Birmingham) was, in 2009, a recipient of one of our first $125,000 Clinical Trial Awards to assess, in collaboration with Aerang Kim and Brigitte Widemann (National Cancer Institute) the drug Sorafenib in a pediatric plexiform tumor clinical trial.

·         Through the Foundation’s NF Preclinical Consortium, a $4M multi-year initiative to accelerate the most promising candidate drugs to the clinic, the laboratories of Tim Cripe and Nancy Ratner (Cincinnati Children’s Hospital Medical School) are assessing a pipeline of candidate plexiform neurofibroma drugs. The Consortium includes collaborations with Novartis, Genentech, Pfizer and Avila Therapeutics.

·         In a cutting edge approach, Foundation Drug Discovery Initiative Awardee Jonathan Chernoff (Fox Chase Cancer Center) is endeavoring to normalize mast cell signaling in plexiform tumors, as abnormal signaling is believed to promote tumor growth. To do this Dr. Chernoff will develop induced pluripotent stem cells (iPS) - a form of adult stem cells - from mouse skin, and transplant these transplanted into the NF1 mouse bone marrow – the cells should differentiate into normal mast cells which then migrate to the tumor and halt its growth.  

·         Young Investigator Awardee Huarui Zheng (University of Michigan) is also targeting mast cells in mouse models plexiform neurofibromas, this time using targeted drug treatments.  Margaret Wallace (University of Florida) has received two Drug Discovery Initiative Awards in the past year for drug testing on plexiform neurofibromas.  One Award tests PTC Therapeutics VEGF-blocking drug PTC-299 (now in clinical trials at Massachusetts General Hospital for NF2), while the other Award tests indoprofen derivative drugs, which target nonsense mutations in the gene to correct neurofibromin protein production.

·         Outside of Foundation funding, other plexiform neurofibroma clinical trials of note are currently under way. These include: CDMRP NFRP Phase II Clinical Trials Consortium is conducting a trial of Rapamycin in plexiform neurofibroma; Children’s Hospital of Philadelphia has initiated a Phase I (safety) trial of photodynamic therapy for these tumors; and Indiana University has pioneered the use of imatinib mesylate (Gleevec) to treat these tumors.
Look for more NF Bites in the coming days and weeks!