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The 2009 NF Conference got off to an exciting start Saturday with a full half day of presentations on ongoing or planned NF clinical trials. Roger Packer opened with an update on the Phase II NF Clinical Trials Consortium. The group has already fulfilled enrolment on the first NF1 trial - of rapamycin in plexiform tumors - and recently opened a trial to assess Lovastatin in NF1 learning disabilities. 

Next Consortium trials may include RAD001 (mTOR inhibitor) for optic pathway glioma as well as a bone trial. Scott Plotkin presented data from a new pilot trial to assess the blood vessel-targeted drug ranibizumab in NF1 dermal neurofibromas. Drug is injected directly into individual tumors and tumor size will be monitored. This trial is still in its earliest stages. Dr. Brigitte Widemann reported that by the end of 2009 another new NF1 trial will commence that combines two drugs - RAD001 and bevacizumab - for treatment of malignant peripheral nerve sheath tumors that have been resistant to other treatment. This combined therapy approach is, as I reported from ASCO, now being used in many tumor therapies.  

 In NF2 trials, Jaishri Blakeley reported on the Children's Tumor Foundation-funded Phase Zero trial to test lapatinib (kinase inhibitor) in vestibular schwannomas. This trial will be ready to enroll the first patient in July. Harry Miao reported on the new trial of PTC-299 (targeting blood vessel growth) in vestibular schwannomas also to commence soon.  

It is tremendous to see these clinical trial options opening up. Looking ahead, the Children's Tumor Foundation will endeavor to provide comprehensive information on all ongoing trials via our website to keep the community abreast of opportunities to participate.  

Friday saw a pre-conference meeting of the Children's Tumor Foundation NF Preclinical Consortium (NFPC), a collaboration of six top-tier labs - at UCSF, House Ear Institute, Washington University, Cincinnati Children's Hospital Medical Center and two groups at Harvard Medical School - each focused on genetically-engineered mouse models of different NF tumors.  Individually, these are highly successful NF research groups; collectively NFPC is a preclinical drug testing powerhouse. Drugs are tested in parallel in the multiple tumor types of NF1 and NF2 to ensure that we do not miss an opportunity: if a drug is not effective in one NF tumor type we can see if it might be effective in another. NFPC is overseen by a committee of seasoned researchers, many from industry, some with 20+ years of experience in drug development. A $4M multi-year commitment for the Children's Tumor Foundation, NFPC should maximize our chances of identifying drug candidates for NF clinical trials. So far NFPC has made tremendous strides, attracted a collaboration with Novartis and further industry partnerships are in planning.

An important element of advancing interesting preclinical drug candidates is to establish a link with the clinical trialists. That in mind after NFPC met Friday we had a one hour ‘crossover' meeting with the physicians of the Phase II NF clinical trials consortium which is funded by the Congressionally Directed Medical Research Program.  This group is a clinical trials version of NFPC connecting multiple clinical sites. Because of the variety of tumor types (plexiform, optic pathway etc.) and other manifestations (bone abnormalities, learning disabilities) seen in NF, an effort like this is required in order to recruit sufficient patients for a clinical trial in a timely manner. In the past year or so the Clinical Trials Consortium has launched 2 trials (for plexiform tumors and learning disabilities) and more are pending.

Scientists and clinicians can often live in two different worlds but the joint meeting of the 2 groups opened a dialog on the drugs in the preclinical pipeline, and those most likely to be of clinical interest. Though early days, this meeting emphasizes the importance of collaboration and open communication among our NF community to ensure that we advance promising drug treatment as quickly as possible to the clinic. We should see this theme continuing through the 2009 NF Conference.

 The American Society of Clinical Oncology (ASCO) Annual Conference is underway in Orlando this weekend. The Children's Tumor Foundation hasn't had a presence at ASCO before because the dates usually conflict with our annual NF Conference, but this year our own meeting is mid June, so we are at ASCO with a booth and attending sessions. Traditionally attracting around 35,000 attendees, the 2009 crowds at ASCO seems sparse according to regulars.  ASCO attendees are largely physicians and clinical researchers, and this is reflected in the meeting content, which is focused on the clinical management of tumors and on emerging drug therapies in clinical trials.  However Saturday began with a more scientific lean - a review of cell signaling pathways involved in regulating embryonic development, but which are also overactive in many cancers. These pathways - hedgehog, Wnt and notch - are now being investigated as drug target for cancer therapies. A few companies now have hedgehog-targeted drugs as advanced as Phase II clinical trials in both children and adults, and a couple of companies have notch-targeted drugs in trials. It is terrific to see developmental biology leading the way to drug therapies.

As I reported last week from the New York Academy of Sciences meeting, drugs that target and ‘normalize' tumor blood vessels have shown significant promise as tumor therapies with bevacizumab (Avastin) leading the way (currently in neurofibromatosis trials for NF2). Bevacizumab's promise seems to be emerging in the clinic as a combination agent to be used with chemotherapy agent temozolomide, surgery or radiation, and may have particular promise in treatment of newly diagnosed tumors. Clinical trialists are still trying to fully understand what bevacizumab can do, and how it works; for example in a small number of patients potential side effects can include impacting wound healing, or cardiovascular events. Of course drug companies are endeavoring to come up with ‘next generation' bevaczumab to improve action and eliminate side effects.

Many pilot clinical trials in a variety of tumors are combining bevacizumab with other drugs, or combining other drugs in pairs, targeting other cellular pathways: cilengitide targeting integrins; talampanel targeting glutamate receptors; as well as drugs familiar to NF researchers that target Ras pathway elements such as gefitinib, erlotinib, temsirolimus... This is exciting to see, but early stage - many studies include only 3 or 4 patients and as a result some of the findings can be hard to interpret. However one of the great things ASCO does for a subset of posters is to have seasoned scientists review and summarize in a brief talk the highlights from a group of posters on a related topic. This puts findings into a realistic perspective with each other - sometimes exactly what is needed.

More to come!