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ASCO closed out this morning with a couple of interesting sessions. The first was on cancer stem cells - how can we best target these elusive cells that are at the core of ongoing tumor growth and recurrence? Pioneering work in this area began in breast cancer but has expanded to many other areas. Stem cells in tumors have a lot in common with the stem cells that are present in embryonic development - the tumor stem cells appear to express developmental markers such as hedgehog, Wnt and Notch (touched on in Saturday's blog) and these markers are being targeted with drugs to block their function and hopefully kill stem cells and prevent tumor recurrence. Though side effects come from the fact that these drugs will target other stem cells in the body doing normal functions such as in the gastrointestinal track, management of these is being addressed.    One of the reasons that pancreatic cancer is so devastating - with the average lifespan following diagnosis being around a year - is that the stem cells in the tumor are really persistent and actually seem to thrive and multiply after treatment with the current standard therapy for pancreatic cancer, gemcitidine. The biology of these stem cells is becoming more understood though and this has led to the concept of a double whammy approach where following gemcitidine treatment tumors are treated with hedgehog-targeted drug which has shown good results in mouse models blocking tumor metastases from human xenografts.   Notch-targeted drugs may also be introduced to this approach.

The final session I attended examined the side effects of blood vessel targeted drugs like bevacizumab and sunitinib including effects on heart and kidney function. These are somewhat rare but can be significant; as more patients are on these drugs for longer they are being closely monitored and clinicians are figuring out how best to overcome side effects. This is important because as a take home message from ASCO 2009 it seems that though they are still being clinically assessed in many tumors types, using VEGF/blood vessel targeting drugs to treat tumors could fast become a baseline tool for tumor management onto which other drug treatments can be added, depending on the patients biology and tumor status. Hopefully this means we are heading in the direction of a move away from, or at least to a reduced use of, chemotherapy.    

A major announcement Sunday at ASCO was that Merck and AstraZeneca are to partner on a Phase I cancer trial in which drugs from both companies will be tested in combination. This may not seem it but it is a landmark moment, and validation of the trend seen at ASCO which is that combining targeted drug therapies is likely to be the future of tumor management,and will require partnering by many more companies.  

One session on Monday reviewed new drugs currently in Phase I safety testing and which target the mTOR pathway and related Ras pathway elements - which is of major interest in neurofibromatosis. These drugs were assessed for safety in a variety of solid tumors, but these early stage studies also revealed the when dosed daily or every other day at fairly modest doses, drugs are showing promise to be safe and also reach the tumors, and shrink them and/or stabilize the disease. Drugs discussed included GDC0941 (a pan PI3 kinase inhibitor), XL765 targets (PI3 kinase, Torc 1 and Torc 2) and MK2206 (a pan Akt inhibitor). All of these drugs could be of potential future interest for neurofibromatosis therapies so we will be monitoring them closely.

Cancer patients can now access unlimited online information about drugs in clinical trials. Armed with this, some patients have advocated for the right to have immediate and direct access to emerging drugs ‘off label' before clinical trials are completed. There may be good cause for this: if all other options for therapy are exhausted; if patient is not eligible for any clinical trial protocols; and if there is enough information that toxicity is not a concern and there is a reasonable chance of some efficacy. This has become a hot button issue and was the theme of a session at ASCO on Monday with speakers from the clinician, ethical and patient advocate perspectives. It is understandable that patients want accelerated access to drugs, but many issues need to be considered. Though clinical trials might seem to some patients like a blockade to drug access, they are an important part of figuring out if a drug is safe and effective. If drugs are made more freely available ‘off label' before trials are fully completed, this could lead to unprecedented side effects (as happened as a result of off-label breast cancer trials in the 1990s) or even to a drug company sponsor using data from off-label uses to promote a drug prematurely.  In addition, insurance could be a concern. A small informal survey of physicians reported at ASCO showed that 80% of doctors have given drugs to patients off-label. However there are no national guidelines on this. As the number of drugs available looks set to increase, one recommendation of this session was that ASCO develop policy guidelines for doctors to address when it is appropriate to prescribe off label.   

It is estimated that around 400 new drug therapies in the pipeline will soon be available for testing in cancer clinical trials. As a result a major focus of ASCO is on designing the best clinical trials, and selecting the right patients for each. In individual tumor trials, it has been seen that some patients respond to a drug, while others don't.  Genetics likely plays a key role in determining this, and for example in colon and breast cancer trials, patients are now enrolled on the basis of their genetic mutation type. This has led to the evolving field of ‘personalized medicine', where drug regimes will be tailored for individual patients.  As one example, a patient's response to drugs might be determined in part by the level of insulin or insulin-like growth factor (IGF1) in blood. Insulin/IGF1 levels are high in obesity and Type 2 diabetes, and both of these groups are in general more likely to develop tumors and within clinical trials are less likely to be responsive to targeted tumor drug therapies. This makes biological sense - insulin/IGF1 binding to the cell stimulates Akt signaling- and Akt is a well-recognized candidate drug target for many tumors (including neurofibromatosis). Interestingly cancer incidence is reduced overall in people taking metformin - an insulin sensitizing drug that reduces the amount of circulating insulin/IGF1 in the blood. For some patients, metformin may have some potential in planning and conducting cancer trials.  

Prioritizing and evaluating cancer drug therapies will require clinicians to partner with multi-disciplinary teams spanning biology to regulatory issues. This will also require that the right endpoints be used for clinical trials so findings can be properly interpreted. Some sophisticated trial models are underway, with multiple ‘arms' (patients treated under different drug combinations). Also there has been a move recently toward surrogate endpoints, measures that allow a trial to be shortened so a go/no go decision can be made earlier. However its important these are still meaningful. Given the dizzying number of clinical trials presented at ASCO, it is not surprising there was a cautionary note from one speaker not to over-interpret small individual studies too soon, but to consider the case for doing large population based studies with more emphasis being placed on long term monitoring of drug effects.   

 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!

The Foundation has been invited to ring the closing bell of the NASDAQ Exchange tomorrow at 4pm.

Board members Dan Altman (Vice Chairman), Laura Bona, Patty Francy,  Linda Martin, John McCarthy (Treasurer), and Stuart Match Suna (Development Comm. Chairman) will join me and our staff at the NASDAQ Marketsite studio in Times Square for this event.

 The closing will be televised on CNBC and other business channels, and while the likely screen time will be very brief, we thank the NASDAQ for this wonderful opportunity to increase public awareness of NF.

 A link to pictures will be provided after the event.  

John 

Genomeweb.com is reporting that Dr. Francis Collins is the front runner to be selected as the new head of the National Institutes of Health.

Dr. Collins most recently served as director of National Human Genome Research Institute (NHGRI), one of the 27 institutes and centers that make up the National Institutes of Health until August 1, 2008.

Most people in the NF community know Dr. Collins as the leader of the team at the University of Michigan that, along with Ray White's team from the University of Utah, discovered the gene that causes NF1 in 1990.   In addition to NF1, he has helped find the genes that cause cystic fibrosis, Huntington's disease and the M4 type of adult acute leukemia. 

We were pleased to have honored Dr. Collins at our Gala Dinner in New York City in 2003, and consider him a long time friend of the Foundation - as I am sure many other organizations do as well.  His work has made a profound difference in NF and so many other diseases and disorders, it is difficult to overstate his record of accomplishment.

   In addition to numerous published research articles, Dr. Collins is the author of the 2006 book The Language of God:  A Scientist Presents Evidence for Belief, which reconciles religious faith and scientific pursuit.

Dr. Collins would make an excellent Director of NIH, but whether he gets this position or not, we continue to look forward to his contributions to research.  

John

This meeting is the largest global event for the biotechnology industry and attracts the biggest names in biotech, offers key networking and partnering opportunities, and provides insights  on the major trends affecting the industry.

As we continue to expand our Drug Discovery Initiative, NF Preclinical Consortium and pilot clinical trials, partnering with pharmaceutical and biotech  will be a key focus for us in the coming years. 

 Several non-profits, including Muscular Dystrophy Association, Multiple Myeloma Research Foundation and the Cystic Fibrosis Foundation have made great progress in this area.  

 A summary of Kim's remarks will be posted to our website in the coming days.

John

Our Chief Scientific Officer, Dr. Kim Hunter-Schaedle, has been appointed to the  International Rett Syndrome Foundation (IRSF) Scientific Advisory Board. 

 Rett Syndrome is a unique  development disorder that is first recognized in infancy and seen almost always in girls. 

Research in general, and the Children's Tumor Foundation and IRSF in particular, benefits from the pro bono service  of researchers and clinicians on a variety of advisory boards.  These independent Board's assist in strategic review, new program development and peer review of grant applications.  

John

Click here to read the full press release from IRSF

We created this blog to supplement the more formal information available on our website, and provide faster updates on research, fundraising, local events and other matters of interest to NF community.

Blog posts will be primarily authored by the following Foundation staff:

John Risner - President
George Orfanakos - Executive Director
Kim Hunter-Schaedle-Ph.D. - Chief Scientific Officer
Garrett Gleeson - Communications Associate