Foundation Spotlight- Stichting Semmy

The Netherlands- a small country with a big impact in the world of DIPG.

• In Pub Med there are four articles from the Netherlands in just over a year!  
• The Netherlands participants in the DIPG Preclincal Consortium being represented by Dannis G van Vuurden, and Esther Hulleman from VU Cancer Center Amsterdam.   They are currently listing two DIPG cell lines (VUMC-DIPG-B, VU-10170) in the Consortium. 
• Amsterdam has been the site of two European DIPG meetings.  

How is it that a country with approximately 15-18 children a year diagnosed with DIPG is doing so much?  On the other side of the Atlantic, it is difficult for me to say for sure; but, I think it is in large part because of a parent-led foundation, Stichting Semmy.

Stichting Semmy is a story like so many other pediatric glioma foundation- started in memory of a precious child.  The  blond haired, 4-year old boy was diagnosed on July 20, 2006.  Radiation and steroids gave him and his family a "honeymoon time" going to Turkey and back to school.  The tumor came back with rapid progression in February 2007.  The hope was to get a new trial with convection enhanced delivery but the research wasn't ready.  Semmy died in his parents' arms on June 22, 2007.

Since then Semmy's parents, John Emmerik and Nicole Bakker, have joined together with some dedicated physicians and researchers  to completely change the approach to DIPG.  Their interests have been deep and wide- awareness, basic science research and clinical research. Many of the achievements listed above can be traced back to support from Stichting Semmy.

Of particular note in the story is IBM.   Stichting Semmy received an IBM Catalyst Grant to assist in funding a central research collaboration cloud for data exchange on DIPG as part of IBM's Smarter Healthcare Strategy.   Given that so few children are diagnosed at any one instittution, being able to exchange data in an efficient and intelligent manner is going to be key.    John Emmerik, Semmy's father, is IBM Netherlands software sales manager.

References:
Stichting Semmy Website- http://www.pontineglioma.com/

Stiching Semmy Facebook- http://www.facebook.com/pages/Stichting-Semmy/228285370605509

Stichting Semmy In the News-
http://asmarterplanet.com/nl/blog/2012/10/stichtingsemmy.html
http://www.ibm.com/ibm/responsibility/initiatives/stories/VoTM-may-12.shtml

Amsterdam Meetings-
(2011) http://www.fondoaliciapueyo.org/images/docanexos/Amsterdam_2011.pdf
(2013) http://www.knaw.nl/Pages/DEF/33/849.html

Pre-Clinical Consortium
http://dipg.blogspot.com/2011/12/new-preclinical-dipg-consortium.html

St Jude Study on Kid's Bones in Antiangiogenesis Trials

1- Angiogenesis  (can be thought of as new blood vessel formation) is considered to be a key process in the development and growth of glioblastomas.
2- Most DIPGs so far have been found to be glioblastomas.

Given these above two facts,  researchers at St Jude Children Research Hospital in Memphis designed two phase 1 trials using antiangiogenic drugs in during radiation and after for newly diagnosed kids with DIPG tumors.   The first study used vandetanib and the second used a combination of vandetanib and dasatinib.    Both of these drugs are oral and affect targeted areas in the molecular pathways.  Vandetanib is a potent VEGFR-2 (vascular endothelial growth factor receptor-2) inhibitor.

Pediatric patients are not just little adults.   A significant difference is that kids grow and mature.   This could be a problem with antiangiogenesis drugs as animal studies showed that this type of inhibition could negatively affect skeletal growth.    Since little had been reported on the effects of these drugs on children's skeletal development, St Jude researchers included this as part of their study.

There were 59 patients (32 girls and 27 boys) evaluated with a total of 119 MRIs and 51 patients had plain knee x-rays.  The children ranged from 2.4-17.6 years (median 6.2 years of age).  The median treatment was 205 days.   Of note, two patients had not progressed- one was 18 months out from diagnosis and the other 60 months.

All of the kids had MRIs of the knees at baseline and 50 had MRIs at 16-19 weeks of therapy.   MRIs showed more abnormalities than plain films.   MRIs showed:

• 1 patient with premature physeal fusion (the growth plate closed too soon), 
• 1 patient focal thickening of the growth plate,
• 2 patients with bony spicules across the growth plate,
• 8 patients with osteonecrosis (one was present at enrollment in the study).

Plain radiographs did not show these abnormalities.

Although this was a short followup time, this is the largest group of kids studied for skeletal changes on these antiangiogenesis agents.   It seems clear that MRI is better in picking up abnormalities.  The authors encourage more long term follow-up monitoring in pediatric patients taking these agents.

Note- this work was supported in part by US National Institute of Health Cancer Center Suppport (CORE) Grant P30 CA-21765, a Center of Excellence grant from the State of Tennessee, AMerican Lebanese Syrian Associated Charities (ASLAC), Noyes Brain Tumor Foundation, Musicians Against Childhood Cancer (MACC), AstraZeneca and The Cure Starts Now Foundation.

Reference:
Magnetic Resonance Imaging Is the Preferred Method to Assess Treatment-Related Skeletal Changes in Children with Brain Tumors
Pediatr Blood Cancer. 2013 Mar 22. doi: 10.1002/pbc.24536. [Epub ahead of print]
Department of Radiological Sciences, St. Jude Children's Research Hospital
Kaste SC, Kaufman RA, Gajjar A, Broniscer A.
http://www.ncbi.nlm.nih.gov/pubmed/23526749

What is VEGF?   http://www.news-medical.net/health/What-is-VEGF.aspx

St Jude Vandetanib Trials-
http://clinicaltrials.gov/ct2/show/NCT00472017?term=vandetanib+St+Jude&rank=1

http://clinicaltrials.gov/ct2/show/NCT00996723?term=vandetanib+St+Jude&rank=2

The TIssue Issue- Molecular Biology of DIPG

DIPG as a chapter section regarding new molecular targets and treatments for brain tumors! 

Chapter 20: New Molecular Targets and Treatment for Pediatric Brain Tumors by James T. Rutka

in Evolution of Molecular Biology of Brain Tumors and the Therapeutic Implications edited by Terry Lichtor and published on February 27, 2013

The main reason for lack of advancement on DIPG has been the lack of tumor tissue (not lack of funding, not lack of interest and not lack of trying).  The almost total absence of tumor tumor tissue meant there was no feasible way to develop specific research on this devastating pediatric tumor.  Let me emphasize that again--    All basic science research with DIPG was essentially impossible without tissue.  However, the past half decade has seen rapid changes and unprecedented collaboration to get tissue both by biopsy and autopsy.

Timeline-
* 2004- the French  decided it the molecular age of tumor biology has reached a stage to reinstitute biopsies.  Simultaneously in North America several hospitals (Sick Kids, St Jude, NIH) made a concerted effort to obtain post-mortem samples.
* Jauary 2009- Dylan Jewett's tumor was donated to Standford.
* February 2010, the first ever DIPG genomic study was published by Sick Kids.
* March 2011, Stanford released news that they had developed a first pediatric DIPG cell line and animal model from the previously donated tumor.
* Today there are more than 30 DIPG cell lines, several institutions that have developed animal models and a handful of DIPG molecular biology papers have been published.

Chapter Highlightss

• From  recent studies it has become common knowledge that pediatric brain tumor (including DIPG) are different from similarly appearing adult tumors.   Not only are pediatric tumors different than adults, but also DIPG are genetically different from other pediatric gliomas

• A growing list of different pathways and factors are being described.   DIPG discussions are soon going to routinely contain a confusing concoction of letters,number, factors and receptors-  EGFR, PDGFA, recetpor tyorosine kinase, retinoblastoma protein, PARP-1, MET and insulin-like growth factor receptor 1.    All these are parts of pathways driving tumors and all have been found in a percentage of DIPGs.

• Drugable targets in DIPG tumors have been found in the molecular biology evaluation of DIPGs.  The paper lists the overall survival and references for seven different clinical trials since 2007 using different targeted drugs- imatinib, tififanib, genfitinib, vandetanib, erlotinib and nimozumab.  In some cases, a subset of patients have been found to survive longer than expected.  Most of these trials though were done blindly so individual patient's molecular biology is not known.

• Recently the first mutated oncogene in DIPG was described- P13KCA.

• The chapter also highlights the challenge of getting these agents into the pons.  The blood brain barrier seems to severely limit access to the pons.   Convection-enhanced delivery and nanoparticles were specifically mentioned as techniques to consider in DIPG.

Five years ago, few would have foreseen a chapter section on DIPG molecular biology!  Looking into near future for DIPG, tumor molecular biology and new therapeutic approaches to get around the blood brain barrier are likely to take center stage.

Chapter Author: James T Rutka- Division of Neurosurgery and Labatt Brain Tumor Centre, The Hospital for Sick Children, University of Toronto, Canada

References:
Claudia C. Faria, Christian A. Smith and James T. Rutka (2013). New Molecular Targets and Treatments for Pediatric Brain Tumors, Evolution of the Molecular Biology of Brain Tumors and the Therapeutic Implications, Dr. Terry Lichtor (Ed.), ISBN: 978-953-51-0989-1, InTech, DOI: 10.5772/53300. Available from:   http://www.intechopen.com/books/evolution-of-the-molecular-biology-of-brain-tumors-and-the-therapeutic-implications/new-molecular-targets-and-treatments-for-pediatric-brain-tumors

Stella- A Shooting Star

It is a story of epic proportions- one that will make you smile and surely make you cry.

Set in a loving home in Canada, a bubbly, red-haired tot lives life as  a terrible monster sucks it away with relentless cruelty.  Those who love her can do nothing to stop it.  Each day is approached with a determination to put a lifetime into as much time as given.

As with all stories,  there are decisions points.... crises.   The very first is whether to treat a fatal disease or not.   In this case, the decision was not to treat the tumor but to live life.   Shockingly, little Stella way outlived her predicted three months by more than a year.    It is a marathon of heartbreak where every few weeks one has to adjust to what more has been lost- impossible to comprehend how much more could possible be taken.  Yet it does.

And there is a climatic finish that will bring many to their knees.    A mother carries her dead child past a line of candles holding vigils witnessing one final gift- taking her child to the hospital to donate  the extremely rare gift to research of a deadly tumor untouched by radiation.   The hope that one day we can stop this evil in it's tracks.

This is the story of DIPG.

This is much more a story of a remarkable family struggling through the unimaginable.

As often is the case, a picture is worth a thousand words.   A video conveys things that words can not- the tears, the fears, the most beautiful child.   Please watch A Year with Stella.
http://www.thestar.com/news/2012/12/10/a_year_with_stella.html

There is also a 3 part article series that tells more-

http://www.thestar.com/news/gta/2012/12/07/given_3_months_to_live_stella_delights_in_the_moment.html

http://www.thestar.com/news/gta/2012/12/08/stella_joy_every_moment_precious.html

http://www.thestar.com/news/gta/2012/12/10/at_3_stella_keeps_coming_back_from_the_brink_rallying_each_time_doctors_warn_the_end_is_near.html

Thanks to the Toronto Star, Catherine Porter,  Aimee Bruner and Mishi Methven for telling the awful truth of DIPG while sharing this precious child, Stella, with the world.