DIPG Around the World: SIOPE-DIPG

During the 2012 European DIPG meeting in Barcelona Spain,  a European DIPG network and registry was presented by Dannis Van Vuurden of the Netherlands.

The SIOPE-DIPG network began in 2011 Amsterdam meeting by members from the UK, France, Germany, Italy, Spain and the Netherlands.  In the 2012 presentations, membership had increased to 18 members:  Germany, United Kingdom, France, Spain, Italy, Poland, Netherlands,  Czech Republic, Portugal, Belgium, Sweden, Austria, Switzerland, Denmark,  Finland, Norway, Ireland and Iceland.

Each country or coalition has a national coordinator:
Austria-  Irene Slavc
Belgium-  Stefaan Van Gool
Czech Repulic-  David Sumerauer
France-  Pierre Leblond
GPOH- Christof Kramm
Ireland- Jane Pears
Italy- Veronica Biassoni
Netherlands- Dannis van Vuurden
NOPHO- Sanna-Maria Kivivuori
Poland- Marta Perek-Polnik
Portugal- Maria João Gil-da-Costa
Spain- Ofelia Cruz Martinez
UK- Simon Bailey
(Note- NOPHO stands for Nordic Society of Pediatric Haematology and Oncology and includes Denmark, Sweden, Finland and Norway.)

Collaboration is critical for the understanding of  DIPG.   One of the most interesting pages of the DIPG Network and Registry presentation is the estimated number of DIPGs in individual countries (see page 10 of the first reference below).  Two-thirds of the participating countries in SIOPE-DIPG are expected to have more than 10 affected children per year!

The comprehensive DIPG Action Points is another highlight.   This included the issues of corticosteroids, quality of life, palliative care, biopsy, biological studies, treatment protocols, autopsy protocols and further research as well as the registry and network.   Of particular note, each issue had a responsible person named in the spreadsheet.

For those interested in who are the movers and shakers on DIPG research in Europe the below references a must to see.

References:
SIOP Europe- DIPG Network and Registy
http://www.cristianriverafoundation.org/media/DIPGworkshopsmedia/401%20-%20NETHERLANDS%20-%20DIPG%20Network%20and%20Registry%20(Van%20Vuurden).pdf

2012 Barcelona DIPG Meeting and Powerpoint Presentation

http://www.cristianriverafoundation.org/workshops.html

Meeting Action Points Spreadsheet

http://www.cristianriverafoundation.org/media/DIPGworkshopsmedia/402%20-%20Action%20Points%20Barcelona%20Meeting%20(Cruz-Van%20Vuurden).pdf

DIPG in the next WHO classification???

In 1956-7 the World Health Organization (CNS) resolved to develop a classification of tumors that would be used around the world.   This was critical to be able to conduct clinical trials and to be able to compare results internationally.   The first brain tumor WHO classification,published in 1979, was based on pathology.  Changes were made in the subsequent three editions to reflect new knowledge from immunohistochemisty and genomics.   The last WHO CNS classification in 2007 added eight "new" entities as well as some additional variants.

Diffuse intrinsic pontine gliomas have not be recognized as a class of tumors unto itself or a variant-- well, not yet by the World Health Organization.   A review article points out that since 2007 there has been significant progress in understanding the molecular biology and genomics of GBMs.  The article also suggests that there are several GBM variants including DIPG.

Perhaps the next WHO CNS classification revision will include diffuse intrinsic pontine glioma!  

On the other hand, this would seem to be a significant deviation from the other classifications that have relied heavily on histopathology to define a tumor type.   A WHO tumor classification based primarily on anatomic location would seem to be an uphill battle.   However, clearly on clinical grounds DIPG is a fairly distinct entity primarily striking a particular age range (5-9) and failing therapies that have made some progress with adult GBMs.  There have been recent advances showing these pediatric diffuse pontine gliomas are molecularly different from adult GBMs and even pediatric supratentorial GBMs.

Pediatric tumors known by location- this is not an isolated concept.   Clinically tectal gliomas and optic gliomas are recognized by anatomical location.   Recently, thalamic gliomas have been suggested as a distinct clinical group.  We know brainstem gliomas are not all the same.

To make advances and aid in international communication, it would seem logical that DIPGs need to be recognized as an entity unto their own.

Reference:
WHO classification of the tumors of the central nervous system  http://en.wikipedia.org/wiki/WHO_classification_of_the_tumors_of_the_central_nervous_system

The 2007 WHO Classification of Tumours of the Central Nervous System
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1929165/

Review Paper:  Established and emerging variants of glioblastoma multiforme:  a review of morphological and molecular features  http://www.termedia.pl/Review-paper-Established-and-emerging-variants-of-glioblastoma-multiforme-review-of-morphological-and-molecular-features,20,19879,1,1.html

Thalamic high-grade gliomas in children: a distinct clinical subset?
http://neuro-oncology.oxfordjournals.org/content/13/6/680.long

Journal Watch- WEE1 Kinase Inhibition Enhances the Radiation Response of Diffuse Intrinsic Pontine Gliomas.

In the February 12, 2013 edition of the Molecular Cancer Therapy journal, the researchers from the VU University Medical Center in Amsterdam published a new paper using (in mice) using a new agent during radiation- a WEE1 Kinase inhibitor called MK-1775.

So far radiation has been the only therapy to transiently relieve the symptoms in children with DIPG.   One of the hopes has been try try to find ways to increase the effectiveness of radiation.   There have been various trials with radiosensitizer (topetecan,  etanidazole,  motexafin-gadolinium, etc); however,  none have been successful for DIPG.  The researchers looked at a new way to try to enhance radiation's effectiveness.

There are a series of proteins in the cell that control cell division.  One of these protein groups is called WEE1 Kinase and controls the G2 cell-cycle in cell division.   The proteins allow for repair of the damage called by radiation.

These researchers found that WEE1 kinase is expressed more in DIPG tissue than normal tissue.  They theorized that if MEE1 Kinase could be inhibited then the cells would have less ability to recover from radiation.  The great thing is that there is a WEE1 Kinase inhibtor available, MK-1755, and we now have DIPG animal models to test out these novel agents.    They tried this and found that this approach and novel agent might show promise for DIPG.

The interesting thing is that this agent, MK-1755, is currently in clinical trials in adults.  Thus, if this drug shows promise it might be somewhat rapidly translated to pediatric trials for children.

Perhaps something to watch for in the future.

References:
WEE1 Kinase Inhibitor Enhances the Radiation Response of Diffuse Intrinsic Pontine Glioma
http://www.ncbi.nlm.nih.gov/pubmed/23270927

Inspiring Kids- Calle and Hope for Caroline Inc

Five year old Caroline Cronk was just diagnosed with a DIPG in November 2012. Yet in that short time Caroline (fondly called Calle), her family and her friends have worked hard to shine as much of a spotlight on DIPG as possible.  Just yesterday, March 2, the Boston Globe updated there remarkable story.
http://www.boston.com/news/local/massachusetts/2013/03/03/when-cancer-strikes-their-child-norwell-couple-fight-back-with-prayer-fund-raisers-and-hope/sT30txaUToDf2PgyGBCb2I/story-1.html

Her story started as so many other kids have.   Calle started having fatigue- then balance issues.  A head tilt and squinting of the eyes were noticed.  Her face became paralyzed on a side.  A walnut sized mass was found in the pons.

What is remarkable is that they have not just focused there energy inward toward there family but have also started a new DIPG foundation- Hope for Caroline Inc.  There are several upcoming fundraisers including a pancake breakfast next weekend and Calle's Miracle Run a month from now.  However, they have already made their mark on DIPG research by contributing $100,000 on Feburary 8th to the Dana Farber lead research trial utilizing brain-stem biopsies "to trace signals driving the tumor and provide targeted treatments".

This trial has been funded by a coalition of private funds from various sources.   Without these foundations helping to make a difference this trial very likely would not be possible.

This novel trial is hoped to completely transform our understanding of DIPG.   The trial is listed to be currently open at 6 institutions in the US- Seattle Children's, Hopkins, Cook Children's in Texas, Lurie Children's in Chicago, Washington University in St. Louis and Dana Farber in Boston.  There are several other collaborating institutions in this trial so there is hope that other hospitals will have this trial open in the future.  

Best Wishes to Calle!
Best of hope to Hope for Caroline- keep up the great work!


References-
Hope for Caroline, Inc http://hopeforcaroline.org/

Clinical Trial- Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG) http://clinicaltrials.gov/ct2/show/NCT01182350?term=DIPG&rank=5

5-year-old Calle Cronk, her family fight rare illness  http://www.bostonglobe.com/metro/2013/02/08/young-calle-cronk-and-her-family-face-unknowns-brain-tumor/dylgSGNkCmuVUHPTcB64zM/story.html

Story of sick Norwell girl goes national; social media attract support

 http://www.bostonglobe.com/metro/2013/02/08/young-calle-cronk-and-her-family-face-unknowns-brain-tumor/dylgSGNkCmuVUHPTcB64zM/story.html