A New Era for Children with Diffuse Intrinsic Pontine Glioma: Hope for A Cure?

"A new era for DIPG has just begun."

So starts the conclusion of this expert review article written last  year by two prominent DIPG researchers from the Netherlands- Marc Jansen and Gertjan Kaspers.   It will behoove one interested in DIPG research to be aware of those names.  They are ones that keep coming up in DIPG issues- publications and European DIPG worshops.   

These experts highlight that there has been a rapid increase in biological understanding of DIPGs.     This has only been able to occur because of the recent availability of DIPG tumor tissue which from  the French re-introduction of biopsies and the North American/Dutch focus on autopsy donation.  This DIPG tissue is critical to the further understanding of DIPG although biopsies and post-mortem tissue each have advantages and disadvantages.

The biopsy issues has been very controversial.   The French group has now preformed over 100 stereotactic biopsies with 0% mortality and a 4% transient morbidity.   An advantage of pre-treated biopsy specimens is that there is a significant risk treatment will change the original molecular characteristics.  The tumor that the children start with very likely is not the tumor molecularly that they die with.

Post mortem tissue carries a high risk of treatment-related genetic changes.   Still, there are advantages.   There is a much greater tissue volume available for study.   This also allows study on tumor hetergeneity (how varied the tumor is) as well as "treatment-resistent subclones".   In addition, it has been from these tumor donations that cell lines and animal models have been developed (greatly adding to research potential).

Even with this "avalanache of gene profiling studies" in DIPG, this will probably not provide the entire answer for cure.  There is at least one other prong to the problem.  The authors pose some thoughtful questions for consideration:

• Why  are all chemotherapy regimens ineffective in DIPG while  some show activity in supratentorally located gliomas, such as  temozolomide?
• Why does imatinib, an inhibitor of the  DIPG key target PDGFRA, not improve survival ? 
• Could  poor drug distribution be at least partly the answer to these  questions?

The short answer likely lies in the blood brain barrier (BBB).  The huge hurdle BBB presents in DIPG will be a subject of future posts, but suffice it to say that we need better studies to investigate drug resistance and drug distribution as well as  new drug delivery options.

It is a new era.   There are researchers focused on understanding this tumor.   There has been a virtual explosion of clinical trials and publications.  There is excitement.

We are, though, at the beginning.    We have just gotten some of the tools to fight, --to understand , --to research, --to make a difference.  It is unlikely that the cure is around the next bend but research is finally moving for children with DIPG.   There is reason to hope that someday there might be a cure.

Note-  DIPG research at the VU University Medical  Center is financially supported by Stichting Semmy (Weesp, The Netherlands).

References: 
A new era for diffuse intrinsic pontine glioma: hope for a cure? 
Gertjan J Kaspers and Marc Jansen 
Pediatric Oncology and Hematology, VU University Medical Center, Amsterdam, The Netherlands Expert Rev. Anticancer Ther. 12(9), 1109–1112 (2012) 
Full Text:  http://www.brainlife.org/reprint/2012/Kaspers_GJ120900.pdf

Stichting Semmy-
http://dipg.blogspot.com/2013/03/foundation-spotlight-stichting-semmy.html

Miette- Sweet Little Crumb

She loved princesses as well as castles, faires and all magical things .

She loved animals- giraffes, elephants and kittens.

She was sweet, courageous, thoughtful, light and bright.

Miette's gorgeous blue eyes, impish smile and golden locks hid a fatal tumor.

Her parents were determined to tell her story from the beginning to the end.  The beginning started on July 25th 2011,  when 5-year-old Miette was diagnosed with a brainstem tumor.   The next day her parents were told there "with radiation there would be a 50% chance she would be here in 1 year and a zero percent chance in two." The end came this week on Tuesday.   Australia's Sweet Little Crumb left this world.

A special thing on this journey- Chicken Mick and his band of merry helpers.   This "big hearted Aussie bloke"put together a Wiggly Whirlwind Weekend sending Miette to Melbourne to meet the Wiggles.  

The story didn't end there though.  They were met by a TV crew at the airport on the flight home and taken home in a fairy pink Hummer.   Although they had agreed to a "lick of paint on her cubby" while they were away and told Chicken Mike that Miette liked animals,  they were not expecting what waited at home.    The front yard was transformed into a little farm and her cubby into an "area fit for a princess".   Here is the story in their own words...

http://www.miettesjourney.com/2012/09/thank-you-chicken-mick-and-his-merry.html

or better yet watch this special video.....

http://au.news.yahoo.com/today-tonight/article/-/14742263/chicken-mick-and-miette

Because of Miette, the Wiggles are now ambassadors to raise awareness of through the Isabella and Marcus Paediatric Brainstem Tumour Fund.  Both Isabelle and Marcus died from DIPG.  The two families started this foundation with the mission to fund Australian research into pediatric brainstem tumors with a focus on DIPG.   Miette joined in with her support making hairclips and bands, selling them online and giving 50% of the proceeds to the charity.

A vision of the  foundation is "to established an Endoswed Chair at the Univeristy of Melbourne, with an affiliated research laboratory in the Victorian Comprehensive Cancer Centre that will perform research to understand the nature of these tumors, develop novel treatments and to participate in international clinical trials."

Miette you will be remembered.

Reference:

Miette's Journey - https://www.facebook.com/miettesjourney

Miette's Journey- http://www.miettesjourney.com/

Chicken Mick-

http://chickenmick.com/index.php?option=com_content&view=article&id=36&Itemid=37

Isabella and Marcus Paediatric Brainstem Tumour Fund- http://www.isabellaandmarcusfund.org.au/index.html

Results of St Jude Phase 1 Trial Published

The results of the St Jude Phase 1 trial using a combination of small molecule inhibitors, vandetanib and dasatinib,  have just been published electronically (ahead of print) in the journal Clinical Cancer Research.

In a look back at DIPG history, this is a really a new kind of trial.   In the past many trials have been radiation and a single agent.  I think we can say with some certainty that DIPG tumors will need more than a single agent for cure- especially for targeted therapies.  These tumors are complex and have so many pathways that it is likely that the tumors will be able to get around a single agent.

In addition, there seems to be rational basis to chose these agents specifically for DIPG.  Vandetanib has a combination of effects on different targets but is a potent VEGF inhibitor.   This is known to be a player in GBMs (and as been said here before when studied histologically most DIPGs have been found to be GBMs).   Dasatinib has its effects at PDGFRA (platelet derived growth factor receptor alpha).  Several recent publications have highlighted the PDGF pathway as being key in the development of DIPGs.

In this study, 25 newly diagnosed children were started on oral dasatinib daily at the start of radiation.   Eight days later oral vandetanib twice a day was added.     Overall the treatment was tolerated well.

• The M:F ratio was 12:13.
• The age range was 2.3 years to 17.2 with a median age of 5.8 years.
• The median treatment time was 184 days.   
• The most significant toxicity was diarrhea.
• Myelosuppresion (drop in blood counts) was seen in three children.
• Two of the children had tumor biospies.  
• There were 12 post mortem tumor donations.  
• All patients progressed on treatment.   
• The one year overall survival was 52% + 10%.
• The 2 year survival was 9% + 6%.  
• The two patient who were on treatment for more than 2 years had typical clinical and radiologic appearance of DIPG

An interesting part buried in the article text was the approach to radiation.  The radiation field encompassed the tumor and a 2cm margin in the transverse (across) and caudal (down) direction and a 3cm margin in the superior direction.  The increased from 2cm to 3cm in the superior direction was based on preliminary results on progression patterns of DIPG patients.   Of note, one patient had extensive bilateral thalamic extension requiring whole brain radiation.

Three of the young children developed symptomatic radiation necrosis in uninvolved brain areas.  Although there was no institutional knowledge of other patients treated with more than standard radiation fields developing radiation necrosis in uninvolved areas, it was felt that the larger margins may have lead to symptomatic radiation necrosis.   Thus the authors do not recommend to use of enlarged radiation fields.

Another interesting finding was that the researchers showed "for the first time that CSF exposure of vandetanib and dasatinib in humans is modest".   They point out that CSF levels is often used as a surrogate marker for brain penetration but that this assumption is not necessarily valid particularly in places where there is a blood brain barrier disruption.  They also point out that although the dasatinib CSF level was low that it did reach sustained levels "similar to those causing significant inhibition of other drug targets.

Additionally, the researchers looked at plasma angiogenic factors (seeing what factors are in the blood). Surprisingly, increased VEGF in this study was associated with longer overall survival whereas in a prior study it was associated with shorter survival.  The hypothesis is that this might be because of an improved inhibition of alternative pathways because of the combination.  Regardless of the reason, it seems to me that we don't understand plasma factor levels yet.

Despite the continued poor results for DIPG clinical trials, there were some interesting findings in this trial.   There is hope the drug testing (such as what we should see with the pre-clinical consortium) might find new promising targets or drug therapies.

Note-

This work was supported by the U.S. National Institutes of Health Cancer Center

Support (CORE) Grant P30 CA21765, by the Cure Starts Now Foundation, by

AstraZeneca, and by the American Lebanese Syrian Associated Charities (ASLAC).

References:

Phase 1 Trial, Pharmacokinetics and Pharmacodynamics of Vandertanib and Dasatinib in Children with Newly Diagnosed Intrinsic Pontine Gliomas

Clin Cancer Res. 2013 Mar 27. [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/pubmed/23536435

Clinical Trials Entry   

http://clinicaltrials.gov/ct2/show/NCT00996723?term=dipg&rank=2

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