Jack's Angels Foundation Supporting CHLA DIPG Research

I've always found that parents are the ones that care most about DIPG.  It is the parents that are the ones that go on fighting against DIPG hoping that one day other parents will not have to endure the same fate as their family.  And it has made a difference.   The parents that have donated their children's tumors, started foundations, created DIPG awareness, funded DIPG research and have brought researchers together collaboratively have made a changed the landscape for DIPG.

Jack's Angels Foundation is another parent-founded and led foundation in memory of a child who died from DIPG.   The Foundation had their first fundraiser earlier this month hosting an art action ofchildren. student and trained artists' works.  The proceeds are to go to Children's Hospital of Los Angeles DIPG Research.

Jack was just 3 years old when on October 28, 2011 he was diagnosed with a DIPG.  Having difficulties with hs speech and right side and a sudden fear of looking up he was admitted to CHLA.   Like so many children Jack had radiation and steroids which gave him time to go to Disney and ride the bus to preschool.  With an eye on quality of life and an eye on hope, the family relates the CHLA doctors gave the "wisest possible cousel concerning available chemotherapies" and that he avoided losing precious time pursuing other therapies that have not been effective.  Just 9 months later, Jack was born into Light on July 30, 2012.

Jack's Angels Foundation has formed to continue to fight agaisnt DIPG with funding of research at CHLA.

CHLA is one of the Pediatric Brain Tumor Consortium institutions.  The physicians and researcher there have been quite interested in DIPG for some time.   In fact, this has been one of the sites that has been specifically looking at imaging characteristics of these tumors.  Although the trial is not open yet at CHLA, they collaborators of the upfront biopsy trial with molecularly determined treatment.  Through the PBTC they are participants in the Imetelstat trial for recurrent DIPG.  And through COG they are participants in the Vorinostat trial for newly diagnosed children with DIPG.

The news article says that CHLA and UCSF are working together and with other hopsitals in a loose consortium of researchers looking for new methods to treat DIPG.  Clearly the upfront biopsy trial fits the bill as both institutions are involved.   However, UCSF has also been doing great work on the advancement of understanding and treatment of pediatric brain tumors- from intranasal administration of agents to unravelling the importance of the K27M mutation.  Since there are so few children with DIPGs, these collaborative efforts are important in pushing research forward as well as disseminating results as quickly as possible.

I am glad to hear this first art auction was a success- hopefully one of many more to come.

Reference-
3-year old's death from rare brain tumor prompts Agua Dulce mom to help find a cure
http://www.dailynews.com/ci_23211490/3-year-olds-death-from-rare-brain-tumor

Jack's Angels Foundation
http://jacksangelsfoundation.com/

Apparent Diffusional and Fractional Anisotrophy of Diffuse Intrinsic Brain Stem Gliomas
http://www.ajnr.org/content/31/10/1879.long

Stanford's Big News- Anti CD47

Recently there has been quite a bit of press over Stanford's research on an anti-CD 47 drug because of a recent publication and potential of upcoming clinical trials.   Now it seems that the FDA has approved this- human clinical trials.   Because I am primarily interested in pediatric brain tumors, I rarely get excited about this type of news as in the past it often has taken years to go from first in man studies to our kids.   However, this might not be the case with this new agent.   It seems that DIPG has been on the minds of the developers of this anti- CD47 antibody already.  Stanford already lists this as a topic in their pediatric brain tumor research program!

So what is so special about this anti-CD47 antibody that it has been called the "Holy Grail" of cancer research?

Apparently cells have these proteins on them called CD47 which tell a person's body "don't eat me".    Those things that are foreign don't have these proteins so the idea is that the immune system will get destroy them.   Cancer cells have alot of these CD47 proteins on them which allows them to continue to survive by tricking the immune system.

A decade ago a Stanford researcher, Irving Weissman, found that leukemia cells had more CD47 on them than normal healthy cells.  Later the researchers found that every type of cancer they tested had high levels of CD47 than healthy cells.  They developed an anti-CD 47 antibody and tested it on tumor cells in petri dishes.  Without the antibody the macrophages (those cells which eating up stuff that shouldn't be there) ignored the cancer cells.   However,  when the samples had the anit-CD47 antibody included the  macrophages destroyed all types of cancer cells.  They then tested the agent on mice with similar effects.

There has been some concern that since all cells have CD47 that there could be some significant side effects in normal tissue.   Although there has been some transient decreases in blood counts other effects were not seen in mice.    The hope is that this will hold true in people as well.

The Stanford team has recieved a four-year $20 million grant for California Institute for Regenerative Medicine to translate these findings from mice to humans.  Since Stanford seems to have the funding, the approval and the interest in DIPG this might be research to watch as sometime in the future this agent might become a clinical trial option for kids with DIPG.

Names to Know:   It seems the Stanford researchers involved in this project and interested in pediatric DIPG included Michelle Monje, Hans Vogel, Paul Fisher, Albert Wong, Irving Weissman and Phillip Beachy as well as David Rowitch (UCSF).

References:
Antidote: On Cancer and CD47
http://www.mmm-online.com/antidote-on-cancer-and-cd47/article/291840/

CD47 Antibody treatment shrinks or eliminate human cancer tumors in mice (Stanford Video)
https://www.youtube.com/watch?v=EyGWZbmjeR0

New Publication- Are DIPGs just resistant to chemo? No!

Last week the highly productive, DIPG-focused Netherlands group from VU University Medical Center in Amsterdam put forth another publication which happens to have free full text available!

This research focuses on unravelling the reasons why chemotherapy has not been beneficial against DIPGs and pediatric high-grade gliomas. Are DIPGs just resistant to the agents?   Or,  is it that something is protecting the cells which causes an otherwise good option to be ineffective?

Part 1- Are glioma cells just resistant to chemotherapy?
To look at the first question, the researchers evaluated 9 pediatric glioma cell lines to eliminate questions of adequate drug delivery.  Three of these cell lines were from children with DIPGs and 6 were from supratentorial high grade gliomas.  Of the 3 DIPG cell lines, all were of different histologic grades- one GBM, one anaplastic astrocytoma and one diffuse fibrillary asrocytomas.   Two of these DIPG cell lines came from children who had not had any treatment.  The other cell line came from an autopsy donation done approximately 2 hours after death.

In the screening of these cell lines, several agents had high level of killing tumor cells.    

When looking at targeted small molecule agents, these did not fare as well as classical chemotherapies.  Some did show some efficacy .  The best of these was bortezomib which resulted in more than 50% reduction in cell line surival in 6/9 cell lines.  There was little or no effect with erlotinib and everolimus.   A hypothesis for this result include that the cell lines were not checked for the targets.   If there was a matching of targets and agents the results might have been better.   Also since there are multiple messed up pathways combined therapy is generally thought to be needed and a single agents is very unlikely to be effective.

In looking at classic chemotherapy agents, melphalan was the only drug that had significiant toxicity in all cell lines.  Interestly that is the exact agent of the new intra-arterial Hopkins DIPG trial!

Other agents that were found to have a signficant effect included doxorubicin, mitoxantrone and BCNU.  The next level included etoposide, thiotepa and carboplatin.  Carboplatin was of special note since that is what the UK in their CED report.

What this means for DIPG is that DIPG is not necessarily resistant to chemotherapy!  Effective drgus might not be the biggest hurdle for a cure for DIPG.  It might be getting them to the tumor cells.

This work was funded by KiKa "Stichting Kinderen Kankervrij"- Dutch Children Cancer-free Foundation.

Tomorrow.....
Part 2- Do the efflux transporters protect the glioma cells?

References:
In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma
PLoS One. 2013 Apr 29;8(4):e61512. doi: 10.1371/journal.pone.0061512. Print 2013.
Free Full Text-  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639279/

KiKa Stichting Kinderen Kankervrij- Dutch Children Cancer-free Foundation
http://www.kika.nl/

DIPG Collaborative Symposium Begins in Cincinnati

Tomorrow the 2nd  DIPG Collaborative Symposium  begins in Cincinnati.   This two track program brings together doctors and researchers in one track and foundations and parents in another (with a potential networking dinner Friday evening).   The goal is to be able to "efficiently fund and inspire diffuse intrinsic pontine glioma cancer research in hopes of finding a wider cure for cancer".   This year there is expected to be approximately 140 from 7 countries.  With the diverse agenda with international speakers on the forefront of DIPG research, I suspect it will be an exciting place to be for those interested in pediatric diffuse intrinsic pontine glioma.

The 2011 DIPG Collaborative Symposium brought about some substantive advances in the infrastructure critical for DIPG research including the DIPG Registry,  the DIPG Preclinical Consortium,  and the DIPG Genomics Repository.

This meeting starts Friday morning with a Keynote Lecture from Canadian geneticist and researcher, Nada Jaboda MD PhD.   Although the topic has not been release I am thinking- H3.3,K27M and epigenetics.   To get a taste of the work she has been doing in unravelling pediatric vs adult astrocytomas (including DIPG) there is a NYU Grand Rounds titled "Rewiring the Epigenome in Pediatric and Young High Grade Astrocytomas" presented on December 18, 2012. (click here to watch the video)  This work has the potential to change how we approach and treat DIPGs.

The meeting continues with a update of research funded through the collaborative and the Cure Starts Now:
Preclinica/Traslantional
* Xiao-Nan Li(Baylor)- an oncolytic picorna virus in a DIPG xenograft mouse model.
* Oren Becher (Duke)- systemic and direct delivery of a PDFGR-alpha antibody.
* Suzanne Baker (St Jude)- establishment and characterization of DIPG renewable tissue resources
* Patricia Baxter (Texas)- Novel BMI-1 inhibitors in brainstem xenograft mouse models.
* Michele Monje (Stanford)- combined targeted therapy for cellular subpopulations in DIPG.

Clinical
Mark Souweidane (Cornell)- CED trial update
multiple- DIPG Registry update

This will be followed by various other sessions especially revolving around biopsy, biologic understanding of DIPG and current trends in clinical trials.   One of the most  anticipated things for me is the Xerecept session on Friday afternoon.   It has been years of waiting for this drug to see if it can decease the suffering caused by steroids in so many DIPG children (click here for video).   Hopefully something substantive will come from this session.

The other track- the parents and foundation track- will meet primarily on Saturday to discuss the Collaborative objectives, structure, prior efforts and success.

The event will culminate with a Once in a Lifetime Gala which looks to be spectacular (sold out- 1200 seat).  This year's three ring circus them features the Cincinnati Circus and Nik Walenda.

Reference:
DIPG Collaborative Symposium Meeting Agenda
https://csn.donordrive.com/assets/csn/files/$cms$/100/2097.pdf

DIPG Preclinical Consortium-
http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html

DIPG Registry-
http://www.dipgregistry.org/

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

New NIH/Hopkins Abstract presented at USCAP

Earlier this month the 102nd Annual Meeting of the United States and Canadian Academy of Pathology was held in Baltimore, Maryland.  Frankly, this isn't a meeting that I have ever followed because I don't remember a pediatric brain tumors presence previously-- and certainly not the unresectable, rarely biopsied diffuse intrinsic pontine glioma.  This just isn't something that pathologist do.  Yet, on a Wednesday afternoon, a DIPG poster- Histology and Immunohistochemical Profile of Diffuse Intrinsic Pontine Gioma- took its place among a myriad of other neuropathology presentations.

This joint NIH/Hopkins abstract presented the characteristics of of 24 DIPGs autopsy specimens.  Histologic results are as follows:
17- GBM with 14/17 having pseudopallisading necrosis and 12/17 with vascular proliferation
5- anaplastic astrocytoma
1- low grade (WHO II)
1- intermediate (features of WHO II and III)

Immunohistochemical results revealed all were GFAP positive.    Regarding the stem cell markers,  22/24 were Oligo2 positive and 19/24 were Sox2 positive.  In addition, 20/24  16/24 were positive for p53 and EGFR respectively.

What does all this mean?   Well, all of these were gliomas.   The high level of stem cell markers would seem to support the hypothesis of a tumor stem cell origin for DIPG.  Understanding the pathways that have gone awry with DIPG we might be able to better identify prognostic markers and potential therapeutic targets.

It also means that DIPG research has began to make strides in tumor biology.   In the future, people that really want to understand DIPG research will have to gain an understanding in pathways and cancer stem cells.  Excellent chapters by Mark Kieran and Michelle Monje are in the ACCO book Understanding the Journey.

Additionally, it means that 24 parents selflessly gave an ultimate gife in the fight against DIPG-without which I don't see any possible way we could get to a cure.  There is no doubt we could not have gotten to this research.   It is with deep gratitude that I recognized these families that endured the unimaginable and jumped over logistical hurdles to make a difference.

Note- Interestingly Oligo2  importance with PDFRA was just mentioned on Friday here with the UCSF research.

Reference-
Abstract-  http://www.abstracts2view.com/uscap13/view.php?nu=USCAP13L_1726

UCSF Research-  http://dipg.blogspot.com/2013/03/focus-on-research-hashizume-laboratory.htm

ACCO DIPG Book-
http://myemail.constantcontact.com/New-FREE-resource-for-DIPG-Families-.html?soid=1102946333954&aid=k63YiippnW8

Case Report- Two Children with Prolonged Survival

During time period between June 2008 and June 2009, Children’s Healthcare of Atlanta treated three children diagnosed with DIPG with radiation followed by temozolomide and avastin.   Two children were still alive at 37 and 47 months from diagnosis.  The other child had progression free survival for 12 months followed by rapid deterioration with death at 14 months from diagnosis. 

Here is the recent case report of these two children who have surpassed the 3-year mark since diagnosis of a DIPG and were still going strong at the time of publication.

Patient 1- was described as an 11-year-old male with a 2 month history of weakness on the left side as well as walking and swallowing difficulties.   The initial MRI showed a 4cmx3.5cmx3cm non-enhancing tumor of the pons and medulla.  

Patient 2-was described as an asymptomatic 7-year-old female who was found to incidentally have a 3cmx2.3cmx2.6cm pontine mass after head trauma.   She was observed closely with serial MRIs.  Two MRIs showed increased tumor size and at 8 months from initial presentation she deteriorated developing a facial palsy, right sided weakness and hydrocephalus.  The tumor was 4.2cmx4.3x3.8cm with new focal areas of enhancement.

The children were treated with temozolomide 200mg/2d/d for 5 days ever 28 days and avastin 10mg.kg.dose every 14 days.   In both patients a 65% decrease in tumor size was seen.   No steroids were needed after 10 weeks from radiation.   The therapy was tolerated well.  At publication both children were doing well and continuing on treatment.  The paper notes that the boy was going to school and playing soccer at 37 months.  

 (Note- the actual paper has several MRI images provided both initially and later for both children.)

The authors speculate that the combination of temozolomide and avastin might deliver more temozolamide to the tumor because avastin might normalize the tumor vasculature.    As support for this theory the authors point to cilengtide altering perfusion which allowed for increased temozolamide delivery  for gliomas.    Perhaps avastin has a similar effect.

An additional advantage of this combination might be the decreased need for steroids.

The authors recommend consideration of an expanded DIPG clinical trial with this combination.

By the way, the female child appears to be atypical both in presentation and focality in her tumor.   On the other hand, the male child seems to have a very typical presentation for DIPG.

Reference:

Prolonged survival after treatment of diffuse intrinsic pontine glioma with radiation, temozolamide, and bevacizumab: report of 2 cases.

J Pediatr Hematol Oncol. 2013 Jan;35(1):e42-6.

http://www.ncbi.nlm.nih.gov/pubmed/23249962

State of the Art DIPG Meeting- March 7/8- Amsterdam

There will be an invitation-only DIPG Colloquium held in  Amsterdam on March 7th and 8th on the "State of the Art in Diffuse Intrinsic Pontine Glioma".

http://www.knaw.nl/Pages/DEF/33/849.html

Listed Agenda Participants-

*Dr M. Monje Deisseroth, Department of Neurology, Stanford Institute for Stem Cell 

Biology and Renegerative Medicine

*Dr C. Hawkins, Department of Paediatric Laboratory Medicine, The Hospital for Sick 

Children

*Dr O. Becher,Department of Pediatrics, Preston Robert Tisch Brain Tumor Center and 

Duke University Medical Center

*Dr O. van Tellingen, Department of Clinical Chemistry, The Netherlands Cancer Institute 

(Antoni van Leeuwenhoek Huis)

*Dr K.E. Warren, Pediatric Oncology Branch, National Cancer Institute

*Dr S. Puget, Department of Neurosurgery, Hôpital Necker Enfants Malades and Université 

Paris Descartes

*Dr.  M. Souweidane, Department of Neurological Surgery, Weill Cornell Medical 

College

*Prof. Dr O. Hoekstra, Department of Nuclear Medicine and PET Research, VU University 

Medical Center

*Dr T. Jaspan, Division of Neuroradiology, Department of Diagnostic Imaging, University 

Hospital Queens Medical Center

The meeting will be followed Saturday morning with an open Masterclass -

*N.Bakker, Stichting Semmy

*Dr C. Jones, Paediatric Molecular Pathology, Institute of Cancer Research

*Dr S. Puget, Department of Neurosurgery, Hôpital Necker Enfants Malades and Université Paris Descartes

*Prof. dr. P. Wesseling, Department of Pathology, Radboud University Nijmegen Medical Center and VU 

University Medical Center

Stichting Semmy is a parent-founded foundation started by Nicole Bakker after her son Semmy died of a DIPG in 2006.   The Stiching Semmy Foundation has been very active in sponsoring collaborative meetings and new research protocols for DIPG.  There is a video from the first International DIPG Conference held in Barcelona which shows work sponsored by Stichting Semmy presented by Viola Caretti and  Dannis Van Vuurden.

http://justonemoreday.org/DIPGConference/NovelTherapeutic.html

A new Preclinical DIPG Consortium

A new Preclinical DIPG Consortium has been unveiled at-
http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html

One of the spectacular things is that this clearly identifies some of the researchers that are truly placing significant emphasis is trying to unravel DIPG.  There are 5 US sites and one each in Canada, France and Amsterdam.  A main requirement to be a site currently seems to have a cell line as well as a funding source.

The DIPG Consortium includes:

• Oregon Health and Science University-  Charles Keller MD, Kellie Nazemi MD, Nate Selden MD, PhD and Dan Guillaume MD, PhD

• Duke University- Oren Becher MD

• Stanford- Michelle Monje, MD, PhD

• Cincinnati Children’s Hospital Medical Center- Maryam Fouladi, DM

• Baylor College of Medicine- Xiao Nan Li, MD,PhD

• University of Toronto- Cynthia Hawkins, MD, PhD

• VU Cancer Center of Amsterdam- Dannis G. van Vuuren, ND MSc and Ester Hulleman

• Institut Gustave-Roussy, Villejuif France- Jacques Grill

The current study is called "Rapid Preclinical Development of a Targeted Therapy Combination for DIPG" which has a goal of attempting rapidly to test agents against cell lines and then animal models to hopefully rapidly translate into clinical trials over the next two years.

 It does seem that this trial is a novel approach in that it will treat DIPG specifically and not rely on adult models or cell lines.  This is important in that pediatric DIPG is molecularly distinct from adult gliomas.

Another interesting thing is that the high throughput screening of agents seems like it is to be limited specifically to 60 already available drugs.  This sounds quite reasonable as why test against agents that might not be available for some time. 

 In addition, combinations of agents will also be tested.  This also seems to be significant as many researchers have said that a single agent is unlikely to be effective against DIPG.

 It seems that after the best agents and combinations are found in vitro (against cells alone) that they will be tested in animal models- likely both xenografts and Oren Becher’s  GEMM (genetically engineered mouse model).  

Note- Xenografts are made when human cells lines are injected into animal to create a tumor.  GEMMs make tumors on their own and are not from human cell lines

People can check back to the website at that entry to check the progress of the study (mid page)-

http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html

Funding for this study has been through parent founded organizations.   The Cure Starts Now provided $100,000 for the North American Institutions.  Also listed were those involved in the DIPG Symposium Collaboration including Reflections of Grace Foundation, The Jeffrey Thomas Hayden Foundation, Cancerfree Kids, Carly’s Crusaders, The Max Lacewell Foundation, Smiles for Sophie Forever Foundation and Benny’s World Foundation for making our project possible.

http://kellerlabblog.blogspot.com/2011/11/thecurestartsnow-funds-dipg.html

Additionally, a $28,000 grant from The Lyla Nsouli Foundation for Children’s Brain Cancer Research in the UK allowed for expansion for  the two participating European collaborators.

http://kellerlabblog.blogspot.com/2011/11/lyla-nsouli-foundation-funds-supplement.html

Prados Predicted Paradigm Shift for DIPG (diffuse intrinsic pontine glioma)

Three years ago, Dr. Michael Prados was interviewed by Accelerated Brain Cancer Cure on his thoughts of advancements coming for pediatric brain tumors.   Dr Prados immediately focused on the paradigm shift occurring in the medical community to develop unique strategies to fight DIPG though analysis of individual biopsy samples predicting things may change quickly for DIPG.

Why did that paradigm shift occur in the prior year?  Well, French physicians published in the Journal of Neurosurgery 4 years of biopsy results for diffuse pontine lesions.  All 24 children survived the procedure and only 2 suffered some sequela from the intervention developing transient cranial nerve palsies.   One of the two has a worsening of a previous hemiparesis.   Two children had their treatment plan altered because of the biopsy results.

Stereotactic biopsy of diffuse pontine lesions in children

http://www.ncbi.nlm.nih.gov/pubmed/17647306

Neurosurgeon Stefanie Puget has come to North America several times to discuss there ongoing work.   It appears she was just at the Bethesda Consensus Conference earlier this month.

However, it seems that events have moved beyond the discussion stage.   The new multi-institution, 4-armed molecular stratification study is listed as open on clinicaltrials.gov opening first at Dana Farber Boston.   The other institutions slated to collaborate in this trial include -

• University of California, San Francisco
• Children's Hospital Boston
• Children's Memorial Hospital
• Children's Hospital Los Angeles
• University of Utah
• Memorial Sloan-Kettering Cancer Center
• Seattle Children's Hospital
• The Children's Hospital, Denver
• Doernbecher Children's Hospital
• Washington University Children's Hospital
• Miami Children's Hospital
• Johns Hopkins University
• University of Florida
• Children's Hospitals and Clinics of Minnesota
• Southwestern Regional Medical Center
• New York University
• University of Rochester
• University of Mississippi Medical Center
• Louisville Children's Hospital
• Children's Healthcare of Atlanta

http://clinicaltrials.gov/ct2/show/NCT01182350?term=pontine+glioma&rank=4

Accelerate Brain Cancer Cure (ABC²) is a U.S. brain tumor foundation started in 2001 by Dan and Steve Case with the mission to accelerate a cure for brain cancer by increasing the number of potential therapies and moving them rapidly into the clinic for patients.  Since inception,  ABC²  has raised more than 16 million dollars investing in each stage of the development pipeline in pushing for a cure.   It is worth taking a look at the diversity of funding they have engaged in striving for a cure.
http://www.abc2.org/smarter-research