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.

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

Be On The Lookout- Notch Pathway and DIPG

With the lag time between presentation at a meeting and publications often times things can just slip under the radar.   For me, this was certainly true of this American Association for Cancer Research abstract presented last year in Philadelphia- "High-level activation of the Notch pathway in diffuse intrinsic pontine glioma".  The title doesn't immediately excite me.  However, packed in this short abstract is a number of significant advancements in DIPG research.

1) MADC, the Mid-Atlantic DIPG Consortium, brought three geographically tied institutions together to fight DIPG.   Johns Hopkins, Children's National Medical Center and the National Institutes of Health-Pediatric Oncology Branch agreed to share DIPG tumor material that had been obtained through timely autopsy donation.

2) From a fresh tissue specimen, the researchers were able to establish a cell line- JHH-DIPG1.   The cell line was evaluated for the Notch pathway as this is known to occur in other aggressive brain tumors. JHH-DIPG1 showed a high level of  Notch pathway activation.  

3) From the cell line, a xenograft animal model was also developed.

So.... what makes this significant?  Well,

First, it is very difficult for any one institution to have enough DIPG tissue for research.   I see these type of collaborative efforts key to being able to crack the code of DIPG.

Secondly, it continues to show that parents will donate tumor after death to try to make a difference in this horrendous disease.    It shows that Stanford was not a fluke.  Cell lines and animal models can be developed for DIPG.

Thirdly, it brings DIPG more on par with other brain tumor and cancer researchers.  We now have cell lines and animal models (not only at Hopkins but also elsewhere).  Without these, research seemed at a standstill.

Finally, there are actual Notch agents that are available!  The pediatric phase 1 with the gamma-secretase inhibitor RO4929097 has already closed because it has reached its enrollment.  We are now just waiting for results.   The research here could be a basis for starting a clinical trial for DIPG with an agent- or at least being able to do more pre-clinical work with an appropriate model.   

References:
AACR Notch Abstract-
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=5eccf257-1e78-44ad-a11d-0cb24040c222&cKey=c6e7a032-873e-4aea-a5af-1b3374b5b338&mKey=%7B2D8C569E-B72C-4E7D-AB3B-070BEC7EB280%7D

Gamma-secretase inhibitor RO4929097 in treating young patients with relapsed or refractory solid tumors, CNS tumors, lymphoma or T-Cell Leukemia
http://clinicaltrials.gov/ct2/show/NCT01088763?term=Notch+brain+tumor&rank=7