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

K27M- Important in DIPG?

It has been less than a year and a half since the St Jude and Canadian researchers came out simultaneously with publications on histone H3 mutations in pediatric glioblastoma and DIPG.  These were the first ever reports on a "recurrent mutation in a regulatory histone in humans to case cancer and it seemed that those mutations may be drivers to alter the chromatinc architecture underlying the formation of pediatric GBMs and DIPGs.  The H3 mutation specifically related to DIPGs seems to be  K27M.

This seemed to generate a huge amount of interest in pediatric high grade glioma/DIPG research as this SNO/PBTF Pediatric Neuro-Oncology Basic and Translational Research Conference held in Fort Lauderdale this week had several abstracts on this exact subject.   In fact 4 of the 11 abstracts in the brainstem glioma section included K27M in their title.

Functional Analysis of the H3.3-K27M Mutaton in DIPG
University of Toronto, Duke University, The Hospital for Sick Children

H3.3 K27M accelerates PDGR-induced brainstem gliomagenesis in vivo
Duke Univeristy and Laboratory of Chromatin Biology and Epigenetic (NY)

Targeting the histone H3.3-K27M mutation for the treatment of diffuse intrinsic pontine gliomas
UCSF and Georgetown

The type of histone H3-variant K27M mutation drives the agressiveness of Diffuse Intrinsic Pontine Gliomas
France and UK

In addition, another abstract lists that all the 20 previsously untreated DIPG specimens in their study had the K27M mutition.  This abstract entitled "The genomic landscape of treatment naive DIPG biopsy samples" was a combined effort from Paris, France; Barcelona, Spain; London, UK and Vancouver, Canada.

It would seem that this K27M mutation is going to dominant upcoming discussions regarding DIPG.   The Allis-Becher research alliance has already produced an elegant paper coming out electronically ahead of print the end of March in Science.  This article found that the K27M point mutation is specific to the for the mistake of methionine for lysine at that location.   No other amino acid mistake in production causes the same problems.  These authors propose that this mutation inhibits a specific complex which promotes tumor formation.   It is more complex than that but that is the general idea.

The potential of importance is varied when looking at these abstacts.   This K27M mutation could be:
-"one of the first prognositic markers when judging results of prospective trials"
-"a target for novel intervention"
-and a mechanism for DIPG formation.

For those interested in DIPG research, I predict the K27M and other histone mutation research is going to be in the forefront in the near future.

Reference:
Brainstem Tumors, Radiaiton Therapy and Medulloblastoma (Platform Presentation Abstracts)
https://soc-neuro-onc.conference-services.net/programme.asp?conferenceID=3467&action=prog_list&session=26434

Inhibition of PRC2 Activity by a Gain of Function H3 Mutation Found in Pediatric Glioblastoma
http://www.ncbi.nlm.nih.gov/pubmed/23539183

Exceptional new Allis lab Science paper on exploding area of histone H3.3 in pedaitric brain cancer
http://www.ipscell.com/tag/h3-3-k27m/

Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children

The USCF pediatric neurosurgical department this week had a publication come out electronically ahead of print regarding biopsy issues for intrinsic brainstem lesions.  These doctors note that the situation with pediatric brainstem tumors is "virtually unlike any other location in the brain" because for these other areas the first step is obtaining a tissue diagnosis to devise an appropriate treatment course.   The reason for the lack of biopsy has been the perception of excessive risk of pediatric brainstem biopsy.   The article also notes that the current approach of investigating a wide array of chemotherapeutic options in multitudinous trials without biologic tumor analysis has not lead to any increased survival in the last two decade.  The authors evaluated the feasibility and safety of pediatric brainstem biopsy at their institution.

Nine children ( 4 male and 5 female witht he average age of 5.7 years) underwent brainstem biopsy between 2000 and 2011 under approval from the Committee for Human Research.   Children were exlcuded from the study if the tumor originated from the cerebellum or cerebral hemispheres, were exophytic or well defined lesions. All included children had typical DIPG imaging features.  The included children presented with cranial nerve palsies (7/9), ataxia (5/9) and headache (3/9).  Rarer symptoms included head tilt, nausea,  weakness on one side and respiratory distress.

The authors did discuss target selection.   All children had stereotactic biospies via a transcerebellar approach. The course was chosen to minimize passing through the brainstem avoiding the lateral edge of the 4th ventical, pontine tegmentum and ventral corticospinal tracts.   In some cases diffusion tensor imaging was used to locate the corticospinal tracts.    Unless there was an obviously enhancing, aggressive area the site selection was just deep to the middle cerebellar penduncle.  One to four specimens were taken.

All cases were gliomas.  Five of the children had high grade gliomas and four were low grade. None of the children suffered intraoperative complications.  One of hte children developed seizures and hypercephalus postoperative which was treated with a shunt.      Seven of the patients underwent radiation and chemotherapy and two underwent chemotherapy only.   All children did experience the natural progresssion of DIPG with decline in neurologic and functional status.  At the time of the publication writing 4 children had died- 2 high grade at 12 months and 2 low grade at 6 and 11 months.

The authors point out the the tremendous lack of progress with DIPG statitics has lead to "therapeutic nihilism".   However, they point out ther are many targeted biologic agents that might have potential on the horizon.   The problem is for phase II trials there will "certainly require tissue in order to determine molecular pheontype prior to treatment assignement".

It seems that this publication is looking specificially forward to those biologic agent trials so that DIPG children will not be excluded just on the basis of not having a tissue analysis.  Although biopsy did not aid the children in this study, it did outline that biopsy can be preformed safely in children with DIPG and gives some tips on the approach of such biospies.

With biospy and convection enhanced delivery I would hope that more pediatric neurosurgeons will become increasingly interested in options for children with DIPG.

References:
Feasibility, safety and indications for surgical biopsy of intrinsic brainstem tumors in children
http://www.ncbi.nlm.nih.gov/pubmed/23666401

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