DIPG in Adolescents- Presentation and Outcomes

ASCO starts tomorrow.   It is the biggest professional cancer meeting in the world.   There will be over 25,000 medical professionals from all over the globe to build bridges to conquer cancer.

The 2013 abstract statistics are amazing.  There were 5306 abstracts submitted from 75 countries.   Of those, 2720 were accepted for presentation at the meeting and another 2034 were additionally accepted for ePublication.   There were 172 abstracts submitted in the area of CNS Tumors and 81 in the field Pediatric Oncology.

One of those CNS abstracts happen to be on DIPGs!

Abstract: Diffuse intrinsic pontine gliomas (DIPG) in adolescents can have different prsentation but similar outcomes compared to middle childhood
Insitutions: NIH and Lurie Children's Hopsital of Chicago
Authors: Kathy Warren, Elad Jacoby and Jason Fangusaro

In this study 46 children between the ages 10-20 years of age (median 13)  were identified.   There was a female to male ratio of 1:0.77.

Symptoms: headache (39%); double vision (27%); cranial nerve issues (27%); dizziness (25%)
Two were incidental

Onset of Symptoms to Diagnosis:  2 days to 5 years (only 9 had symtoms less than 2 weeks)

Radiation: 39/42 patients had radation; 36% did not improve or got worse during riadation: 63% remained on steroids at the end of radation

Time to Progression: (n-32 for data available) 8 months median with a range of 2 months- 2.5 years; 2 alive and 1 in active treatment at time of abstract submission

Conclusion:  Adolescents are more like kids than adults with diffuse intrinsic pontine lesions with similarly abysmal survival stats.

Reference:
Diffuse intrinsic pontine gliomas (DIPG) in adolescents can have different prsentation but similar outcomes compared to middle childhood
http://abstracts2.asco.org/AbstView_132_118298.html

Prenatal DIPG- a case report!

On May 16th the jounal Pediatric Radiology published an unsual case report of a a pre-natal DIPG written from the department of neurosurgery and diagnostic imaging t Brown University.

In this situation a 33 year female who had previously delivered 3 children without complications had an ultrasound at 33 weeks gestation.   Unfortunately the ultrasound revealed a markedly enlarged head of a size more than 40 weeks but with an abdominal circumference and femur length of 33 weeks.   There was also triventricular hydrocephalus without evidence of spina bifida.

A fetal MRI was then obtrained which showed a mass with the epicenter in the pons extending into the midbrain, medulla and cerebellar peduncles.  The expansile mass had poor margins.  There was severe hydrocephalus.  No abnormalities were seen outside the brain.   A diagnosis of diffuse pontine glioma was made.  

The chid was delivered at 36 weeks, 4 days becaue of the big head and had Apgar scores of 7 and 9.  A repeat MRI was preformed and confirmed the prior findings.   The boy underwent placement of an extraventricular drain because of signs of increased intracranial pressure.   The child died from respiratory failure at day 3.

At autospy the lesions was found to be primarily an infiltrative anaplastic oliogdendroglioma with areas of astroctyoma grade IV differentiation.

Although I have posted on neonatal tumors in the past (click here for prior blog post), the rarity of brainstem lesions in the neonatal period makes it difficult to know exactly what to do.   Ther have been a few cases that have done well in the very young.  There are other resports of the typically horrendous course of DIPG in the neonatal period.  As researchers attempt to understand more about DIPG, this case adds to the library of knowledge regarding DIPG.  The authors sugggest that autopsy studies should be strongly encouraged to learn more about this atypical situation.   I would add that perhaps including this in the DIPG registry would also be helpful.

Reference-
Prenatal MRI characterization of brainstem glioma
in Pediatric Radiology
http://www.ncbi.nlm.nih.gov/pubmed/23677423

Spontaneous regression of a diffuse brainstem lesion in the neonate.  Report of two cases and review of the literature
http://www.ncbi.nlm.nih.gov/pubmed/16206736

Lesion Regression
http://www.ncbi.nlm.nih.gov/pubmed/?term=AIREWELE+brainstem

Diffuse intrinsic brainstem tumors in neonates.  Report of two case.
http://www.ncbi.nlm.nih.gov/pubmed/18447673

Meagan's Walk 2014

Well, the date has been set for 2014 Meagan's Walk!

OK, I guess  that shouldn't be a surprise as for more than a decade Meagan's Walk has been happening the Saturday of Mother's Day weekend in Toronto, Canada.   I was remiss in posting earlier about this amazing event.  Every year, thousands of people come out to for a leisurely 5K walk ending at The Hospital for Sick children.   The partipants then form a human chain all around the hospital to give the hospital and the kids a loving hug.  All this is done to raise awareness and funds for pediatric brain tumor research.

Over the years, Meagan's Walk has raised more than 2.7 million dollars for Sick Kids brain tumor research.  They directly fund preclinical research at the Arthur and Sonia Labatt Brain Tumour Research Center lead by Dr James Rutka as well as clinical care and research initiative lead by Dr Eric Bouffet.

So one might ask exactly why is this is a DIPG blog.   Yes, Meagan had a diffuse brainstem glioma.  The little girl's story is one that has been repeated again and again.   She loved life playing with frineds and cuddling every little living creature.   She died June 17, 2001 just about 7 months from diagnosis.   Yet as we with so many of our kids,  "Meagan's story is one of courage, spirit and hope."    And as with so many parents, Denise- her mom, has continued to strive to make the story different for other families.

Sick Kids has been a powerhouse of reasearch for DIPG and all pediatric brain tumors.   I am sure Meagan's Walk has been part of the reason.

Although this video is a few years old, pictures are worth more than all the words I could write here.  Hearing the story from the mom and founder of Meagan's Walk is better than anything I could say.

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

Their Ultimate Last Stand- McKenna Claire Foundation

When the beautiful, green-eyed, blond 7 year-old California kid, McKenna Claire Wetzel, started to throw up in January 2011 it was just thought to be the flu that had been going around.   After of week of illness and a couple visits to the doctor, her parents started to notice a wandering left eye.   The CT Scan that followed found the DIPG.

Good friends and good times- two of life's greatest gifts.    MckKenna's parents worked hard for both.   They had been told that this tumor was not survivable.   Thus, they told their oldest child that they were doing thing to make Mckenna feel better- sadly not to cure her.   She traveled to Hawaii, to tapings of both American Idol and Dancing with the Stars and sat on the floor at the Laker's game.   She continued to go to second grade and every Tuesday night was "homework parties" at her house.  The parties were more about community and friendship than homework.   As things worsened her friend, Katie, would sit for hours holding McKenna's hand in silence.  

Just six months from hearing DIPG, McKenna passed away.   As devastating as this was, the Wetzel's were making one "last stand" against the tumor.   They decided to donate Mckenna's tumor to Michele Monje's lab at Stanford.  A lab tech from Stanford flew down as a guardian for this precious gift as it came to a new home- a place striving to learn how get rid of "that stupid tumor".

However, the Wetzel's realized that funded research would be able to do more.  To honor McKenna and "perpetuate the sense of community",  the McKenna Claire Foundation was born.    In less than 2 years the foundation has raised approximately a half million dollars.    One amazing thing was last May (Brain Cancer Awareness Month) the Chevron Corporation raised $292,466 at some of their California convenience stores.

These funds have been provided to Michele Monje's lab at Stanford which had grown a cell line from McKenna's tumor.   And although cell lines haven't been easy to transport, Michele Monje's lab seems to have overcome this hurdle.   McKenna's tumor now is also being studied by researchers in England and Australia!

Some of that funding had gone to fund the position of "tumor cell line guardian".   OK,  Anitha Pannuswami's official title is laboratory manager at Monje’s lab at Stanford.   Often times salary funding is not part of grants, but I believe this has been a important factor in being able to do more in DIPG research.    Anitha Pannuswami's job is to watch over McKenna's tumor as well as 5 other children's at the Monje lab.   She also handles shipping them in ice to any researcher in the world who wishes to study DIPG.  This is defnitely increasing DIPG reasearch internationally.

This May's Brain Cancer Awareness Month, the Chevron Corporation has expanded their support through their convenience stores throughout California.  The Mckenna Claire Foundation has several other events already planned for 2013. 

McKenna's tumor is flying like a butterfly around the world.   Without a doubt, the McKenna Claire Foundation  and the targeted partnership with Stanford is changing the landscape for DIPG Research.   I predict both will be well worth watching.

References:
Tumor that killed girl could keep others alive
http://www.bendbulletin.com/article/20130427/NEWS0107/304270355/

Chevron customers raise $292,466 for McKenna Clair Foundation fight against pediatric cancer
http://www.orangecounty.com/articles/chevron-41266-foundation-claire.html#

Mckenna Claire Foundation
http://mckennaclairefoundation.org/

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

One of the longstanding questions for DIPG has been."Why doesn't chemo work?"
There have been dozens of trials using all kinds of agents and all of them have virtually the identical Kaplan Meier Curve.  The think we don't know is why that is.   Often times one hears about something in the blood brain barrier that limits chemotherapy effectiveness.   Other times one wonders if it is something in the glioma cells themselves that make them more resistant.   The Netherlands paper tried to answer one part of this in better defining ABC transporters in pediatric glioma.

ABC transporters essentially function as little door ways in the cell's membrane either usher substances into the cell (importers) or out of the cells (exporters).   The exporters are tone ones that are a problem withe drug resistance.   The transporters pump drugs and toxins out of the cells.

There have been 3 different ABC transporters found that escort drugs out of cells.   These include P-glcyoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance associated proteins (MRPs, ABCC1).

This Netherlands study looked at the above 3 ABC transporters in each of the glioma cell lines.   All cell lines were negative for P-gp.  Only one supratentorial pediatric glioma cell line had BRCP1.  High levels of MRP1 was found in 4 of the 9 glioma cell lines.  That included 2 of 3 of the DIPG cell lines.

 The researchers then looked at actual tumor sample sections to try to determine the amount of ABC transporters in the glioma cells versus the blood vessels. They found that P-gp was not present in most of the glioma cells but was presesnt moderately in the tumor's blood vessels.   BCRP1 was not present in the glioma cells but was highly pressent in the blood vessels. Only MRP1 was seen in both the glioma cells and the blood vessels.   A chart on the cell lines tested (including 2 of the 3 DIPG samples) is available (click here to see chart).

So, what does this mean for DIPG now?

That is hard to say.   So far tying to inhibit the ABC transporters with different agents have been problematic because of significant toxic side effects.   These ABC transporters are meant to protect normal cells as well.   However, since  most of the ABC transporters seem to be in the blood vessels  a way around this blood-brain barrier could be direct tumor delivery (i.e., convenction enhanced delivery).  The researchers also suggest developing drugs that are not a substract for these transporters could also increase chemotherapy effectiveness.

It does tell us that in trying to find a cure for DIPG that we can not just focus on finding targets within the cancer biology but also need to work on finding ways for new agents to be able reach these targets.

Note:  The ATP-binding cassette transporters issue was featured in a recent blogspot regarding a new abstract out of Oren Becher's lab in Duke.

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

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/

ABC transporters limit dansantinib efficacy in mice
http://dipg.blogspot.com/2013/04/abc-transported-limit-dasatinib.html

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/

More than 2 Million- DC Race for Hope!

Today was the 16th year for the DC Race for Hope.   It drew over 11,000 people and raised more than 2 million dollars!  The facebook page says that the count is more than 2.3 million and counting.   Check  out the pictures on their page.   It is heartening to see the street with people filled supporting the fight against brain tumors.

One of the teams for the past several years has been David Cook.  He is the Season 7 winner of American Idol.  He also lost his brother to a 10 year battle with brain cancer.  This week he was back on the Idol stage and specific mention was made of his passion for supporting brain tumor research. (Click here to see the video)

In it's history the DC Race for Hope has raised more than 17 million for brain tumor research.  The funds go to the National Brain Tumor Society and Accelerated Brain Cancer Cure (ABC2).  These foundations are fighting all brain tumors- many kinds and all ages.

Perhaps at one time pediatric brain tumors seemed to be off on their own but not anymore.  To me, it definitely seems that DIPG research has matured in the past few years that it has now naturally melded into other glioma research.

I was taken by surprised when ABC2 decided not only to provide funds for the DIPG Preclinical Consortium (initiated at the first DIPG Collaborative Symposium) but also provided strategic advice "to help the research consortium preform DNA (exon) sequencing of all DIPG cell lines, their primary tumor and paired normal DNA via the laboratory of Dr Paul Spellman at OHSU.

And the National Brain Tumor Society sponsored and attended the DIPG Collaborative Symposium.   Their  Pediatric Research Initiative seems to be exactly what are  top priorities for DIPG- molecular profiling and neuordevelopmental biology (gliomagenesis).  The National Brain Tumor Society grants in 2010 funded the ground-breaking work DIPG genomic work of both Cynthia Hawkins in Toronto and Suzanne Baker of St. Jude which has reported some of the most exciting results for DIPG- particularly the histone/K27M findings.

Times are changing.  Just a few years ago there was no preclinical DIPG research.   Now DIPG research has garnered the interest and inclusion from larger brain tumor organizations.   DIPG does have alot in common with adult GBMs- particularly poor statistics, invasiveness and the blood brain barrier.  The combined efforts with these other organizations seems to be a great thing in fighting DIPG.

Reference:
DC Race for Hope-
http://www.braintumorcommunity.org/site/PageServer?pagename=RFH_DC_Homepage

Dr Souweidane CED Trial on 8th Patient

The Cristian Rivera Foundation, a significant support of the Cornell convection enhanced delivery (CED) trial for newly diagnosed children with DIPG, announced in their April 2013 newsletter that the primary investigator, Dr. Mark Souweidane, is now up to his 8th patient in this trial that opened at the end of 2012.

This is a very exciting, innovative trial for DIPG where a catheter is placed from the top of the head down in to the brainstem.   A few weeks after traditional radiation, a radiolabelled antibiody is infused directly in to the pons.   Thus, the blood brain barrier is no longer a problem in getting an agent into the tumor.

This is different than other DIPG CED trials in that it uses a radiolabelled antibody.   The antibody is
8H9 which has been found in several different tumors.   This is linked to 124I which is radioactive.   Since radiation has been the only thing that has made a dent in survival statistics the hope seems that this targeted radiation will clean up some of the cancer cells that have thus far been radioresistant with routine radiation.

This trial is the culmination of more than a decade of research utlitizing CED in the brainstem undertaken by Dr Souweidane and his team at Cornell.  Below is a video illustrating how CED is performed.

For more information about this trial,  about the trial and contact information for Dr. Soweidane click here.

Related Blog Post:
UK Gives CED a Go
http://dipg.blogspot.com/2013/04/uk-gives-ced-go.html

DIPG Collaborative

The DIPG Collaborative "is an association of foundations unified with the mission of efficiently funding and inspiring DIPG research in hopes of finding a wider cure for cancer".   From The Cure Starts now website it says that the Collaborative Council is to:
1) provide the tools and information to families whose children face the difficult diagnosis of pediatric brain cancer.
2) provide a warm and caring envirnoment to share information, discuss options and support one another.
3) make available accurate and easy to understand information for families that are newly diagnosed.  

A major kick off of the DIPG Collaborative was the 2011symposium that brought 13 foundations together with researcher to find substantive ways to research DIPG jointly together.    From that meeting several research infrastructure developments occurred which now really allows us to start to unravel DIPG.   These included the DIPG Preclinical Consortium, the DIPG Resgistry and the DIPG Genomics Repository.

If one hasn't looked at the Preclinical Consortium,  I think it is worth the time as it is impressive.  It is less than 4 years from when the first cell line was promulgated in Michelle Monje's lab (from tissue donated by Dylan Jewett).  Through the consoritum we now have ten institutions working together on more than 30 cell lines (as well as various animal models) trying to find the best single agents or combinations in those cell lines to be a  basis for rapid translation into clinical trials.   Every week there is an update on the consortiums work including DNA and RNA analysis. This is fully funded byt the Foundational Leadership Partnters of the DIPG Colaborative.

The DIPG Registry is equally impressive.  There is a section for medical professionals including sections on enrollment information and consultations.   There is also a section for parents where one can make contact for second opinions and also search for open clinical trials.  Parents can make contact with the registry to discuss enrollment- even for children who have died.  There already is some specific research in the works.

The DIPG Collaborative Symposium starts today, however, the major work of the DIPG Collaborative for foundations starts tomorrow.   The first session is on objectives for the next two years.   It would be really interesting to see the direction this collaborative is moving.

There are three levels of support:
Foundational Leadership Partners - The Cure Starts Now, The Cure Starts Now Australia, Jeffrey Thomas Hayden Foundation, Hope for Caroline, Soar with Grace, Reflections of Grace Foundation, The Lyla Nsouli Foundation

Foundation Partners- Smiles for Sophie Forever, Benny World,  The Team Julian Foundation

Symposium Sponsors- Max Lacewell Foundation, Love Chloe Foundation, Caroline's Miracle Foundation, Ellie DIPG Research Fund,  American Childhood Cancer Organization,  Pray Hope Believe Foundation, National Brain Tumor Society, Lurie Children's Hospital of Chicago, Cincinnati Children's Hospital

References:
CSN DIPG Collaborative Council
http://www.thecurestartsnow.org/about/foundation/councils/DIPGcollaborative/

DIPG Collaborative

http://dipg.org/

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/

Voices on Pediatric DIPG Biopsy- Mark Kieran MD PhD

Identification of Novel Biologic Targets in the Treatment of 

Newly Diagnosed Diffuse Intrinsic Pontine Glioma

ASCO 2012 Education Session Presentation

The third speaker on the 2012 ASCO session was Mark Kieran from Boston presenting "Identification of Novel Biologic Targets in the Treatment of Newly Diagnosed Diffuse Intrinsic Pontine Glioma".  Certainly Dr Kieran has been enduring in his passionate belief that non-treated tissue is going to be critical to the understanding and hopefully cure of DIPG.   He has worked much of the past decade to bring the standard of care for typical pediatric DIPG in line with advancements in neurosurgical techniques and cancer molecular biology research.  The video announcing that DIPG biopsy would be an educational session at 2012 ASCO much have provided a sense of satisfaction that this issue had reached prominence enough to be discussed at a significant cancer meeting. (click here to watch announcement video)

The first video I saw of Dr Kieran discussing this advancements in neurosurgery and cancer molecular biology research that makes DIPG biopsy possible and critical in understanding pediatric DIPGs was back in 2009.   The first international DIPG conference in Barcelona, Spain sponsored by the Alicia Pueyo Foundation included a presentation on this issue.  (click here for video)  The 2012 video shows how far we have come in the DIPG community as well as with cancer molecular biology.

Dr Kieran points out that the understanding DIPG biology is in it's infancy.    Few existing publications are on non-treated (biopsy specimens).  Treatment has the potential of significantly altering the genomics of a tumor.   However, there have been some consistencies:

* P53 loss/mutation is present in a significant number of tumors.

* The RTK-Ras-PI3K-Akt pathway is altered in a number of tumors. 

* PTEN loss might mean that mTOR might be a target.

* Hedgehog-dependent cancer stem cells might be a target.

Regardless of the ultimate biology of DIPG, we can definitely say that DIPG is different from both adult and pediatric high grade gliomas.   Treatment for kids with DIPG can not be based on these other tumors.

There is a caveat- just finding drugable targets might not alter the outcome with DIPG.  So for this approach has not changed the prognosis in adult GBMs despite a huge amount of available tissue.  We are at the beginning.   We don't know yet.   There is hope and optimism that this is a start. 

References:

From boos to hope: Challenging the dogma about deadly brain stem gliomas

http://childrenshospitalblog.org/from-boos-to-hope-challenging-the-dogma-about-deadly-brain-stem-gliomas 

Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma
http://www.ncbi.nlm.nih.gov/pubmed/22190243