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

ABC transporters limit dasatinib efficacy in mice

Ever since the first whole genome DIPG profile paper from Sick Kids in Canada came out in 2010, there has been interest in platelet derived growth factor receptor alpha.  This is because all the samples (9 post-mortem and two pretreated surgical samples) showed PDGRF-alpha expression.  The hope was that PDGFR-alpha could be a target to make a difference in DIPG.   The search was on for an agent to try.

An available PDGFR-alpha antagionist was found, dasantinib.  This Bristol-Myers-Squibb drug is marketed under the name Sprycel for the indication chronic myelogenous leukemia (CML).  When looking in clinicaltrials.gov, there are already 219 trials up for this drug.  It has been already been tried on adults and in children.   The availability and prior use seemed to make this drug easily translatable to trials for DIPG kids.  St. Jude has completed one trials using dasatinib and vandetanib and another open trial using dasatinib and crizotinib.

The thing about dasatinib is that it seems that it can be pumped out a a cell because by ABC (ATP-binding cassette) transporters.   This is a "superfamily" of  proteins that transport things (such as sugars, lipids, toxins and drugs) across the cell membranes.  Three of these ABC transporters are known to cause chemoresistance.  These are MDR, ABDG2 and ABCB1.  Datinib is known to be a substrate for MDR and ABCG2.

An abstract from Oren Becher's lab at Duke is going to be presented at the SNO/PBTF Pediatric Neuro-Oncology Basic and Translational Research Conference next month in Fort Lauderdale looking at whether altering these transport proteins can alter dasatinib activity.   They did this by making DIPG mouse models that were deficient in the transporters ABCG2 and MDR.  At the first signs of tumor, these mice were given dasantinib.  The mice were sacrified a day later and the brains examined for specific things (caspase-3 and phospho-histone H3).

There was no difference in phosoph-histone H3 whether the transporter was present or not in the mice. However,  mice without the transporter had a 20 fold increase in caspace C levels as compared to those mice with the transporter.

These researchers concluded that these ABC transporters impact dasatinib's efficacy.  Further study is need to see if transporter-deficient mice can live longer when treated with dasatinib and if a transporter inhibitor (such as elacridar) can increase efficacy hopefully increasing survival.

Reference:
ABC transporters, ABCG2 and MDR, limit the efficacy of dasatinib in a diffuse intrinsic pontine glioma (DIPG) mouse model
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=740371

Brain distribution and bioavailability of elacridar after different routes of administration in the mouse
http://www.ncbi.nlm.nih.gov/pubmed/22611067

Oren Becher Lab at Duke
http://pediatrics.duke.edu/faculty/details/0541183

Is Biopsy Safe in DIPG? An Institutional Experience

This spring abstract season which means one can comb through the abstracts to find the newest research being presented- sometimes more than a year before publication.   The hope in finding and highlighting relevant meeting abstracts is to significantly shorten that time period in figuring out who is doing what.  

On of the meetings with potential is the 26th Annual American Society of Pediatric Hematology and Oncology (ASPHO) Anual  Meeting being held in Miami from April 24-27.   With all the different pediatric blood and cancer disorders, I don't usually expect much success in looking for brain tumor abstracts let alone DIPG.   This year, though,  I was surprised by abstract 750 (page S67):

Is Biopsy Safe in Diffuse Intrinsic Pontine Glioma?

An Institutional Experience

The surprise didn't end there.   Although the institutions is one of the collaborators for the multi-institutional trial with molecular determination for treatment by upfront biopsy,  it is not one that has been obviously on the forefront of the US biopsy debate- Children's Hospital of Michigan in Detroit.  

These authors report on 22 newly diagnosed children with DIPG between 2002 and 2012.    Stealth guided biopsies were performed in 68% of the cases.   There were no deaths related to biopsy.  Three of the fifteen children undergoing biopsy has transient issues post-operative which resolved within two weeks.   The issues included one child developed a facial nerve palsy, one child has some speech difficulty and extremity weakness and the third has ataxia and swallowing difficulties.

All biopsies showed gliomas (grade 2-4). 

The authors conclude that biopsy at their institution has been relatively safe and the resulting tissue will allow for molecular profiling which may lead to targeted therapy and perhaps in the future prolonged survival or a cure.

So, why is the percentage of biopsy so high at this institution?   These authors report a case of theirs in which a child was found to have a PNET tumor rather than a glioma.   Subsequently, biopsy is considered in the majority of these tumors at diagnosis.

Reference:
Molecularly Determined Treatment of Diffuse Intrinsic Pontine Glioma
http://clinicaltrials.gov/ct2/show/NCT01182350?term=dipg&rank=5

Genetic and histopathological spectrum of paediatric diffuse intrinsic pontine gliomas

Sick Kids instituted an brainstem glioma project back in 2003 in hopes of trying to understand diffuse intrinsic pontine glioma.   To do this the researchers reached out to families with an autopsy-based protocol asking for consideration of post-mortem tissue donation.    This decade commitment and collaborative effort against DIPG has lead to another DIPG abstract for the upcoming SNO/CBTF supported 2013 Pediatric Neuro-Oncology Basic and Translational Research Conference.  This one comes from Sick Kids in conjunction with Oren Becher from Duke.

The researchers examined 71diffuse intrinsic pontine tumors:

• 65 were high grade gliomas, 8 were low grade and 3 were PNETs.
• survival was not related to grade.
• leptomeningeal spread was present in one third of cases.
• 68% had K27M-H3.
• these tumors were histologically heterogenous, however increased homogeneity  was found of the histone mutation.
• the histone mutations were also present in low grade tumors that had worse outcomes.

The authors conclude with a call for "incorporation of histological and molecular data"- specifically stating  "histone mutational status at biopsy"- in designing new therapies for DIPG.

There has been a rash of publication regarding K27M mutations recently.   Several of the other abstracts for this meeting feature this histone mutation in DIPG.   I am sure more will be coming in the future.

Reference:
Genetic and histopathological spectrum of paediatric diffuse intrinsic pontine gliomas
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=73797

Inhibition of PRC2 Activity by a Gain-of-Function H3 Mutation Found in Pediatric Glioblastoma

http://www.sciencemag.org/content/early/2013/03/27/science.1232245

St Jude Looks at Long Term DIPG Survivors

At a poster session for the 3rd biennial Pediatric Neuro-Oncology Basic and Translational Research Conference next month,  physicians from St Jude Research Hospital will be presenting a retrospective review of their patients who had prolonged survival despite being given a diagnosis of diffuse intrinsic pontine glioma.

These physicians reviewed the records of DIPG patients at St Jude from October 1, 192 to May 31, 2011.  Of the 191 patients there were 5 long time survivors with a median time from diagnosis being 9.3 years!    It seems 4 out of 5 of these patients had some atypical clinical or imaging features that put them on the side of potentially better outcomes than the average.

All these survivors underwent neurocognitive testing.  Interestingly, and unfortunately like so many other children who undergo brain radiation, cognitive function was impacted in 4 of 5 patients- two falling in the range of borderline/mild mental retardation.   These findings will become increasingly important when there is better survival statistics for DIPG.

The researcher point out that prolonged survival does not equal cure.   Two of the patients had progression years after their initial treatment with radiation.

It will be interesting to see what comes of this.  Certainly the DIPG Registy could become very important to bring the information on all long term survivors together at one place.   

Reference:
Clinico-radiologic characteristics and neurocognitive assessment of long-term survivors of diffuse intrinsic pontine glioma
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=738281

Focus on Research- Mitochondria and DIPG (New Australian Abstract)

The 3rd biennial Pediatric Neuro-Oncology Basic and Translational Research Conference jointly sponsored by the Society of Neuro-Oncology and the Children's Brain Tumor Foundation will be held on May 16th and 17th in Fort Lauderdale Florida.   Several of the already available abstracts are several on DIPG.   One of the ones that caught my eye will be a poster presentation from Australian researchers entitled " Targeting mitochondria and metabolism as a novel therapeutic approach in the treatment of Diffuse Intrinsic Pontine Glioma". 

The interest in cellular metabolism in cancer goes back the early 1900's with  Otto Heinrich Warburg. The Warburg Hypothesis says "the prime cause of cancer is the replacement of the respiratory of oxygen in normal body cells by a fermentation of sugar."  He speculated that tumor development is driven by insults to the mitochondria which affects cellular respiration.  Mitochondria have become a potential target for cancer therapy.   One of the key mitochondrial proteins implicated in cancer has been adenine nucleotide translocase (ANT).

In this abstract, the researchers used DIPG neurospheres to evaluate the effectiveness of an ANT inhibitor PENAO.    This agent appears to have first hit the internet in 2011, when some of the authors unveiled this novel compound at AACR in an abstract " PENAO: A small molecule tumor metabolism inhibitor".  In the AACR abstract PENAO led arrest of proliferation and apoptosis of tumors cells.  It was well tolerated by IV and subcutaneously in mice.

In this study, the use of PENAO on DIPG neurospheres was found to be a "promising therapeutic strategy" to treat DIPG.  In addition, combination with a MRP1 ( multidrug resistance-associated protein ), Reversan,  increased the effect.   Effectiveness of PENAO was also increased by 3-bromopyruvate.

This is interesting research with a different approach to DIPG in utilizing mitochondrial small molecule inhibitors.   Now, the challenge would seem to be in the steps to translate this from bench to bedside.   The great thing now compared to just a few years ago is that several institutions have been able to developed DIPG animal models to be able to preform the necessary translational research.

Reference:
Targeting mitochondria and metabolism as a novel therapeutic approach in the treatment of Diffuse Intrinsic Pontine Glioma
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=740145

Mitochondria and Cancer: Past, Present, and Future
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581248/

Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer
http://www.ncbi.nlm.nih.gov/pubmed/20950584

Inhibition of Glycolysis in Cancer Cells: A Novel Strategy to Overcome Drug Resistance Associated with Mitochondrial Respiratory Defect and Hypoxia
http://cancerres.aacrjournals.org/content/65/2/613.full

Focus on Research: 3 New DIPG Abstract This Week!

One of the frustrating things about medical research is the delay between when research is presented at a scientific meeting and when it actually gets to publication.   Unfortunately, sometimes the gap is more than a year.   For this reason, I trawl around the meeting abstracts which might have potential.    One such meeting is the American Association of Cancer Research (AACR) concluding it's five-day Annual Meeting tomorrow.    I am thrilled to report there are DIPG presentations at this meeting.

Here are the citations for the three presented abstracts:

1)  Nathalene Truffaux, Ludivine Le Dret, Stephanie Puget, Gilles Vassal, Birgit Geoerger, Jacques Grill.
Activity of dasatinib and potential escape mechanisms in diffuse intrinsic pontine glioma (DIPG) models
 In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013 {Abstract 2763}

2)  Sridevi Yadavilli, Madhuri Kambhampati, Oren J. Becher, Tobey MacDonald, Ravi Bellamkonda, Roger J. Packer, Javad Nazarian. 
NG2 upregulation and its defective asymmetric distribution in pediatric brainstem glioma and diffuse intrinsic pontine glioma
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013. {Abstract 5004}

3)  Marianne Hutt, Wendy Goldstein, Javad Nazarian, Antoinette Price, Kah Jing Lim, Katherine Warren, Howard Chang, Charles Eberhart, Eric Raabe.
Targeting the Notch and mTOR pathways in diffuse intrinsic pontine glioma
In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; 2013.  {Abstract 5049}

The first abstract is from the French researchers that have pioneered the way for biopsies.  The second is from National Children's in DC, Duke and Emory/Georgia Institute of Technology.  The third is from the Mid Atlantic DIPG Consortium (MADC).  The MADC abstract appears to be an extension of the abstract we highlighted here on March 23this year.

As the abstracts are meant for a group of researchers, they are most definitely highly scientific.  Here is one thing to take away-  it is possible to establish cell lines from freshly biopsied DIPG material.   The French group has been able to establish 12 lines in this way!