Biomarkers for DIPG?

So far it has been difficult to predicatively monitor DIPG tumor. MRI’s have not been found to be predictive. Other advanced imaging techniques are and have bee studied. The issue of biomarkers has also been approached. Unfortunately with DIPG, tissue analysis is something that is rarely done because of the infrequency of biopsies with this tumor. However there has been some investigation of urinary and blood biomarkers.

The recent publication from the NIH regarding a pegylated inteferon for DIPG had a small subsection on the evaluation of urinary VEGF (vascular endothelial growth factor) and serum bFGF (basic fibroblast growth factor) and MMP-9(matrix metalloproteinases).   Interestingly what was found in the small number of patient that had low urine VEGF, low serum bFGF) and a non-rising level of MMP-9 were more likely to survive longer than 2 years.  On the other hand, none of those with high urine VEGF, high serum bFGF and a rising level of MMP-9 were long-term survivors.

This is not a new concept for cancer or brain tumors. In fact in 2008 Boston Children’s reported on a panel of urinary biomarkers that predicted presence and response to therapy. The issue that is evolving is the study of serum and urine biomarkers for DIPG.

Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma
J Neurooncol. Feb;86(3):313-9. Epub 2007 Oct 2.
http://www.ncbi.nlm.nih.gov/pubmed/17909941

A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma. Cancer. 2011 Nov 15. doi: 10.1002/cncr.26659. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/22086404

Urinary biomarkers predict brain tumor presence and response to therapy.
Clin Cancer Res. 2008 Apr 15;14(8):2378-86.
http://www.ncbi.nlm.nih.gov/pubmed/18413828

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

A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma

The NIH based study lead by Kathy Warren utilizing low dose pegylated interferon for children with newly diagnosed DIPGs recently was published on line ahead of print in the journal Cancer.  The rationale behind this study was the finding that low dose administration of interferon alfa produced” more significant inhibition of angiogenesis-regulating genes, tumor vascularization, and tumor growth compared with the higher intermittent dose schedule. These effects were lost at higher doses, suggesting that metronomic administration of IFNs may have a more robust antitumor effect.”

In this study, 32 children between the ages of 1.8 and  14.8 years (mean 5.3 years) were given pegylated interferon subcutaneously (a shot under the skin) weekly starting 2-10 weeks after radiation until disease progression or unacceptable toxicity.  The idea was to try to have a continuous low dose of inferferon.

There were no grade 4 toxicities and no child stopped interferon because of toxicity.

The overall survival at 2 years was 14.3%  The median time to progression from diagnosis was 235 days, and the median OS from diagnosis was 351 days. 

The authors concluded, “Although low-dose PEG-Intron therapy did not significantly improve 2-year survival in children with DIPG compared with an historic control population, it did delay the time to progression.”

The narrowness of the eligibility criteria in this study is particularly interesting as it shows the advancement in understanding that not all brainstem tumors are the same.   This stricter eligibility criterion seems to be trying to eliminate those tumors that might have an underlying aspect giving it a better prognosis and thus skew the data.  The eligibility criteria defined as:

• Age less than 21 years
• Diffuse intrinsic tumor with epicenter presumed in the pons
• Signal abnormality involving 50% or more of the pons on T2-weighed sequence at diagnosis
• Involvement of the ventral pons
• No expophytic component
• No patients with known or suspected neurofibromatosis type 1

The paper pointed out that the increasing delineation of a DIPG tumor can make it very difficult to compare results with past papers that did not define the patient population in this way.   Those that previously included focal tumors and those with exophytic components might have mistakenly high overall survival statistics.  For those interested in comparing studies analysis of the eligibility criteria is going to be important.

A phase 2 study of pegylated interferon α-2b (PEG-Intron®) in children with diffuse intrinsic pontine glioma Cancer.  2011 Nov 15. doi: 10.1002/cncr.26659. [Epub ahead of print] 
http://www.ncbi.nlm.nih.gov/pubmed/22086404

Call To Action: Criminals Stealing From Our Families Whose Children have Died

This is shocking…..    There are criminals out there just looking around for kids who have died and then claim them as dependents before some families can file.   Those families that have been targeted must then have to prove that their child was actually their child. 

How can something so appalling happen?  How can people get the social security number? 

Well, actually for those in the know it is very easy.   It is the government who made it mandatory for this data to be rapidly available after an individual’s death.  The thought was not bad or evil.   The Death Master File (yes, that is what is called) was meant particularly for financial institutions to try to prevent others from using a dead person’s SSN to gain credit.   In addition, there was a movement toward more transparency.   What wasn’t considered at that time was the ease of information transfer that would come years later with the internet.   Likely it wasn’t considered how genealogy sites would used the Death Master File. 

So, how easily available is this Death Master File available?   Well, one can even get it as a app- http://itunes.apple.com/us/app/ssdmf/id453279465?ls=1&mt=8

Or if you don’t want to go to all that trouble one can just use one of the genealogy sites.

It seems that the DIPG community has been particularly hard hit  with a dozen or more families being hit this year.   Here is an article from Nov 17 the Huffington Post…..  http://www.huffingtonpost.com/2011/11/17/why-thieves-are-stealing-childhood-cancer-victims-identities_n_1093481.html

On Nov 18, Representative Sam Johnson (R- TX) along with seven co-sponsors introduced a bill  to try to curtail this fraud perpetrated on our grieving families.: 

H.R.3475 -- Keeping IDs Safe Act of 2011 
http://thomas.loc.gov/cgi-bin/query/z?c112:H.R.3475:

Please consider calling and writing your Representative to bring awareness to this issue.  
http://www.house.gov/ 

Unfortunately, it might not be possible to close this loophole before the next tax cycle in 2012 so it is likely that many families will continue to be vulnerable to this fraud.