Foundation Spotlight- A Cure From Caleb Society

Many of the recent posts have been highly scientific.   It the spring season of new abstracts so I guess it isn't to be unexpected.   However, sometimes I feel that I just need to sit back and look at pictures to gain perspective on more than molecular pathways.  Today I did just that.   I looked at pictures of a little boy I got to know only from the internet.

Caleb loved hockey and jokes but his life was completely derailed at age 8 when he was diagnosed with DIPG.  Due to the persistence of his parents got a second round of radiation at progression that gave them another 9 months.  This was something that simply wasn't done before and was only happened due to the valiant fight of this family.

Caleb still inspires fighting for change through the A Cure From Caleb Society which specifically fund s DIPG research.  This past Friday, the foundation hosted a Spring Dance to create awareness and fund research.

The research A Cure From Caleb Society is supporting is that of Cynthia Hawkins, MD PhD of Sick Kids.   Dr. Hawkins has been on the leading edge of many recent advances in DIPG research-from creating an post-mortem tissue collection program at Sick Kids to the first publication of DIPG molecular analysis.  She was also instrumental in the Toronto DIPG Think Tank in 2010 and is a participant in the DIPG Preclinical Consortium.    I am sure there is going to be much more research coming from this lab as in addition to yesterday's abstract there another one that will be presented at the same conference.

And for Caleb- we are not chicken and will continue to work on crossing the road to a cure.

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!  

Focus On Researh- Xiao Nan Li

Dedicated to a special boy,  Paul Alexander Coleman III, who is continuing to make an impact.....

Because of the trifecta of basic science hurdles- no tissue, no cell lines, no animal models- DIPG bench research has only recently begun.  This has only been possible because of the efforts of a few individuals struggling to make the previously impossible possible- make animal models from an inoperable tumor.  One of these pioneers- Xiao Nan Li MD, PhD (Baylor College of Medicine/Texas Children's Cancer Center).

Dr Li's interest is in the fields of cancer stem cells, experimental therapeutics and diagnostic markers with a particular focus on developing "clinically relevant animal models" for preclinical testing.

I first became aware of Dr Li when a fellow brain tumor parent sent her son's post-mortem specimen across the from the east coast to Texas to try to make a difference for medulloblastoma.  The lab wasn't only interested in medulloblastoma.   Dr Li has established more than 25 xenograft mouse models of several different pediatric brain tumors.  At some time,  a post mortem DIPG specimen was obtained and through the lab's work a door was unlocked for DIPG.  Dr Li was able to establish a DIPG animal mouse model from this tissue and the scientific value of DIPG autopsy specimens skyrocketed.

Although the lab is interested in fighting all pediatric brain tumors there seems to have been a special focus on DIPG.   Texas Children's has cell lines and thus became one of the initial members of the DIPG Pre-clincal consortium which is collaboratively working on rapid analysis of the cell lines and drug testing.

The lab has at least 5 different DIPG mouse xenografts that can be used for other types of research.  One of these research endeavors is using oncolytic viruses in the DIPG mice he developed.  Dr Xaio Nan Li will be presenting his work in a mouse model on eliminating therapy resistant DIPGs with an oncolytic virus at the DIPG Symposium in Cincinnati on May 3rd.   A link to the grant executive summary funded by the Cure Starts Now is listed below.

This oncolytic virus research is exciting especially in light of the recent publication out of University of Alabama looking at this issue in pediatric gliomas.   Although the publication is a different virus, the idea is essentially the same.  Novel therapies are going to be needed to eliminate treatment resistent subpopulations while sparing normal tissue.  Oncolytic virus have been one of the innovative treatment that might be a weapon in the future against DIPG as well as other gliomas and brain tumors.

References:
Neuro-Oncology Research Lab of Dr Xiao Nan Li
http://ccitonline.org/tccc_production_old/cancer-genomics-li/

Harnessing Autopsied DIPG Tumor Tissues for Orthotopic Xenograft Model Development in the Brain Stems of SCID mice- Grant Award Final Report
http://www.dtic.mil/cgi-bin/GetTRDoc?AD=ADA568355

Eliminating Therapy-Resistant Diffuse Intrinsic Pontine Gliomas with Oncolytic Picorna Virus SVV-001: an in vivo Study in Intra-brain Stem Xenograft Mouse Models- Grant Executive Summary
http://www.thecurestartsnow.org/_pdfs/grant_2011-11_texas.pdf

Pediatric glioma stem cells: biologic strategies for oncolytic HSV viral therapy.
Front Oncol. 2013;3:28. doi: 10.3389/fonc.2013.00028. Epub 2013 Feb 28.
http://www.ncbi.nlm.nih.gov/pubmed/234506

Results of St Jude Phase 1 Trial Published

The results of the St Jude Phase 1 trial using a combination of small molecule inhibitors, vandetanib and dasatinib,  have just been published electronically (ahead of print) in the journal Clinical Cancer Research.

In a look back at DIPG history, this is a really a new kind of trial.   In the past many trials have been radiation and a single agent.  I think we can say with some certainty that DIPG tumors will need more than a single agent for cure- especially for targeted therapies.  These tumors are complex and have so many pathways that it is likely that the tumors will be able to get around a single agent.

In addition, there seems to be rational basis to chose these agents specifically for DIPG.  Vandetanib has a combination of effects on different targets but is a potent VEGF inhibitor.   This is known to be a player in GBMs (and as been said here before when studied histologically most DIPGs have been found to be GBMs).   Dasatinib has its effects at PDGFRA (platelet derived growth factor receptor alpha).  Several recent publications have highlighted the PDGF pathway as being key in the development of DIPGs.

In this study, 25 newly diagnosed children were started on oral dasatinib daily at the start of radiation.   Eight days later oral vandetanib twice a day was added.     Overall the treatment was tolerated well.

• The M:F ratio was 12:13.
• The age range was 2.3 years to 17.2 with a median age of 5.8 years.
• The median treatment time was 184 days.   
• The most significant toxicity was diarrhea.
• Myelosuppresion (drop in blood counts) was seen in three children.
• Two of the children had tumor biospies.  
• There were 12 post mortem tumor donations.  
• All patients progressed on treatment.   
• The one year overall survival was 52% + 10%.
• The 2 year survival was 9% + 6%.  
• The two patient who were on treatment for more than 2 years had typical clinical and radiologic appearance of DIPG

An interesting part buried in the article text was the approach to radiation.  The radiation field encompassed the tumor and a 2cm margin in the transverse (across) and caudal (down) direction and a 3cm margin in the superior direction.  The increased from 2cm to 3cm in the superior direction was based on preliminary results on progression patterns of DIPG patients.   Of note, one patient had extensive bilateral thalamic extension requiring whole brain radiation.

Three of the young children developed symptomatic radiation necrosis in uninvolved brain areas.  Although there was no institutional knowledge of other patients treated with more than standard radiation fields developing radiation necrosis in uninvolved areas, it was felt that the larger margins may have lead to symptomatic radiation necrosis.   Thus the authors do not recommend to use of enlarged radiation fields.

Another interesting finding was that the researchers showed "for the first time that CSF exposure of vandetanib and dasatinib in humans is modest".   They point out that CSF levels is often used as a surrogate marker for brain penetration but that this assumption is not necessarily valid particularly in places where there is a blood brain barrier disruption.  They also point out that although the dasatinib CSF level was low that it did reach sustained levels "similar to those causing significant inhibition of other drug targets.

Additionally, the researchers looked at plasma angiogenic factors (seeing what factors are in the blood). Surprisingly, increased VEGF in this study was associated with longer overall survival whereas in a prior study it was associated with shorter survival.  The hypothesis is that this might be because of an improved inhibition of alternative pathways because of the combination.  Regardless of the reason, it seems to me that we don't understand plasma factor levels yet.

Despite the continued poor results for DIPG clinical trials, there were some interesting findings in this trial.   There is hope the drug testing (such as what we should see with the pre-clinical consortium) might find new promising targets or drug therapies.

Note-

This work was supported by the U.S. National Institutes of Health Cancer Center

Support (CORE) Grant P30 CA21765, by the Cure Starts Now Foundation, by

AstraZeneca, and by the American Lebanese Syrian Associated Charities (ASLAC).

References:

Phase 1 Trial, Pharmacokinetics and Pharmacodynamics of Vandertanib and Dasatinib in Children with Newly Diagnosed Intrinsic Pontine Gliomas

Clin Cancer Res. 2013 Mar 27. [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/pubmed/23536435

Clinical Trials Entry   

http://clinicaltrials.gov/ct2/show/NCT00996723?term=dipg&rank=2

Dylan Warriors- a pivotal change for DIPG

The last two posts about the sonic hedgehog pathway have been quite medical.   When trying to decipher the medical terms it is easy to miss the amazing lengths families have gone to try to make a difference in the course of DIPG.   In this instance, we actually know a specific child and family that started it all- the Jewett family.  This is a remarkable story of a family and a researcher joining forces to completely change the world for DIPG.  Through the donation of Dylan's tumor to Stanford the entire landscape for DIPG research has changed.

The thinking has changed from "it isn't possible" to "it is possible"!

*It is possible that parents will want to donate tumor after their child has died.
*It is possible that we can grow cell lines and make animal models from this donated tissue.
*It is possible from that information we can chose new ways to try to fight DIPG.
*It is possible for families, foundations and researchers to come together to make a difference.

Thank you Jewett family, Dylan's Warriors, Michelle Monje and the doctors at Stanford.

Note:  We now not only do we have that one cell line but more than 30 others DIPG cell lines!

Please watch their story at-
https://www.youtube.com/watch?v=pdFfWhQ9964

References:
Dylan's Warriors- http://curedipg5.com/ or www.facebook.com/CureDIPG

Dylan's Story- http://www.kidsvcancer.org/tissue-donation/information-for-families/donation-stories/dylan/

DIPG Preclinical Consortium-
http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html