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

A New Era for Children with Diffuse Intrinsic Pontine Glioma: Hope for A Cure?

"A new era for DIPG has just begun."

So starts the conclusion of this expert review article written last  year by two prominent DIPG researchers from the Netherlands- Marc Jansen and Gertjan Kaspers.   It will behoove one interested in DIPG research to be aware of those names.  They are ones that keep coming up in DIPG issues- publications and European DIPG worshops.   

These experts highlight that there has been a rapid increase in biological understanding of DIPGs.     This has only been able to occur because of the recent availability of DIPG tumor tissue which from  the French re-introduction of biopsies and the North American/Dutch focus on autopsy donation.  This DIPG tissue is critical to the further understanding of DIPG although biopsies and post-mortem tissue each have advantages and disadvantages.

The biopsy issues has been very controversial.   The French group has now preformed over 100 stereotactic biopsies with 0% mortality and a 4% transient morbidity.   An advantage of pre-treated biopsy specimens is that there is a significant risk treatment will change the original molecular characteristics.  The tumor that the children start with very likely is not the tumor molecularly that they die with.

Post mortem tissue carries a high risk of treatment-related genetic changes.   Still, there are advantages.   There is a much greater tissue volume available for study.   This also allows study on tumor hetergeneity (how varied the tumor is) as well as "treatment-resistent subclones".   In addition, it has been from these tumor donations that cell lines and animal models have been developed (greatly adding to research potential).

Even with this "avalanache of gene profiling studies" in DIPG, this will probably not provide the entire answer for cure.  There is at least one other prong to the problem.  The authors pose some thoughtful questions for consideration:

• Why  are all chemotherapy regimens ineffective in DIPG while  some show activity in supratentorally located gliomas, such as  temozolomide?
• Why does imatinib, an inhibitor of the  DIPG key target PDGFRA, not improve survival ? 
• Could  poor drug distribution be at least partly the answer to these  questions?

The short answer likely lies in the blood brain barrier (BBB).  The huge hurdle BBB presents in DIPG will be a subject of future posts, but suffice it to say that we need better studies to investigate drug resistance and drug distribution as well as  new drug delivery options.

It is a new era.   There are researchers focused on understanding this tumor.   There has been a virtual explosion of clinical trials and publications.  There is excitement.

We are, though, at the beginning.    We have just gotten some of the tools to fight, --to understand , --to research, --to make a difference.  It is unlikely that the cure is around the next bend but research is finally moving for children with DIPG.   There is reason to hope that someday there might be a cure.

Note-  DIPG research at the VU University Medical  Center is financially supported by Stichting Semmy (Weesp, The Netherlands).

References: 
A new era for diffuse intrinsic pontine glioma: hope for a cure? 
Gertjan J Kaspers and Marc Jansen 
Pediatric Oncology and Hematology, VU University Medical Center, Amsterdam, The Netherlands Expert Rev. Anticancer Ther. 12(9), 1109–1112 (2012) 
Full Text:  http://www.brainlife.org/reprint/2012/Kaspers_GJ120900.pdf

Stichting Semmy-
http://dipg.blogspot.com/2013/03/foundation-spotlight-stichting-semmy.html

New NIH/Hopkins Abstract presented at USCAP

Earlier this month the 102nd Annual Meeting of the United States and Canadian Academy of Pathology was held in Baltimore, Maryland.  Frankly, this isn't a meeting that I have ever followed because I don't remember a pediatric brain tumors presence previously-- and certainly not the unresectable, rarely biopsied diffuse intrinsic pontine glioma.  This just isn't something that pathologist do.  Yet, on a Wednesday afternoon, a DIPG poster- Histology and Immunohistochemical Profile of Diffuse Intrinsic Pontine Gioma- took its place among a myriad of other neuropathology presentations.

This joint NIH/Hopkins abstract presented the characteristics of of 24 DIPGs autopsy specimens.  Histologic results are as follows:
17- GBM with 14/17 having pseudopallisading necrosis and 12/17 with vascular proliferation
5- anaplastic astrocytoma
1- low grade (WHO II)
1- intermediate (features of WHO II and III)

Immunohistochemical results revealed all were GFAP positive.    Regarding the stem cell markers,  22/24 were Oligo2 positive and 19/24 were Sox2 positive.  In addition, 20/24  16/24 were positive for p53 and EGFR respectively.

What does all this mean?   Well, all of these were gliomas.   The high level of stem cell markers would seem to support the hypothesis of a tumor stem cell origin for DIPG.  Understanding the pathways that have gone awry with DIPG we might be able to better identify prognostic markers and potential therapeutic targets.

It also means that DIPG research has began to make strides in tumor biology.   In the future, people that really want to understand DIPG research will have to gain an understanding in pathways and cancer stem cells.  Excellent chapters by Mark Kieran and Michelle Monje are in the ACCO book Understanding the Journey.

Additionally, it means that 24 parents selflessly gave an ultimate gife in the fight against DIPG-without which I don't see any possible way we could get to a cure.  There is no doubt we could not have gotten to this research.   It is with deep gratitude that I recognized these families that endured the unimaginable and jumped over logistical hurdles to make a difference.

Note- Interestingly Oligo2  importance with PDFRA was just mentioned on Friday here with the UCSF research.

Reference-
Abstract-  http://www.abstracts2view.com/uscap13/view.php?nu=USCAP13L_1726

UCSF Research-  http://dipg.blogspot.com/2013/03/focus-on-research-hashizume-laboratory.htm

ACCO DIPG Book-
http://myemail.constantcontact.com/New-FREE-resource-for-DIPG-Families-.html?soid=1102946333954&aid=k63YiippnW8