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

Be On The Lookout- Notch Pathway and DIPG

With the lag time between presentation at a meeting and publications often times things can just slip under the radar.   For me, this was certainly true of this American Association for Cancer Research abstract presented last year in Philadelphia- "High-level activation of the Notch pathway in diffuse intrinsic pontine glioma".  The title doesn't immediately excite me.  However, packed in this short abstract is a number of significant advancements in DIPG research.

1) MADC, the Mid-Atlantic DIPG Consortium, brought three geographically tied institutions together to fight DIPG.   Johns Hopkins, Children's National Medical Center and the National Institutes of Health-Pediatric Oncology Branch agreed to share DIPG tumor material that had been obtained through timely autopsy donation.

2) From a fresh tissue specimen, the researchers were able to establish a cell line- JHH-DIPG1.   The cell line was evaluated for the Notch pathway as this is known to occur in other aggressive brain tumors. JHH-DIPG1 showed a high level of  Notch pathway activation.  

3) From the cell line, a xenograft animal model was also developed.

So.... what makes this significant?  Well,

First, it is very difficult for any one institution to have enough DIPG tissue for research.   I see these type of collaborative efforts key to being able to crack the code of DIPG.

Secondly, it continues to show that parents will donate tumor after death to try to make a difference in this horrendous disease.    It shows that Stanford was not a fluke.  Cell lines and animal models can be developed for DIPG.

Thirdly, it brings DIPG more on par with other brain tumor and cancer researchers.  We now have cell lines and animal models (not only at Hopkins but also elsewhere).  Without these, research seemed at a standstill.

Finally, there are actual Notch agents that are available!  The pediatric phase 1 with the gamma-secretase inhibitor RO4929097 has already closed because it has reached its enrollment.  We are now just waiting for results.   The research here could be a basis for starting a clinical trial for DIPG with an agent- or at least being able to do more pre-clinical work with an appropriate model.   

References:
AACR Notch Abstract-
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=5eccf257-1e78-44ad-a11d-0cb24040c222&cKey=c6e7a032-873e-4aea-a5af-1b3374b5b338&mKey=%7B2D8C569E-B72C-4E7D-AB3B-070BEC7EB280%7D

Gamma-secretase inhibitor RO4929097 in treating young patients with relapsed or refractory solid tumors, CNS tumors, lymphoma or T-Cell Leukemia
http://clinicaltrials.gov/ct2/show/NCT01088763?term=Notch+brain+tumor&rank=7