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