Prados Predicted Paradigm Shift for DIPG (diffuse intrinsic pontine glioma)

Three years ago, Dr. Michael Prados was interviewed by Accelerated Brain Cancer Cure on his thoughts of advancements coming for pediatric brain tumors.   Dr Prados immediately focused on the paradigm shift occurring in the medical community to develop unique strategies to fight DIPG though analysis of individual biopsy samples predicting things may change quickly for DIPG.

Why did that paradigm shift occur in the prior year?  Well, French physicians published in the Journal of Neurosurgery 4 years of biopsy results for diffuse pontine lesions.  All 24 children survived the procedure and only 2 suffered some sequela from the intervention developing transient cranial nerve palsies.   One of the two has a worsening of a previous hemiparesis.   Two children had their treatment plan altered because of the biopsy results.

Stereotactic biopsy of diffuse pontine lesions in children

http://www.ncbi.nlm.nih.gov/pubmed/17647306

Neurosurgeon Stefanie Puget has come to North America several times to discuss there ongoing work.   It appears she was just at the Bethesda Consensus Conference earlier this month.

However, it seems that events have moved beyond the discussion stage.   The new multi-institution, 4-armed molecular stratification study is listed as open on clinicaltrials.gov opening first at Dana Farber Boston.   The other institutions slated to collaborate in this trial include -

• University of California, San Francisco
• Children's Hospital Boston
• Children's Memorial Hospital
• Children's Hospital Los Angeles
• University of Utah
• Memorial Sloan-Kettering Cancer Center
• Seattle Children's Hospital
• The Children's Hospital, Denver
• Doernbecher Children's Hospital
• Washington University Children's Hospital
• Miami Children's Hospital
• Johns Hopkins University
• University of Florida
• Children's Hospitals and Clinics of Minnesota
• Southwestern Regional Medical Center
• New York University
• University of Rochester
• University of Mississippi Medical Center
• Louisville Children's Hospital
• Children's Healthcare of Atlanta

http://clinicaltrials.gov/ct2/show/NCT01182350?term=pontine+glioma&rank=4

Accelerate Brain Cancer Cure (ABC²) is a U.S. brain tumor foundation started in 2001 by Dan and Steve Case with the mission to accelerate a cure for brain cancer by increasing the number of potential therapies and moving them rapidly into the clinic for patients.  Since inception,  ABC²  has raised more than 16 million dollars investing in each stage of the development pipeline in pushing for a cure.   It is worth taking a look at the diversity of funding they have engaged in striving for a cure.
http://www.abc2.org/smarter-research

PBTC Phase 2 Study Results for Temozolomide/06-Benzylguanine

An abstract was released ahead of print for a phase 2 Pediatric Brain  Tumor Consortium study on recurrent/progressive high-grade gliomas and brainstem gliomas utilizing the combination of temozolomide and 06-benzylguanine (06 BG).  The study was initially put up on clinicaltrials.gov in January 2006.

O6-Benzylguanine and Temozolomide in Treating Young Patients With Recurrent or Progressive Gliomas or Brain Stem Tumors

http://clinicaltrial.gov/ct2/show/NCT00275002?term=06+temozolomide&rank=10

The thought was that the two agents may work differently to stop tumor growth and that combined chemotherapy might kill more cells.   Temozolomide is an alkylating agent that interferes with DNA replication.  This mechanism of action has seemed dependant on the ability to methylate DNA primarily at the N7 of 0-6 position on guanine.  Some cells were found to be able to repair this DNA damage.  The hope that O6 BG might overcome some of that repair issue.

Of the 41 children evaluated, 16 had brainstem gliomas.  There were no sustained objective responses with any in the brainstem glioma group, however, one patient had long term stable disease of more than 6 courses (28 day course). 

It was concluded that this combination “did not achieve target response rate for pediatric patients with recurrent or progressive high grade glioma or brainstem glioma.”

A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study   
http://www.ncbi.nlm.nih.gov/pubmed/21968943

Columbia’s new treatment for DIPG - CED Topotecan

In September, Columbia University announced that neurosurgeons Richard Anderson and Jeffrey Bruce have successfully used convection enhanced delivery (CED) with the agent topotecan for two pediatric DIPG patients.
http://www.columbianeurosurgery.org/2011/09/anderson-and-bruce-beating-the-odds-with-new-cancer-treatment/

CED requires fine catheters to be placed directly into the tumor.  This approach allows for therapy to be placed directly in the tumor avoiding systemic toxicity and higher dosages.

Dr Bruce has worked for more than a decade in development of CED for malignant gliomas.   His initial publications were in 2000 with a rat glioma model.  In 2011, Bruce has authored three publications regarding CED with topotecan for malignant glioma. 

Tissue distribution and antitumor activity of topotecan delivered by intracerebral clysis in a rat glioma model
http://www.ncbi.nlm.nih.gov/pubmed/11126910

Convection-enhanced delivery of topotecan into a PDGF-driven model of glioblastoma prolongs survival and ablates both tumor-initiating cells and recruited glial progenitors
www.ncbi.nlm.nih.gov/pubmed/21464045

Regression of Recurrent Malignant Gliomas with Convection-Enhanced Delivery of Topotecan
http://www.ncbi.nlm.nih.gov/pubmed/21562434

Prolonged intracerebral convection-enhanced delivery of topotecan with a subcutaneously implantable infusion pump
http://www.ncbi.nlm.nih.gov/pubmed/21750007

In addition to Columbia, the NIH also has a CED trial open for recurrent DIPG children utilizing a different agent -
An Open Label Dose Escalation Safety Study of Convection-Enhanced Delivery of IL13-PE38QQR in Patients With Progressive Pediatric Diffuse Infiltrating Brainstem Glioma and Supratentorial High-grade Glioma
http://clinicaltrial.gov/ct2/show/NCT00880061?term=pontine+glioma&rank=20

The NIH has piloted CED in the brainstem not only for DIPG but also for other issues.  In 2007, the NIH published technical notes on two children that received CED therapy.  One of these children had a DIPG and the other had Gaucher’s Disease.
Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note.
http://www.ncbi.nlm.nih.gov/pubmed/17639894

Nimotuzumab and Vinorelbine Concomitantly to Radiation and as Maintenance for Diffuse Pontine Glioma in Childhood

On September 25^th, YM Bioscience presented a poster presentation at the ECCO-EMSO meeting in Stockholm, Sweden regarding the combined use of Nimotuzamab and vinorelbine with radiation in pediatric DIPG entitled:
"Nimotuzumab and Vinorelbine Concomitantly to Radiation and as Maintenance for Diffuse Pontine Glioma in Childhood: Promising Results on a Series of 13 Patients"
http://www.news-medical.net/news/20110927/Data-from-YM-BioSciences-nimotuzumab-clinical-trials-to-be-reported-at-ECCO-ESMO-2011.aspx

This appears to a companion to the 2011 ASCO presentation in Chicago.   In this study, the Italian researchers reported on a series of 12 children.  They noted that all children were treated on an outpatient basis and none had suffered significant treatment related side effects.  For the 12 children (ages from 3-13), the progression free survival at 9 months was 69 ± 21% and the 12 month overall survival  was 81.5 ± 12 %.  The researchers believed this combination shows promise for DIPG

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=77258

Many researchers feel that combination therapy is going to be important in combating DIPG.  It is exciting to see the combination therapy research.

DIPG Consensus Conference

On October 6 and 7^th in Bethesda, a potentially pivotal meeting took place.
http://web.ncifcrf.gov/events/DIPG/default.asp

This invitation-only conference brought together physicians that care for children with diffuse intrinsic pontine gliomas to talk about several key current issues facing DIPG research.  Some of the presentation titles include:

• A Death Sentence Without Tissue Diagnosis
• Translating Genomics Into Novel Therapeutic Strategies in Pediatric DIPG
• Using A Genetically Engineered Mouse Model of Brainstem Glioma as a Preclinical Tool
• Development of an International DIPG Registry
• Personalized Medicine in Translation: From the Tissue to Treatment in a Single trial
• Rapid Preclinical Development of Targeted Therapy Combinations for DIPG

Hopefully a Consensus Statement or White Paper will be issued as was done with the Toronto DIPG Think Tank.

http://www.ncbi.nlm.nih.gov/pubmed/21901544

The agenda and presenters can be found in the following link-
http://web.ncifcrf.gov/events/DIPG/agenda.pdf

JCO Releases St Jude DIPG Study Ahead of Print

On September 19^th, the Journal of Clinical Oncology published online a St Jude original report on the molecular analysis of diffuse intrinsic pontine gliomas entitled:

Genomic-Wide Analyses Identify Recurrent Amplification of Receptor Tyrosine Kinase and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma.

A press release from Memphis heralded this landmark event as “the largest study ever of a rare childhood brain tumor”. 

http://www.eurekalert.org/pub_releases/2011-09/sjcr-krg091911.php

Other news articles highlight “possible new treatment targets for diffuse intrinsic pontine gliomas” and speculates that (this research) “may tip the scales in the current debate about tumor biopsies.”  http://www.marketwatch.com/story/key-regulatory-genes-often-amplified-in-aggressive-childhood-tumor-of-the-brainstem-2011-09-19

So what is the big news from this study?

First, DIPGs are a distinct subclass of gliomas.  They are different from their counterparts not only in location but also in tumor molecular biology in some ways.  In comparing DIPGs to other pediatric and adult gliomas they found “higher expression of particular HOX gene family members in DIPGs compared to non-brainstem gliomas.”   These HOX genes play an important part in the development of the hindbrain.    Suzanne Baker, St Jude senior developmental biologists said “those differences offer clues about where DIPGs begin and suggest the HOX family of genes might be involved.”

What does this mean?

Well, it would seem to explain the reason that other high grade glioma (HGG) research can not be reliably translated to DIPGs as we have seen with the recurrent dismal results with temozolomide in DIPGs despite it being a first line treatment with adult glioblastoma.     Even HGG pediatric studies might not be comparable.   Thus, DIPG will need to have its own research and clinical trials.

Secondly, it gives another point to start in trying to unravel the development of DIPGs… the HOX genes.  This seems somewhat novel in DIPG literature; however, there are researchers in other areas that are working on HOX genes and hindbrain development.

Thirdly, this is only the beginning.   To truly understand DIPG, there will need to be more samples and more studies.