DIPG - Current Status and Future Strategies

The September 27^th issue of journal Child’s Nervous System included a review article evaluating where we are with the treatment and research of diffuse intrinsic pontine gliomas.  These authors performed an extensive literature review particularly looking at clinical trials, evolving molecular biology and new therapeutics.

 In their review they found-

• Radiation is the only treatment that has consistently shown clinical and radiographic improvement.  Approximately 70% of the children receiving radiation will have clinical improvement and 30-70% will have radiographic improvement.
• Multiple studies using a combination of radiation and another agent with generally unimpressive results.  Such agents have included RMP-7/carboplatin, topetecan/cisplatin, tamoxifen,  vincristine/vp-16, cisplatin, temozolomide,  vandetanib, and tipifarnib.  However, the vandetanib study showed that those patients that had a higher plasma VEGF level to start had a longer progression free survival whereas those patients that has increasing levels of VEGF with treatment had a shorter progression free survival. (Original vandetanib study- http://www.ncbi.nlm.nih.gov/pubmed/20921456 )
• “No single chemotherapeutic agent alone or in combination, either in a neoadjuvant oradjuvant setting, has proven to increase disease-free survival or alter overall survival in these children with primary or progressive disease.”  This has included avastin and irinotecan which has had some success in adults. 

The prognosis has remained dismal for more than two decades.   This ‘virtual standstill’ for improved prognosis is leveled at:

•  The lack of biologic knowledge about these tumors.
•  Assumptions that adult and pediatric high grade gliomas are the same.
•  The poor drug access to the tumor because of the blood brain barrier.  
•  The lack of experimental models.

Recommendations included:

1. A shift in treatment paradigm to include a diagnostic biopsy to “identify key molecules of unique signaling pathways which could provide clues to potential targets.
2. Development of preclinical (i.e., mouse) models.
3.  “The need to design phase I study with routine sampling along with CED of therapeutic agents is imperative in these fatal tumors.”
4. “Further exploration of these different imaging modalities needs to be continued, and should facilitate better understanding of tumor architecture and metabolic profile as well as to provide more accurate prediction of extent and duration of response following radiation and adjuvant  therapies.”
5. Evaluation of immunotherapy, gene therapy and other innovative techniques.

Diffuse intrinsic pontine glioma-current status and future strategies.

Childs Nerv Syst. 2011 Sep;27(9):1391-7. Epub 2011 Apr 30.
http://www.ncbi.nlm.nih.gov/pubmed/21533575

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