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

Clinical Trial Update- Arsenic Trioxide (ATO) with Radiation in the Newly Diagnosed (Phase 1)

On March 3^rd, the Journal Neuro-Oncology electronically published the results of the phase 1 trial using arsenic trioxide (ATO) in combination with radiation for newly diagnosed pediatric high-grade gliomas.   This phase 1 trial, exclusively opened at Johns Hopkins (primary investigator Kenneth Cohen), was first submitted to clinicaltrials.gov in November 2004 and was completed in January 2011.    As a phase 1, the aim was to determine toxicity and dosing information--not effectiveness against the tumor.  

Rationale:   Arsenic trioxide affects cells in a different way than radiation.   In mice, ATO has shown destruction of the tumor vasculature and near-complete blockage of blood flow to the tumor.   This has resulted in central tumor death (necrosis).   The hope was that ATO would kill the poorly perfused, hypoxic, radio-resistant areas of a tumor while radiation would kill the tumor in well-oxygenated areas.

Format:  The format was to have groups of 3-6 patients receive escalating doses of arsenic trioxide until the MTD was established.  Each child received radiation once daily for 5 days a week for 6 weeks.  A child also received arsenic trioxide over 1 hour with radiation.   The first group received the ATO only once a week.  Each subsequent group had another day of the week added until the last group received ATO with every radiation treatment.  A total of 24 children entered the trial.   Those that progressed during radiation or family chose to stop treatment was removed from the study.  Twenty-one children had evaluable results. 

Results:  The trial included 12 DIPGs, 4 AAs and 5 GBMs.  Because children could receive additional therapy after 30 days from radiation, no response assessment was done.   The study does note that all children died of their tumor.   With DIPG the median time to death was 10 months (range 2-22 months).    There was no dose limiting toxicity.

Conclusion:  The article concluded that arsenic trioxide could be given with each radiation treatment.

 Interestingly, the article states that there have been a number of recent preclinical studies that have shown an effect on cancer stem cells trough an effect on Notch and Sox2.   Other research has shown that the hedgehog pathway might be antagonized and thus be helpful in other tumors as well (such as Sonic hedgehog driven medulloblastomas).  Although there is one adult glioma study using arsenic trioxide in combination with temozolmide and radiation on clinicaltrials.gov, there are no pediatric glioma studies open using arsenic trioxide.    The question now is whether there will be a phase 2 trial.

For those families that participated in this trial- thank you.   This work provides important information to move forward in trying to find a cure for DIPG.  Even if it doesn't provide the cure hope for, research tends to stimulate research.  There is much, much more research into DIPG than when when this study initially opened in late 2004.  People are searching for a cure.

References:

A phase 1 trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood

http://www.ncbi.nlm.nih.gov/pubmed/23460318

Arsenic Trioxide and Radiation Therapy in Treating Young Patients with Newly Diagnosed Gliomas

http://clinicaltrials.gov/ct2/show/NCT00095771?term=arsenic+trioxide+glioma&rank=3

The Clinical Trial Process

http://www.dukehealth.org/health_library/health_articles/the_clinical_trial_process