Vismodegib? Why a Sonic Hedgehog Inhibitor?

Yesterday we posted about the yet-to-be opened Vismodegib trial for refractory DIPGs.   Although the trial rationale isn't listed in the clinicaltrials.gov posting, for those following DIPG publications  a sonic hedgehog inhibitor will likely recall Dr. Michelle Monje's publication two years ago.  In this publication, the authors indicate that Hedgehog signaling happens in DIPG propagation and that this could lead to "unique therapeutic avenues to treat DIPG".

Sonic hedgehog inhibition has been a subject with medulloblastoma for years as it is estimated that about 1/3 of medulloblastoma tumors may have a sonic hedgehog driver.   In fact there are two open trials listed in clinicaltrials.gov for recurrent medulloblastoma.     Thus, there is an agent already been tried in kids with brain tumors and a pathway found in molecular analysis of a DIPG.   This trial seems to put those to items together to try something new for DIPG.

The full text of the Monje paper is available.  Warning it is highly medical.    However, it appears to be a seminal article for DIPG for several reasons.
1) It highlighted that valuable information can be obtained from post-mortem donation.
2) It showed for the first time that neurospheres/cell lines can be developed from post-mortem tissue
3) It explicitly stated the relationship between brain development and the typical timing of DIPG occurrence.

The paper points out there are two very different general types of pontine tumors- those that occur in in the dorsal pons (pontine tegmentum) and those that develop in the vental pons (base of the pons).  Dorsal pontine tumors have very favorable courses with survival for years or decade, where as vental pontine tumors are often aggressive, diffuse and lead to death with in a year of so.  They feel that they identified a neural precursor-like cell populations (pretty much like stem cells) that has been seen in the ventral pons.   The interesting thing is this cell is seen most durin middle childhood- the exact same time as pediatric DIPG occurs.  This suggests there  might be something that goes wrong in these cells wich may be the reason for DIPGs to strike this age and this region of the brain.

The article below is not easy reading but worthwhile not only to further understand this upcoming trial but also to gain further insight into the role neurodevelopmental biology will likely play in unravelling DIPG.

References:
Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma
Free Full Text-  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060250/

New Upcoming New Trial- Vismodegib

A new clinical trial  for DIPG has appeared on clinicaltrial.gov-
Evivedge (Vismodegib) in the Treatment of Pediatric Patients with Refractory Pontine Glioma

This novel phase 2 trial using the oral sonic hedgehog inhibitor agent in DIPG chidren age 3-18 is not yet open but appears that it is in the works at Phoenix Children's Hospital and Helen DeVos Chldren's Hospital.    The interesting thing is that this trial is open to  kids with residual disease after initial therapy  or at the time of recurrence/progression as confirmed by MRI.   It appears that residual disease means more than 10mm of tumor measured on MRI after receiving radiation.    Thus, although this initially appeared to perhaps be a recurrence trial, it seems it will be open to children that have measurable disease immediately following radiation.

Vismodegib (also known of GDC-0449) has been used in clinical trials in adults and children with refractory medulloblastoma in the past.    A portion of medulloblastomas seem to have the sonic hedgehog pathway as a driver.   This seems like this might also be true for DIPG.

This trial sponsored byVan Adel Research Institute.  The Van Adel Research Institute has been highly involved in the Neuroblastoma and Medulloblastoma Translational Research Consortium.  The next meeting of the NMTRC is May 6-7.

Contacts:
Phoenix Children's Hospital (Phoenix, Arizona)
Contact: Sam Chimienti     602-546-0188     schimienti@phoenixchildrens.com
Principal Investigator: Amy Rosenfeld, MD            

Helen DeVos Children's Hospital (Grand Rapids, Michigan)
Contact: Shannon Mackeigan     616-267-1162     shannon.mackeigan@helendevoschildrens.org
Principal Investigator: Albert Cornelius, MD  
Principal Investigator: Giselle Sholler, MD 

References:
Clinical Trial Listing-
http://clinicaltrials.gov/ct2/show/NCT01774253?term=pontine+glioma&rank=8

NMTRC Conference-
http://www.vai.org/about-vai/news-and-events/upcoming-events/NMTRC.aspx

Van Adel Institute-
http://www.vai.org/

Case Report- Two Children with Prolonged Survival

During time period between June 2008 and June 2009, Children’s Healthcare of Atlanta treated three children diagnosed with DIPG with radiation followed by temozolomide and avastin.   Two children were still alive at 37 and 47 months from diagnosis.  The other child had progression free survival for 12 months followed by rapid deterioration with death at 14 months from diagnosis. 

Here is the recent case report of these two children who have surpassed the 3-year mark since diagnosis of a DIPG and were still going strong at the time of publication.

Patient 1- was described as an 11-year-old male with a 2 month history of weakness on the left side as well as walking and swallowing difficulties.   The initial MRI showed a 4cmx3.5cmx3cm non-enhancing tumor of the pons and medulla.  

Patient 2-was described as an asymptomatic 7-year-old female who was found to incidentally have a 3cmx2.3cmx2.6cm pontine mass after head trauma.   She was observed closely with serial MRIs.  Two MRIs showed increased tumor size and at 8 months from initial presentation she deteriorated developing a facial palsy, right sided weakness and hydrocephalus.  The tumor was 4.2cmx4.3x3.8cm with new focal areas of enhancement.

The children were treated with temozolomide 200mg/2d/d for 5 days ever 28 days and avastin 10mg.kg.dose every 14 days.   In both patients a 65% decrease in tumor size was seen.   No steroids were needed after 10 weeks from radiation.   The therapy was tolerated well.  At publication both children were doing well and continuing on treatment.  The paper notes that the boy was going to school and playing soccer at 37 months.  

 (Note- the actual paper has several MRI images provided both initially and later for both children.)

The authors speculate that the combination of temozolomide and avastin might deliver more temozolamide to the tumor because avastin might normalize the tumor vasculature.    As support for this theory the authors point to cilengtide altering perfusion which allowed for increased temozolamide delivery  for gliomas.    Perhaps avastin has a similar effect.

An additional advantage of this combination might be the decreased need for steroids.

The authors recommend consideration of an expanded DIPG clinical trial with this combination.

By the way, the female child appears to be atypical both in presentation and focality in her tumor.   On the other hand, the male child seems to have a very typical presentation for DIPG.

Reference:

Prolonged survival after treatment of diffuse intrinsic pontine glioma with radiation, temozolamide, and bevacizumab: report of 2 cases.

J Pediatr Hematol Oncol. 2013 Jan;35(1):e42-6.

http://www.ncbi.nlm.nih.gov/pubmed/23249962

Typical Versus Atypical- What does that mean?

At one time all gliomas of the brainstem were thought to have an equally poor outcome.   Over the years (especially with better imaging), we have come to find not all brainstem gliomas are the same.—  and actually some brainstem gliomas (tectal gliomas, cervicomedullary gliomas, focal gliomas) were found to have a favorable prognosis.  However, the vast majority of brainstem gliomas- perhaps 85%- were diffuse and intrinsic and pontine.   These DIPGs, diffuse intrinsic pontine gliomas were all though to the same terrible life expectancy.

Now it has been found that not all DIPGs are the same.   Some children initially diagnosed with diffuse intrinsic pontine gliomas unexpectedly had prolonged survival.   There seems to be increasing understanding that some of these tumors are typical with the predicted short survival; then there are others that are atypical and might have longer time.

So what makes a DIPG atypical versus typical?  

 Well, there have been developing imaging appearance and clinical presentation criteria that may put a child on one side or the other. 

Typical Imaging-

1)   The tumor is diffuse without exophytic components or focality,   The tumor is mixed in through normal tissue like “sand in grass” or “pepper in jello”.

2)   The epicenter is located in the pons.  

3)   A majority of the base of the pons is affected.    Some trials require 50% while others require infiltration of 2/3 of the basis pons.

Typical Clinical Features-

1)   Age- So far seems to be written as more than 3 years of age to 18 or 21.  Younger and older patients with diffuse intrinsic pontine tumors are more likely to have prolonged survival.

2)   Clinical Symptoms Triad- Children at the time of presentation tend to have 2 out of 3 typical symptoms.   The typical triad includes a) ataxia/unbalanced gait, b) cranial nerve signs, and c) “long tract signs”- often weakness on one side.

3)   Symptom progression-Symptoms progress rapidly within one to two months from onset to diagnosis.

So, what difference does typical versus atypical make?   

Those with atypical radiographic appearance or clinical  features a may have increased survival.   This may be because these tumors are not high grade gliomas.  Thus, many DIPG trials are requiring biopsy for those children that are atypical.  If one is atypical a difference treatment course might be recommended.

It is likely better to know if a child is atypical before choosing a treatment course.   To get another opinion one can contact the DIPG Registry (http://dipgregistry.org/patients-families/second-opinion/)
or potentially contact a primary investigator of a DIPG trial (www.clinicaltrials.gov).

Note:  As we gain more understanding of diffuse intrinsic pontine tumors the categorization and definitions will probably change just as we have seen over the last couple decades.