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/