Research And Grants

Cincinnati Children's Hospital Medical Center - $100,000

Dr. Rachid Drissi
Grant Amount

$100,000.00

Date

February 2015

Research Type

Clinical

Cancer Type

DIPG


Epigenetic alterations as therapeutic targets in pediatric brain tumors

We and others co-discovered the presence of activating mutations in ACVR1 in 25% of human DIPGs in 2014. Subsequently, my laboratory has developed a murine DIPG model incorporating R206H ACVR1 and observed that R206H ACVR1 significantly accelerates brainstem gliomagenesis. In addition, short-term treatment with a bone morphogenetic protein pathway inhibitor (LDN-212854), significantly reduced proliferation in this model. Furthermore, we have preliminary data that the MAPK pathway is upregulated in human DIPGs with ACVR1 mutations and that the MAPK pathway remains activated in our murine DIPG model despite BMP pathway inhibition.

Therefore, we hypothesize that inhibiting both the BMP pathway and the MAPK pathway will significantly prolong survival of ACVR1 mutant DIPG-bearing mice. Here are proposing to test two treatment strategies: 1) LDN-212854 (a BMP pathway inhibitor) in combination with a MEK inhibitor (PD-0325901), and 2) E6201, a small molecule inhibitor that inhibits both the BMP pathway and the MAPK pathway. Of note, both PD-0325901 and E6201 are already in clinical trials in adult cancers.

The biology in pediatric HGG is poorly understood and understudied. There is a crucial need to identify targets to design new therapeutic agents. This pilot study will significantly contribute to the understanding of the biology of this devastating disease and may lead to the recognition of a targetable pathway and ultimately to a cure.  This is the first study targeting EZH2 in pediatric brain tumors.