Preclinical Evaluation of a BMP inhibitor in combination with a MEK inhibitor to treat DIPG

Project: Research project

Description

Diffuse intrinsic pontine glioma or DIPG is an incurable childhood brain tumor. We and others have co-discovered the presence of activating mutations in Activin A receptor type 1 or ACVR1, a receptor in the bone morphogenetic protein (BMP) pathway, in 20-30% of human DIPGs. Interestingly, activating mutations in ACVR1 are clonal, present throughout the natural history of the disease suggesting that they are good therapeutic targets. Using the RCAS/tv-a system we have developed a DIPG mouse model incorporating R206H ACVR1, and H3.1K27M (an onco-histone that commonly partner up with ACVR1 mutations in DIPG), and noted that R206H ACVR1 significantly accelerates brainstem gliomagenesis. In addition, we have also observed that short-term treatment with LDN-212854, an ACVR1 inhibitor, can significantly inhibit the BMP pathway in vivo (as measured by ID1 protein) and significantly reduce proliferation in the tumor as measured by phospho-H3 (Serine 10). Clinical trial experience in patients with DIPG suggest that tumors as genetically complex as DIPGs are unlikely to have clinically meaningful responses to therapies with single agents and promising combination therapies are desperately needed. Here we propose to evaluate the efficacy of BMP pathway inhibition in combination with mitogen-activated protein kinase (MAPK) pathway inhibition in our ACVR1 mutant DIPG model using two approaches: first we will combine LDN-212854 with PD-0325901, the most brain penetrant MEK inhibitor, and second, we will evaluate the efficacy of E6201, a drug currently in phase II clinical trials in adults with melanoma that potently inhibits both ACVR1 and MEK and is highly brain penetrable. As the standard of care for children with DIPG is focal RT, these approaches will be tested with radiation. The rationale for combining BMP pathway inhibitors with MEK inhibitors is the known cross-talk between the two pathways as well as preliminary analysis from our lab that human ACVR1 mutant DIPGs have elevated MAPK pathway activation. Results from these preclinical studies will help inform future preclinical studies and clinical trial development targeting mutant ACVR1 in children with DIPG.
StatusActive
Effective start/end date1/1/186/30/20

Funding

  • Cure Starts Now (Agmt 12/13/17)

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Bone Morphogenetic Proteins
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Mutation
Type I Activin Receptors
Bone Morphogenetic Protein Receptors
Clinical Trials
Phase II Clinical Trials
Brain
Therapeutics
Standard of Care
Brain Neoplasms
Glioma
Histones
Serine
Brain Stem
Melanoma
Neoplasms
Radiation
Pharmaceutical Preparations