Diffuse Intrinsic Pontine Glioma (DIPG) is a rare pediatric brain tumor for which no cure or efficacious therapies exist. Recently, novel mutations in ACVR1, a BMP pathway receptor, were discovered that commonly co-occur with a K27M mutation in the gene encoding histone H3.1 (H3.1 K27M) in DIPG patient samples. The overall objectives of this proposal are to identify the mechanisms by which mutant ACVR1 and H3.1 K27M contribute to DIPG pathogenesis and to uncover strategies to pharmacologically target these mutations or downstream signaling molecules. Our central hypothesis is that mutant ACVR1 and H3.1 K27M contribute to brainstem gliomagenesis by activating the Stat3 and Notch signaling pathways, respectively. We plan to use novel genetically engineered mouse models representing primary tumors growing in their native microenvironment to interrogate the effects of both mutant ACVR1 and H3.1 K27M on gliomagenesis, proliferation, apoptosis, cell differentiation, self- renewal, cell motility, and angiogenesis in vitro and in vivo. We will also use both genetic and pharmacologic tools to determine the contributions of Stat3 and Notch to ACVR1-mediated functions and to H3.1 K27M-mediated functions, respectively. Finally, we will test a panel of ACVR1, Stat3, and Notch inhibitors in vitro and in vivo in both human and murine DIPG models. Once it is understood how ACVR1 mutations and H3.1 K27M contribute to DIPG pathogenesis, the relevant developmental pathways can be manipulated pharmacologically, resulting in new and innovative therapeutic approaches that are based upon the basic biology inherent, and specific, to DIPG. We anticipate these outcomes will have a positive impact by 1) laying the foundation for future pre-clinical and clinical trials for DIPG, 2) characterizing the first genetically engineered mouse models of DIPG driven by mutant ACVR1 and H3.1 K27M, and 3) advancing our understanding of signaling pathway activities that are essential for DIPG growth.

Public Health Relevance

The proposed research is relevant to public health because a better understanding of the mechanisms by which H3.1K27M and ACVR1 mutations contribute to Diffuse Intrinsic Pontine Glioma or DIPG pathogenesis using genetic mouse models and human models will help identify effective therapies. Because Diffuse Intrinsic Pontine Glioma or DIPG is an incurable brain cancer that primarily afflicts children, the proposed research is especially relevant to the part of the National Cancer Institute's mission, which supports research to the cause, diagnosis, prevention, and treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA197313-06
Application #
9880404
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Mietz, Judy
Project Start
2016-08-05
Project End
2022-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Children's Memorial Hospital (Chicago)
Department
Type
DUNS #
074438755
City
Chicago
State
IL
Country
United States
Zip Code
60611
Hoeman, Christine; Shen, Chen; Becher, Oren J (2018) CDK4/6 and PDGFRA Signaling as Therapeutic Targets in Diffuse Intrinsic Pontine Glioma. Front Oncol 8:191