Summary
Glioblastoma multiforme (GBM) is the most aggressive and lethal of all brain tumors. Despite extensive efforts
to improve treatment, current GBM therapy only marginally prolongs median survival from about 12 months to
over 14 months. A variety of strategies have been attempted to improve treatment, but all have proven to be only
incrementally better than the current standard of care. Without the discovery of unique properties of gliomas that
could make them effective targets for treatment, GBM will continue to have an extremely poor prognosis. The
long-term goal of our laboratory is to understand the fundamental role of GTP metabolism in cancer growth using
GBM as a model system. To that end, we published in Molecular Cell (2016) the discovery of lipid kinase
PI5P4Kß as an intracellular GTP sensor regulating the cells needs for GTP. In the course of investigating GTP
metabolism, we further published in Nature Cell Biology (2019) that increased GTP synthesis is directly linked
to the aggressive nature of GBM tumor proliferation. The GTP metabolic reprogramming is induced by
upregulation of inosine monophosphate dehydrogenase-2 (IMPDH2), activating de novo GTP biosynthesis for
the promotion of ribosomal biogenesis and protein synthesis. Importantly, a unique feature of treatment resistant
GBM stem-like cells (GSCs) is exclusive dependence on de novo GTP synthesis. In unpublished preliminary
studies, we have discovered that IMPDH2 is markedly resistant to the damaging effects of reactive oxygen
species (ROS). Importantly, ionizing radiation exerts its cell killing effect on tumor through DNA breaks directly
and secondary to the generation of ROS, which accounts for 60-70 % of DNA lesions. This high ROS
resistance appears to a critical and specific feature of IMPDH2. The central hypothesis guiding this proposal is
that IMPDH2 promotes GBM growth by i) being resistant to the damaging effect radiation induced ROS, ii)
inducing de novo GTP synthesis required for GSCs survival. We will test this by exploring the molecular
mechanisms of the ROS resistance using the structural and molecular analyses of IMPDH2 and its mutants.
(Aim 1) and GSC’s high dependence on de novo GTP biosynthesis (Aim 2). In Aim 3, we will use the IMPDH2
inhibitor, mycophenolic acid (MPA) and its prodrug, mycophenolate mofetil (MMF) on in vivo GBM models
tracking tumor growth and GBM microenvironments with a secondary objective to determine if these inhibitors,
by virtue of their anti-inflammatory and anti-angiogenic properties, reduce the cerebral edema commonly seen
in GBM (Aim 3). Completion of these aims will identify the mechanisms through which IMPDH2 regulates de
novo GTP synthesis thereby driving on GBM tumor growth. These insights, when combined preclinical data on
MMF, a drug already approved for its immunosuppressive effects, has the potential to result in rapid translation
to human GBM.
Project Description
