Therapeutic resistance and aggressive malignancy in glioblastomas: the contribution of GTP metabolism through regulation by IMPDH2

Active Project Grant Awarded Last action

Award ID
R01CA255331
Recipient
Awarding agency
Obligated
$3,577,771

Award facts

Assistance listing
93.395 Cancer Treatment Research
Completion date 88% complete
Originally
Funding
  • $3,164,290.00 Federal
  • $413,481.00 Non-federal
Place of performance
Cincinnati, OH 45221, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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 In unpublished preliminary studies, we have discovered that IMPDH2 is markedly resistant to the damaging effects of reactive oxygen species (ROS).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

Transactions

Action Federal Non-federal Date
Amendment $0 $0
Amendment $386,881 $0
Amendment $367,131 $0
Amendment $387,730 $0
Amendment $387,730 $0
Amendment $403,928 $0
Amendment $403,928 $0
Amendment $413,481 $0
Original award $413,481 $413,481

Subawards

Subrecipient Amount Awarded
Subrecipient not on record Amend 3 - Structural analysis of IMPDH2 to define the role of oligomerization and conformational changes in its activity. $7,560
Keio University Amend 4 - Metabolomics and proteomics analysis to define the role of IMPDH and its regulation in cellular metabolism $10,000
Emory University Therapeutic resistance and aggressive malignancy in glioblastomas: the contribution of GTP metabolism through regulation by IMPDH2 $13,208
Childrens Hospital Medical Center Amendment #3 $0
Childrens Hospital Medical Center Amend #3 $2,641
Subrecipient not on record Amend #2 $7,560
Keio University Amend #1 $16,200

Quick answers

Who received award R01CA255331?

R01CA255331 was awarded to Cincinnati Univ Of by National Cancer Institute (National Institutes of Health) on July 7, 2021.

How much is award R01CA255331 worth?

$3,577,771 has been obligated on R01CA255331: $3,164,290 in federal funding and $413,481 in non-federal funding.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login