Investigating altered serine metabolism as a therapeutic vulnerability in isocitrate dehydrogenase mutant gliomas

Active Project Grant Awarded Last action

Award ID
F31CA314068
Recipient
Awarding agency
Obligated
$88,316

Award facts

Assistance listing
93.398 Cancer Research Manpower
Completion date 0% complete
Originally
Place of performance
Ann Arbor, MI 48109, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Gliomas are the most common adult malignant cancer of the central nervous system and remain largely incurable. Many gliomas (including oligodendrogliomas and many astrocytomas) harbor driver mutations in isocitrate dehydrogenase (IDH), resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2- HG). D-2-HG promote tumorigenesis through epigenetic dysregulation, altered redox homeostasis, and impaired DNA repair. Accordingly, IDH-mutant (IDHM) gliomas represent a distinct molecular subclass of gliomas with unique metabolic dependencies and limited treatment options. Preliminary data suggest that IDHM gliomas exhibit altered serine metabolism, including decreased glucose-derived serine biosynthesis and impaired uptake of extracellular serine due to disrupted glycosylation of serine transporter, ASCT2. Given the essential role of serine in nucleotide synthesis, antioxidant defense, and cellular proliferation, this metabolic alteration may represent a selective vulnerability. The long-term objective of this proposal is to identify how mutant-IDH drives unique metabolic dependences in gliomas to inform new treatments for this deadly disease. This project will test the central hypothesis that IDHM disrupts both DE novo serine synthesis and extracellular serine uptake, creating a targetable metabolic liability. Specific aim 1 will define the mechanisms by which D-2- HG regulates serine metabolism using isotope tracing and biochemical assays in isogenic cancer-derived cell models. Specific aim 2 will evaluate the therapeutic potential of restricting serine availability in IDHM glioma models, in vitro, in orthotopic in vivo systems, and in combination with radiation therapy, a standard-of-care treatment for these cancers. Together, these studies will advance understanding of IDH-driven metabolic reprogramming and provide rationale for novel metabolic therapies. Insights gained from this work may also inform broader strategies for targeting nutrient dependencies across diverse cancer types. This research will be conducted within a multidisciplinary training environment at the university of michigan under the mentorship of DRS. Daniel wahl and yatrik shah. The fellowship includes targeted activities to develop scientific expertise, critical thinking, communication skills, and mentorship experience. This integrative training plan will support the applicant's development into an independent investigator focused on metabolism- driven therapeutic vulnerabilities in cancer.

Transactions

Action Obligated Date
Amendment $44,158
Amendment $0
Original award $44,158

Quick answers

Who received award F31CA314068?

F31CA314068 was awarded to Regents Of The University Of Michigan by National Cancer Institute (National Institutes of Health) on December 1, 2026.

How much is award F31CA314068 worth?

$88,316 has been obligated on F31CA314068.

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