The Identification and Targeting of Altered NAD+ Metabolism in Glioblastoma

Glioblastoma (GBM) is an aggressive malignancy characterized by extensive intra and intertumoral heterogeneity. NAD+ is a crucial metabolite involved in energy production, redox balance, and DNA-damage repair, and its biosynthesis and consumption are elevated in GBM. This dissertation investigates the upregulation of NAD+ metabolism in GBM and evaluates multiple strategies to target this vulnerability. We first performed transcriptomic analyses from The Cancer Genome Atlas and Genotype Tissue Expression database and identified multiple enzymes involved in NAD+ synthesis and consumption are upregulated in GBM compared to normal brain tissue. We investigated one such enzyme, NAD(P)H quinone oxidoreductase (NQO1). Elevated expression of NQO1 made GBM cells uniquely sensitive to the NQO1-bioactivatable compound β-lapachone. β-lapachone induced acute DNA damage and NAD+ depletion. However, GBM cells may evade this depletion through activation of NAD+ biosynthesis pathways. We performed additional studies and demonstrated GBM cells predominantly maintain NAD+ levels through the salvage pathway. Pharmacologic inhibition of the salvage pathway with FK866 sustained β-lapachone mediated NAD+ depletion and combination led to synergistic toxicity. These results identified NQO1 expression as a potential marker of susceptibility to β-lapachone. We next investigated targeting of ribose synthesis, the basic building block for nucleotide synthesis, as a mechanism for global NAD+ biosynthesis inhibition. We observed GBM cells exhibited significant metabolic flexibility to maintain ribose levels. GBM cells readily incorporate either extracellular glucose or uridine to promote cell growth and maintain NAD+ levels during metabolic stress. In our final study, we describe a methodology for the detection of the NAD+ associated vault complex and vault-associated RNAs (vtRNA) in GBM. Vault complexes may confer multi-drug resistance in cancers, and here we demonstrate vault components including small non-coding vtRNAs are highly expressed in U87 GBM cell line. Vault components were expressed in normal human astrocytes with differential expression of select vtRNA isoforms. We provide a foundation for further evaluation on the potential function of vtRNAs in GBM. Together, my work has demonstrated NAD+ to be a metabolic vulnerability in GBM and the identification of NQO1 as well as other select enzymes involved in NAD+ biosynthesis to be potential targets for the treatment of GBM.

Name thesis:degree_name

Pharmacology and Toxicology (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2026

Author dc:creator

• Chang-Gu, Bruce Kenneth 1998-

Committee members dc:contributor.committeemember

• Khanipov, Kamil (kakhanip@UTMB.EDU)
• Zhang, Kangling (kazhang@UTMB.EDU)
• Puduvalli, Vinay (vpuduval@mdanderson.org)
• Valdes Quevedo, Pablo (paavalde@UTMB.EDU)
• Falzon, Miriam (mfalzon@UTMB.EDU)

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12834

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12834