Targeted Therapy for Glioblastoma via Purine Metabolism Modulation

NU 2019-086

INVENTORS

• Atique Ahmed*
• Cheol Park
• Jack Shireman

SHORT DESCRIPTION

This technology introduces a targeted approach for glioblastoma treatment that modulates purine biosynthesis by targeting the ARL13B-IMPDH2 interaction using repurposed FDA-approved and internationally-used drugs.

BACKGROUND

Glioblastoma is an incurable, aggressive form of cancer with low survival rate, high recurrence, and limited treatment options. Existing treatments, such as temozolomide, face challenges due to rapid development of chemoresistance, highlighting the critical need for alternative strategies. Repurposing clinically proven drugs offers a promising short-term pathway to improve patient outcomes while bypassing lengthy new drug development processes.

ABSTRACT

Northwestern researchers have identified ARL13B as a novel regulator of the purine biosynthesis pathway, which glioblastoma cells depend upon for aberrant proliferation. The current standard of care therapy for glioblastoma is an alkylating chemotherapeutic agent called temozolomide (TMZ) which exerts its primary form of toxicity through DNA alkylation of purine bases, which are then recycled by cancer cells using the salvage purine biosynthesis pathway. By engaging directly with IMPDH2, the key rate limiting enzyme for purine biosynthesis, ARL13B enables de novo purine synthesis, allowing cancer cells to evade TMZ-induced DNA damage. Leveraging FDA-approved compounds such as CellCept and internationally-used drugs like Mizoribine, the inventors demonstrate that targeted disruption of the ARL13B-IMPDH2 interaction along with TMZ treatment promotes use of the salvage purine biosynthesis pathway in glioblastoma cells, leading to robust survival benefits for in vivo and in vitro models of glioblastoma. This strategy holds potential to serve as an adjunct to current therapies, thereby potentially transforming the treatment paradigm for glioblastoma patients.

APPLICATIONS

• Novel treatment strategy for chemoresistant glioblastoma
• First-line or secondary therapy option that expands treatment choices for patient subpopulations with therapeutic resistance

ADVANTAGES

• Utilizes FDA-approved and internationally-studied drugs to expedite treatment delivery
• Reduces developmental costs compared to novel drug discovery
• Can be combined with existing chemotherapeutic alkylating agents to enhance efficacy

PUBLICATIONS

• Shireman, J., Atashi, F., Park, C., Warnke, L., Miska, J., & Ahmed, A. (2018). CILIARY PROTEIN ARL13B PROMOTES CHEMORESISTANCE BY MODULATE GLIOBLASTOMA PURINE BIOSYNTHESIS. Neuro-Oncology, 20(Suppl 6), vi75.

IP STATUS

Issued US Patent 11,786,542