Summary:

The National Cancer Institute (NCI) seeks licensees for matched patient-derived 3D Isocitrate Dehydrogenase (IDH)-mutant glioma cell lines, 403L and 403H, generated from the same patient before and after malignant transformation from WHO grade 2 to WHO grade 4 disease. This research material provides an opportunity to study IDH-mutant glioma progression, temozolomide-associated hypermutation, invasion, metabolism, and treatment resistance.

Description of Technology:

IDH-mutant gliomas often begin as lower-grade tumors but remain incurable and frequently progress to higher-grade disease through malignant transformation. This is clinically important but difficult to study because matched low-grade and high-grade tumor materials from the same patient are rare. Further, fixed tumor specimens are limited for repeated mechanistic or drug-response experiments.

Researchers at the National Cancer Institute (NCI) developed a matched pair of patient-derived cell models, 403L and 403H, from the same patient before and after malignant transformation. 403L was established from a WHO grade 2 IDH-mutant astrocytoma. 403H was derived from the recurrent WHO grade 4 tumor following radiation and temozolomide treatment. Both cell lines: (1) grow as 3D spheroids, (2) retain endogenous IDH1 R132H expression, and (3) were authenticated to the patient's germline by short tandem repeat (STR) profiling (100% match for 403L; 93.33% match for 403H).

The high-grade 403H line shows increased invasive behavior, temozolomide-associated hypermutation (tumor mutational burden of 70.07/Mb vs. 3.96/Mb in 403L), upregulated epithelial-mesenchymal transition (EMT) signaling (whereas Notch signaling is enriched in 403L), and changes in glioma-associated metabolism, including 2-hydroxyglutarate (2-HG), glutamine, fatty acid metabolism, and lactate/pyruvate flux. Furthermore, 403H showed significantly greater 3D invasion than 403L (p<0.0001). 403H formed infiltrative high-grade glioma in 4 of 5 orthotopically xenografted NSG mice. In contrast, 403L did not form tumors within 18 months.

Researchers at NCI seek licensees interested in using these cell lines as research tools for neuro-oncology studies. The models may be useful for studying IDH-mutant glioma progression, malignant transformation, tumor recurrence, treatment resistance, and preclinical response to IDH-targeted, DNA damage response, metabolic, or combination therapies.

Potential Commercial Applications:

• Development of cancer therapeutics targeting IDH-mutant gliomas, including:
  • IDH inhibitors
  • DNA damage response agents
  • Metabolic drugs
• Modeling of tumor evolution, recurrence, and temozolomide-associated hypermutation
• Development of novel assays for glioma invasion, metabolism, and drug screening
• Preclinical screening tool for IDH-targeted, DNA damage response, metabolic, or combination therapies
• Comparative profiling of molecular, epigenetic, and metabolomic differences between low-grade and transformed gliomas

Competitive Advantages:

• Minimized genetic background variability
• Unique clinical model of the temozolomide-associated hypermutator phenotype and acquired treatment resistance
• Stable 3D tumor spheroids provide a unique model retaining endogenous IDH1 R132H expression and grade-specific stem and lineage markers (SOX2, NESTIN, GFAP, OLIG2, beta 3-Tubulin)
• Distinct functional models permitting the comparative interrogation of in vitro invasion and in vivo tumorigenicity