TMOD-16. Generation of orthotopic patient-derived xenografts from progressive oligodendroglioma without TMZ-induced hypermutation

BACKGROUND Establishing faithful patient-derived xenograft (PDX) glioma models is necessary for the analysis of malignant tumor pathology and the development of new treatments. Previously successful oligodendroglioma PDX models have been derived from patients who received multiple rounds of temozolomide and developed subsequent mismatch repair deficit hypermutation. PI3K/AKT/mTOR signaling pathway gene alteration represents a major pathway promoting xenograft formation in these oligodendrogliomas. As opposed to the previous findings, we report here a successfully generated oligodendroglioma PDX model from a non-hypermutant recurrence, and compare the genomic alterations within this PDX to those found in prior oligodendroglioma models. CASE PRESENTATION AND RESULTS A 58-year-old female presented with a two-decade history of progressive left frontal oligodendroglioma. The patient was initially diagnosed as oligodendroglioma (Grade II). Proton radiotherapy was administered due to progressive FLAIR hyperintense growth at year 9 of diagnosis. The patient then completed 6 cycles of PCV chemotherapy for progressive disease at year 17. A small enhancing lesion later appeared at year 21, for which ivosidenib was initiated but halted shortly thereafter (6 weeks) due to poor tolerability. Over the next several months, the imaging showed a growing nodular-enhancing cystic recurrence, and the patient underwent subtotal re-resection at year 22. Pathology from this recurrence revealed oligodendroglioma with microvascular proliferation, necrosis, and mitotic activity (oligodendroglioma, IDH-mutant and 1p/19q-codeleted, grade 3). A reproducibly lethal, intracerebral PDX was successfully generated in mice from the tumor specimen and was passaged for 4 generations. Gene sequencing panels demonstrated low tumor mutation burden, and documented the presence of mutations in IDH1 and TERT promoter, as well as TP53, in both the patient and PDX samples, but no other genetic driver mutations were found, including alteration of PI3K/AKT/mTOR pathway. CONCLUSION We report the successful engraftment of a progressive oligodendroglioma without hypermutation, with a distinct genetic profile. Further molecular pathological analyses are underway to elucidate the underlying mechanism for malignant progression and successful xenograft formation.