Abstract B091: Establishment and characterization of a panel of naive and pretreated brain cancer XPDX models

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Abstract The survival rate of aggressive brain cancers like glioblastoma averages less than eighteen months with few treatment options. However, advances in molecular testing have identified novel cancer drivers leading to the development of new therapies. To assist in the development of these and future therapies, we established and characterized a panel of brain cancer XPDX models representing newly diagnosed and recurrent disease from either naive or clinically treated patients and tested sensitivities towards temozolomide (TMZ) and targeted agents. Forty-five models were established in immune-deficient mice including thirty-three from newly diagnosed and twelve from recurrent patients, six of which were treated with TMZ and four with TMZ plus additional therapies prior to sample collection for model development. All models were confirmed and subtyped including forty glioblastomas, two gliosarcomas, two astrocytomas and one oligodendroglioma; further characterization was performed including IHC, WES, and RNAseq. For in vivo studies, all models were evaluated against TMZ and some with ADCs or targeted therapies based on IHC or identified variants. Endpoints in all studies included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C<0%) versus Day 0 tumor volume was also reported. Differential IHC staining for HER2, Nectin-4, and Trop2 was reported in all models. Molecular characterization identified somatic EGFR mutations including A289V (ST2223), W731C (ST5666), R108K (STF162), and G719D (STF347), and a P848L germline mutation in ST108. EGFRvIII rearrangements were found in some models including ST2399, ST2741, ST3354, ST3765, and ST4314, and several fusions identified including EGFR:SEC61G (ST4314), SPECC1L:NTRK2 (ST5344), CDKN2A:MTAP (STF431), and FGFR3:TACC3 (STF503, STF572). Several PIK3CA variants were reported including E542K (STF347) and H1047R (ST096) along with an IDH1R132H mutation in the STF347 oligodendroglioma model. In vivo, 25% of newly diagnosed and 50% of recurrent models were resistant to TMZ therapy. Treatment with trastuzumab deruxtecan or sacituzumab resulted in tumor regressions in some models, and ST5344 was found sensitive to entrectinib (%T/C=11%). We have established and characterized a panel of brain XPDX models and benchmarked them against various cancer therapies. This panel can be utilized as a valuable tool in developing novel therapies for brain cancer patients. Citation Format: Alyssa Simonson, Johnnie Flores, Jennifer Garcia, Delaney Rushing, Jim Lund, Justine Hruzek, Ian Sturgill, Arlene Salazar, Natalia Banos, Lorena Mozas, Kenneth Stevens, Mia Macedo, Rodolfo Castellanos, Lisa Gonzales, Rose Garcia, Sara Ferguson, Ashley Jamison, Christopher Nelson, David Smith, Chris Takimoto, Michael Wick, Andrew Cunningham. Establishment and characterization of a panel of naive and pretreated brain cancer XPDX models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B091.

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