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bioRxiv · 10.1101/2023.08.23.554432

BIRC3: A Prognostic Predictor and Novel Therapeutic Target in TMZ-Resistant Glioblastoma Tumors

Morelli, M.·Franceschi, S.·Lessi, F.·Aretini, P.·Pastore, A.·Corradi, E.·Marranci, A.·Gambacciani, C.·Pieri, F.·Grimod, G.·Montemurro, N.·Giacomarra, M.·Menicagli, M.·Ferri, G.·Pasqualetti, F.·Sanson, M.·Picca, A.·Di Stefano, A. L.·Santonocito, O. S.·Mazzanti, C. M.
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Abstract

BackgroundGlioblastoma (GB) is an incurable malignant tumor of the central nervous system, with a poor prognosis. Robust molecular biomarkers associated with therapeutic response or survival are still lacking in GB. Previously, using NADH-fluorescence lifetime imaging (NADH-FLIM), as a new drug screening precision medicine ex-vivo approach, we categorized patient-derived vital tumors into TMZ responder (Resp) and non-responder (Non-Resp) groups, revealing differentially expressed genes. MethodsExpanding on our previous study, we assessed TMZ response in a larger cohort of primary and recurrent ex-vivo live GB tumors (n=33) using NADH-FLIM. Transcriptome analysis was performed to characterize TMZ Resp and Non-Resp cases, and in-silico and functional cellular investigations were conducted to explore the efficacy of potential biomarkers. ResultsGenes dysregulated in the previous study showed consistent expression patterns. BIRC3, a potent apoptosis inhibitor, was significantly upregulated in TMZ-resistant samples. BIRC3 expression complemented MGMT status as a prognostic factor in multiple TCGA cohorts. BIRC3 functioned as a prognostic factor of survival also in separate European private glioblastoma cohorts. The BIRC3 antagonist, AZD5582, in combination with TMZ, effectively reversed TMZ resistance by restoring apoptosis in glioblastoma cell lines and patient-derived organoids. ConclusionsBIRC3 holds promise as a prognostic biomarker and predictor of TMZ response in GB. Assessing BIRC3 expression could aid in stratifying patients for combined TMZ and AZD5582 therapy. Our study highlights the potential of functional precision medicine and BIRC3 assessment as a standard tool in glioblastoma clinical oncology, improving outcomes. KEYPOINTSO_LIBIRC3, previously overlooked, identified through dynamic precision medicine using TMZ perturbation of glioblastoma tissue as a robust prognostic factor. C_LIO_LIThe gene BIRC3 is an independent prognostic factor associated with shorter survival and TMZ resistance, rigorously validated across various case studies and datasets, including two expansive European case studies. C_LIO_LIProposal of anti-BIRC3 drug, AZD5582, shows promise as a novel therapeutic option to overcome TMZ resistance in GB tumors, providing hope for improved outcomes and personalized treatment strategies for patients with limited treatment options C_LI IMPORTANCE OF THE STUDYGlioblastoma (GB), an aggressive cancer type with a bleak prognosis, lacks dependable biomarkers for treatment prediction. Few markers like MGMT promoter methylation, IDH1 mutation, TERT gene mutations, and EGFR amplification are known, but their predictive consistency varies. Temozolomide (TMZ) resistance, seen in over 50% of GB patients, complicates matters. BIRC3, an apoptosis-inhibiting gene, displays heightened expression in TMZ-resistant tumors. Our study examined BIRC3 in GB patient samples, finding it an independent prognostic factor linked to shorter survival and TMZ resistance. Our research builds upon Wang et al.s 2016 and 2017 findings, delving deeper through TCGA data and European case studies. BIRC3s consistent prominence suggests its significance, with functional experiments confirming its role. We assessed AZD5582, targeting BIRC3, which, when combined with TMZ, curtailed cell growth and induced apoptosis. Notably, AZD5582 countered TMZ resistance in patient-derived GB-EPXs, except for low BIRC3 cases. Our precision medicine approach enhances personalized therapies and outcomes, highlighting BIRC3s potential as a prognostic marker and AZD5582 as a new therapy for TMZ-resistant GB.

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Morelli, M., Franceschi, S., Lessi, F., Aretini, P., Pastore, A., Corradi, E., Marranci, A., Gambacciani, C., Pieri, F., Grimod, G., Montemurro, N., Giacomarra, M., Menicagli, M., Ferri, G., Pasqualetti, F., Sanson, M., Picca, A., Di Stefano, A. L., Santonocito, O. S., Mazzanti, C. M.. 2023-08-24. BIRC3: A Prognostic Predictor and Novel Therapeutic Target in TMZ-Resistant Glioblastoma Tumors. https://doi.org/10.1101/2023.08.23.554432

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