Abstract 69: Integrin αVβ3 targeted PET/CT for the assessment of bevacizumab therapy in patient-derived glioblastoma xenografts

Abstract Introduction: Glioblastoma continues to be the most aggressive type of brain cancer. Standard treatment includes surgical resection, concomitant chemoradiation therapy (CRT) with temozolomide (TMZ) followed by adjuvant TMZ (Stupp’s regimen). Bevacizumab (BEV), a monoclonal antibody targeting vascular endothelial growth factor (VEGF) A, is approved for recurrent glioblastoma with no significant benefit in the total population of recurrent glioblastoma patients. However, responders to BEV experience clinical improvement and prolonged survival. Nevertheless, no predictive biomarker for treatment effect has been identified. This study evaluates tumor angiogenesis using [68Ga]Ga-NODAGA-E[c(RGDyK)]2 (RGD2) PET/CT targeting integrin αVβ3 to predict response to BEV combined with conventional therapy in patient-derived xenograft (PDX) models with postoperative primary or recurrent glioblastoma, aiming to guide clinical patient selection. Experimental procedures: Tumors from four patients with primary or recurrent glioblastoma were enrolled for preclinical efficacy evaluation in PDX models (PDX 1-4) to receive BEV monotherapy, Stupp’s plus BEV, Stupp’s alone, or saline. PDX patient tissue were selected based on clinical treatment regimen. PET/CT with RGD2 was performed at baseline and post-therapy. To assess the correlation between treatment efficacy and tracer uptake, tumor uptake of RGD2 was compared with survival outcomes. Immunohistochemistry (IHC) was used to assess glioblastoma and angiogenesis markers. Results: PDX models with increased uptake of RGD2 at baseline (PDX 1: 6.2±0.66 max%ID/g) showed better response rate to Stupp’s plus BEV compared with PDX models with low uptake (PDX 3: 2.1±0.25 max%ID/g). PDX models of both primary (PDX 1) and recurrent (PDX 4) glioblastoma had better survival with Stupp’s plus BEV therapy compared with BEV monotherapy, Stupp’s, and saline. PDX 1 treated with Stupp’s plus BEV had better survival with a median survival time of 70 days (95% CI: 63-77 days) compared with BEV monotherapy (p<0.0001), Stupp’s (p<0.05), and controls (p<0.0001). Additionally, PDX 4 treated with Stupp’s plus BEV had better survival with a median survival time of 49 days (95% CI: 42-56 days) compared with BEV monotherapy (p<0.0001), Stupp’s (p=0.0009), and controls (p<0.0001). IHC showed upregulated angiogenesis markers (CD31, CD34, VEGF, and integrin αvβ3) in PDX tumors with high RGD2uptake. Conclusion: Our results indicate that RGD2 can be used as a predictive biomarker for treatment response to BEV in PDX models of glioblastoma. Translationally, RGD2 PET imaging could be used in clinical settings to predict responses to BEV combination therapy. Furthermore, our results support the investigation of BEV in clinical trials as part of first-line adjuvant therapy, potentially advancing its role in improving treatment outcomes in glioblastoma patients. Citation Format: Anne Skovsbo Clausen, Ida Vang Andersen, Malene Martini Clausen, Aleena Azam, Julie van Krimpen Mortensen, Emilie Graae Lund, Thomas Haargaard Urup, Andreas Kjaer. Integrin αVβ3-targeted PET/CT for the assessment of bevacizumab therapy in patient-derived glioblastoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 69.