Abstract P005: Fibroblast Activation Protein (FAP)-targeted radioligand therapy as a promising treatment for glioblastoma
Authors: Jeanjean Pauline , Dove Rachel , Azrour Ines Camille , Kwock Samantha , Taylor Sarah , Smolev Sarina , Czernin Johannes , Carlucci Giuseppe , Nathanson David , Mona Christine , Besserey-Offroy Elie 
Published: January 2025

Abstract
Introduction: Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The 5-year survival rate is only 4% despite the current standard treatment approaches of surgery, chemotherapy, and radiation. Fibroblast Activation Protein (FAP)-targeted radioligand therapy (RLT) has emerged as a potential alternative to traditional radiation methods. FAP is a protein highly expressed in Cancer-Associated Fibroblasts (CAFs) and on GBM cells. It can be targeted by radiolabeled molecules for selective tumor irradiation, to enhance treatment precision and reduce damage to healthy tissue. Here we evaluated the relevance of FAP inhibitor 46 (FAPi-46) as a molecular probe for Radioligand Therapy (RLT) in GBM models. Methods: U87MG, a human GBM cell line shown to express human FAP and SB28, a murine GBM cell line engineered to express murine FAP were used as GBM models. NSG and C57BL6J mice were, respectively, inoculated with U87MG and SB28 cells subcutaneously. Tumor growth was evaluated by computed tomography (CT). FAP expression was assessed by 68Ga-FAPi-46 PET imaging when tumors reached around 100 mm3 prior to treatment. Mice were subsequently randomized into 4 groups: (1) vehicle, (2) 5 mg/kg temozolomide (TMZ), (3) 60 kBq 225Ac-FAPi-46, and (4) 5 mg/kg TMZ and 60 kBq 225Ac-FAPi-46. Dose of TMZ and 225Ac-FAPi-46 were increased for the SB28 study. Overall survival was tracked. Blood was collected 24h before, after, and 7 days after RLT treatment to assess blood toxicity. Tumor were resected 24h after RLT treatment to further evaluate DNA-damage. Results: Our results show that combining TMZ with 225Ac-FAPi-46 successfully delays tumor progression and extends survival in immunocompromised mice bearing subcutaneous human U87MG GBM tumors. In the SB28 GBM model neither TMZ nor a single dose of FAPi-RLT alone affected tumor growth or survival, confirming its in vivo resistance to both chemotherapy and radiation. However, by adapting the 225Ac-FAPi-46-RLT regimen, we observed a significant reduction in tumor volume and an increase in survival in immunocompetent mice. These results suggest that higher doses of 225Ac-FAPi-46-RLT can overcome resistance in this model. Conclusion: In conclusion, our study shows that 225Ac-FAPi-46-RLT could be an effective treatment for GBM, with positive results across different tumor models. To further investigate the efficacy of FAP-targeted RLT for GBM, we have initiated an evaluation of immune cell infiltration within subcutaneous SB28 tumors. Using immunohistochemistry, RNA sequencing, and flow cytometry, ongoing studies will characterize the immunogenic response induced by RLT in this GBM model.
Citation Format: Pauline Jeanjean, Rachel Dove, Ines Camille Azrour, Samantha Kwock, Sarah Taylor, Sarina Smolev, Johannes Czernin, Giuseppe Carlucci, David Nathanson, Christine Mona, Elie Besserey-Offroy. Fibroblast Activation Protein (FAP)-targeted radioligand therapy as a promising treatment for glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P005