Abstract C091: Validation of the U87MG human glioblastoma cell line xenograft model as a platform for the development of radioligand therapy and other targeted therapeutics

Abstract A major obstacle in anti-cancer therapy research is the development and validation of suitable in vivo models to examine tumor efficacy. Glioblastoma (GBM) is currently the most common and aggressive primary brain tumor. Despite the standard treatment approaches of surgery, chemotherapy and radiation, the 5-year survival rate is only around 5% with an average survival time after diagnosis of less than 18 months. In addition, traditional chemo and radiotherapy can have deleterious off target effects, damaging healthy tissue and severely impacting patients’ quality of life. Recently, targeted radioligand therapy (RLT) has emerged as a potential alternative to traditional radiotherapy methods, offering selective tumour cell targeting, improving treatment precision, and reducing damage to non-cancerous tissue. Fibroblast Activation Protein (FAP) is a membrane bound protein that has limited expression in normal tissues, but which is highly expressed both in Cancer-Associated Fibroblasts (CAFs) and on GBM cells. As such it is an attractive target for novel therapeutics, including radiolabeled molecules. Lutetium (Lu), and specifically lutetium-177 (177Lu), is a beta-emitting radionuclide used in targeted radionuclide therapy, often in conjunction with chelating agents. Chelators (e.g., DOTA) bind the lutetium ion, forming a stable complex that allows for targeted delivery of the radioactive payload to specific cells or tissues in the body. FAP-2886 is a FAP binding peptide, which when coupled to a radionuclide such as 177 Lu has potential application as an imaging and therapeutic agent. One of the critical needs in the development of FAP targeted RLT is the availability of validated, robust pre-clinical models to ascertain therapeutic efficacy. Here we present target expression and anti-tumor efficacy data using [177Lu]Lu-FAP-2886 in an immunocompromised mouse model bearing the subcutaneous U87MG human FAP-expressing glioblastoma cell line tumor xenograft to demonstrate its suitability for assessment of FAP as a target for both efficacy and biodistribution studies. In addition, we also examine the expression of other clinically relevant targets in this model, including CD228, CAIX, DLL3, and integrins using flow cytometry. These studies demonstrate the utility of the U87MG model for pre-clinical development of a range of target-based therapies with potential applications in multiple therapeutic areas including RLT, antibody drug conjugate (ADC), and small molecules. Citation Format: Peirang Cao, Jackson Chan, William MacCuaig, Soumya Ullas, Ji Youn Lee, Julian Goggi, Michael Bruce, Valerie Yost, Michael Batey, Rachel Stewart. Validation of the U87MG human glioblastoma cell line xenograft model as a platform for the development of radioligand therapy and other targeted therapeutics [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 C091.