Abstract C089: Somatostatin directed radiopharmaceutical therapy for medulloblastoma spares healthy brain radiation

Abstract Purpose: Radiation treatment is delivered to the entire brain and spine to reduce tumor recurrence in children with medulloblastoma. Long term survivors suffer debilitating neurotoxicity from radiation to the healthy brain. Thus, more precise treatments are needed. We hypothesize that targeted radiopharmaceutical therapy will result in higher uptake within the tumor while sparing the surrounding healthy brain. Methods: A bio-informatics analysis of a large dataset (n=1641) was performed to identify a surface marker (SSTR2) that was enriched in medulloblastoma. Validation was done through immunohistochemical staining of patient tumor specimens (n=13). SSTR2 receptor number in medulloblastoma tumor cells was quantified by flow cytometry. Octreotate, a SSTR2-targeted peptide, was radiolabeled with copper-64 and in vitro uptake was assessed in patient-derived cell lines and in vivo uptake in a mouse with an intracranial tumor. In vivo uptake was assayed using positron emission tomography (PET). Results: RNA-seq analysis revealed increased expression of several surface markers including PROM1, EPHA2, and SSTR2 in comparison to normal cerebellum. We elected to focus on SSTR2 given that it has a clinically validated targeting peptide (Octreotate). We observed increased SSTR2 expression in several medulloblastoma molecular subtypes with median z-scores of 0.45 for group 3, 0.47 for group 4, 0.47 for the WNT subtype. One way ANOVA followed by post-hoc testing demonstrated significant differences in SSTR2 expression between group 3, group 4, and WNT subtypes and normal cerebellum (p<0.001). Thirteen out of 14 tumor specimens had 3+ immunohistochemical staining as determined by a board-certified pathologist (D.M.). We determined that the D341 medulloblastoma cell line had the highest number of SSTR2 receptors with a mean and standard deviation of 10,082 +/- 5,934 when compared to our three other cell lines. We explored targeting the SSTR2 receptor using Octreotate radiolabeled with copper-64 (64Cu-DOTA-TATE) and found that specific uptake of 64Cu-DOTA-TATE was highest in D341 cells with a mean and standard deviation of 39,272 +/- 826 counts as compared to 280 +/- 73 counts in D341 cells blocked with excess peptide. Furthermore, 64Cu-DOTA-TATE uptake was increased in all our cells in comparison to cells blocked with excess peptide (p < 0.01). The mean standardized uptake value (SUV) following PET imaging of a mouse with an intracranial tumor was 0.31 in the tumor and 0.08 in the healthy brain at 1 hour, and 0.17 in the tumor and 0.08 in the healthy brain at 24 hours post-injection of 64Cu-DOTA-TATE. Conclusion: The data presented here validates the SSTR2 receptor as a target for selective delivery of radioactivity to intracranial medulloblastoma tumors with reduced radiation exposure to the normal healthy brain. This data supports further investigation of using SSTR2-radiopharmaceuticals to deliver therapeutic radionuclides for tumor-specific radiation with the potential to decrease long term neurotoxicity. Citation Format: Saad Sheikh, Mohamad Rahmdel, Daniel Marker, Kevin Hitchens, Jessie R. Nedrow. Somatostatin directed radiopharmaceutical therapy for medulloblastoma spares healthy brain radiation [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 C089.