Abstract 1829: Treating breast cancer brain metastases in the leptomeninges through p-selectin targeted delivery of EZH2 PROTACs.

Abstract Breast cancer brain metastases (BCBMs) occur in 10-15% of all breast cancer patients with dismal median survival rates as low as 1 month for patients with leptomeningeal metastases (LMs). In BCBMs, EZH2, a histone methyltransferase, has been found to have non-enzymatic oncogenic function promoting metastatic proliferation and decreased overall survival. Thus, degradation versus inhibition of EZH2 in brain metastases could be a powerful strategy to treat BCBMs and LMs if a therapeutic could accumulate to therapeutic doses in the cerebrospinal fluid. In this study, we use an EZH2 proteolysis-targeting chimera (PROTAC) enabling degradation of EZH2 in BCBMs and LMs. We find that an EZH2 PROTAC administers cytotoxic efficacy in brain metastatic (Br) and leptomeningeal (LM) derivatives of breast cancer cell lines while inhibitors have no effect. Proteomics data and mitochondrial assays suggest this discrepancy can be attributed to mitochondrial complex I and electron transport chain dysfunction. PROTACs often have poor brain penetrance due to their hydrophobic nature and large molecular weight, but they can be encapsulated in P-selectin targeted nanoparticles (nanoPROTACs). We have previously shown that P-selectin can be presented selectively on primary brain tumor cells to deliver nanoparticles across the blood brain barrier in vivo. Here, we discover using humanized models of BCBMs that P-selectin is selectively presented on tumor and leptomeningeal vasculature. Only intraperitoneal delivery of P-selectin targeted EZH2 nanoPROTACs demonstrate remarkable degradation of EZH2 in LMs 48 hours after administration. This work demonstrates the ability to deliver PROTACs selectively to brain metastases and offers a therapeutic platform to extend BCBM patient survival. Citation Format: Raashed Raziuddin, Logan Hillger, Annie Ikemoto, Daniel Heller. Treating breast cancer brain metastases in the leptomeninges through p-selectin targeted delivery of EZH2 PROTACs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1829.