Abstract B010: Development of folate receptor alpha targeted FOXM1 inhibitors for ovarian cancer
Authors: Karpf Adam R. , Vorderbruggen Makenzie , Rikhtechi Pedram , Muñoz-Trujillo Catalina , Liu Cassie , Matherly Larry H , Kim Sung Hoon , Katzenellenbogen Benita S. , Katzenellenbogen John A. , Garrison Jered C. 
Published: March 2024

Abstract
FOXM1 is a transcription factor that plays a canonical role in cell cycle progression. In addition, FOXM1 contributes to diverse oncogenic phenotypes including cell invasion and metastasis, metabolic reprogramming, and cancer stemness. Notably, FOXM1 is the top biomarker of poor prognosis in human pan-cancer, is associated with poor prognosis in high-grade serous ovarian cancer (HGSOC) and is the most frequently activated oncogenic pathway in HGSOC. Together, these data implicate FOXM1 as a potential high impact therapeutic target in HGSOC and other cancers. In this context, several small molecule inhibitors (SMI) of FOXM1 have been described, and these include compounds that disrupt FOXM1 DNA binding and compounds that promote FOXM1 proteolytic degradation. Recently, we have identified and described a series of novel diarylethene-based compounds (i.e., NB compounds) that fall into the second class of molecules (FOXM1 degraders) and have shown that NB compounds are potent inhibitors of FOXM1 in cancer cells. The aims of the present study were two-fold: 1) investigate the activity of NB compounds using HGSOC cell models, and 2) develop methods to specifically deliver NB compounds to HGSOC cells, thus increasing drug efficacy and reducing potential toxicities. To address the first aim, we used gene and protein expression analyses and cell biological measurements. Our resulting data revealed that NB compounds are potent and efficacious FOXM1 inhibitors in HGSOC cells, leading to FOXM1 pathway suppression and robust induction of apoptosis. In addition, NB compounds displayed specificity to FOXM1 over other FOX family members and can be used in synergistic combinations with other relevant SMI. To address the second aim, we are developing nanomedicine approaches for the HGSOC-specific delivery of NB compounds. Specifically, we are generating NB compound-loaded polymersomes capable of targeting folate receptor alpha (FRα), which is highly expressed on the surface of HGSOC cells. The necessary polymers needed for the proposed nanoconstruct have been synthesized and characterized by nuclear magnetic resonance. Polymersomes have been formulated through emulsification and were characterized by dynamic light scattering. Drug loading, drug release, polymersome stability, transmission electron microscopy, and fluorescence spectroscopy studies are currently ongoing. Planned biological assays include cellular uptake, drug release, IC50, target engagement, and cytotoxicity studies in HGSOC cells with variable FRα expression. In summary, we provide data supporting the utilitity of NB compound FOXM1 inhibitors as HGSOC therapeutics and are optimizing NB compound use by directing the inhibitors to HGSOC cells using FRα-targeted nanomedicines.
Citation Format: Adam R. Karpf, Makenzie Vorderbruggen, Pedram Rikhtechi, Catalina Muñoz-Trujillo, Cassie Liu, Larry H Matherly, Sung Hoon Kim, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Jered C. Garrison. Development of folate receptor alpha targeted FOXM1 inhibitors for ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B010.