Horizontal blocking of metastatic growth factors signaling by low molecular weight heparin derivative to control ovarian cancer progression

Abstract

Conventional ovarian cancer treatments include surgery, radio/chemotherapy, and targeted therapies aimed at signaling pathways like transforming growth factor-β (TGFβ) and vascular endothelial growth factor (VEGF). However, targeted therapies often fall short due to the activation of alternative pathways and lack of patient responses. Thus, the use of a single targeted therapeutic to block more than one pathway simultaneously, termed as horizontal pathways, is hard to achieve due to their structural rigidity and uniformity. Heparin's vast structural diversity allows it to bind with and regulate many proteins via binding to their heparin-binding domains. Here, we aim to address the limitation of horizontal targeting approach by using a low molecular weight heparin-based compound conjugated with seven taurocholic and tetrameric deoxycholic acids (LHTD4). LHTD4 has shown promise as an orally active anti-angiogenic agent, effectively inhibiting VEGF and TGFβ pathways crucial for ovarian cancer progression. LHTD4 significantly reduced TGFβ and VEGF receptor phosphorylation in SKOV3 cells, attenuated EMT-genes, and suppressed malignant spheroid formation. In mouse models of orthotopic and peritoneal ovarian cancer metastasis, LHTD4 decreased tumor growth and metastasis, prolonged survival, and prevented malignant ascites formation. LHTD4's ability to block horizontal pathways offers a promising therapeutic strategy to halt ovarian cancer metastasis at different stages of progression.