Evaluation of Novel LHRH-receptor Directed Therapeutic Candidates in Preclinical 2D and 3D Models of Triple Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) has the worst prognosis among the breast cancer subtypes, partly due to its lack of traditional treatment targets estrogen receptors, progesterone receptors or amplification of the human epidermal growth factor receptor 2. Chemotherapy is the primary mode of treatment but causes various damaging side effects. In many TNBC cases, the disease often recurs after an initial successful response, leading to intractable metastatic disease. There are limited targeted therapeutics for TNBC, reflecting the scarcity of uniquely targetable components.

Furthermore, those available treatments provide a significant, but modest improvement in overall survival compared to non-selective chemotherapy. Hence, it is imperative to identify novel targets in TNBC and more effective treatments for this underserved disease. Models that better capture the characteristics of the whole TNBC tissue rather than focusing exclusively on the epithelial component are likely to yield more novel durable treatments. Recent research highlights the critical role of breast cancer-associated fibroblasts (BCAFs) in tumour progression, drug resistance, and metastasis. Therefore, incorporating BCAFs into preclinical TNBC models is essential for drug discovery, emphasising the need for effective, selective treatments that target the entire TNBC tissue environment.

This thesis explored luteinising hormone-releasing hormone receptor (LHRH-R) as a newly identified target for TNBC therapy. Additionally, building on previous work by the Varamini team, who had already designed a novel LHRH-R-targeting peptide-drug conjugate (MLD5-PDC), this study further demonstrated the potential of the MLD5-PDC as a promising treatment for TNBC employing both 2D and 3D models. Furthermore, the comparison and optimisation of 3D model development in this thesis provided a foundational dataset for future therapeutic advancements.