Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It accounts for ~15% ofall breast cancer yet is responsible for 30% of breast cancer deaths. TNBC is treated primarily by conventionalchemotherapy; however, resistance to therapy is common, leading to high mortality rates. Importantly, thebenefit of current therapeutic strategies used in chemoresistant TNBC; i.e., immunotherapy and antibody-drug conjugates, is confined to only a fraction of patients, and survival benefit is limited. Therefore, there isan urgent need to identify novel and effective treatment strategies to overcome resistance to chemotherapy.Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key mediator ofchemoresistance in TNBC (Saatci et al, Nature Communications, 2020). We showed that LOX isoverexpressed in chemoresistant tumors, and its inhibition re-sensitizes the most aggressive breast tumorsto doxorubicin using several clinically-relevant mouse models. However, the available LOX inhibitors areeither non-selective or has toxicity. Hence, our main objective in this project is to develop potent, specific andwell-tolerated LOX inhibitors to overcome chemoresistance in TNBC that has a high translational potential.Through high-throughput compound library screening and hit-to-lead conversion studies, we identifiedcompounds with potent on-target cellular engagement of LOX, with good oral pharmacokinetics (PK) andwith chemosensitizer effect without major toxicity (US PTO 17/693,371 and PCT/US2022/20086, patentpending). Starting from our current non-optimized lead molecule, we aim to develop lead compounds withincreased potency, safety and drug-likeness. To accomplish this goal, in Phase I of this Fast-Track STTRgrant, we will generate a diverse library of small molecules via an extensive structure activity relationship(SAR) study using our initial pharmacophore. We will test the synthesized inhibitors with respect to the degreeof LOX enzymatic activity inhibition, LOX binding and selectivity towards LOX. We will perform the off-targetassessment of the inhibitors using CEREP screen as well as kinome profiling. The shortlisted candidates willfurther be tested in ECM crosslinking and 3D chemosensitization assays using both cell lines and organoids.Inhibitors with better efficacy, selectivity and stability will move to Phase II. In Phase II, we will perform severalADME assays, including metabolic stability/identity, Caco-2 permeability and transport, cardiotoxicity andgenotoxicity, plasma protein binding, CYP inhibition/induction/reaction phenotyping to improve drug-likeproperties while maintaining on-target potency in TNBC cells. Detailed PK/PD and toxicity analyses of themost promising candidates will be carried out followed by testing their chemosensitizer effect using bothstate-of-the-art immunodeficient (cell line- and patient-derived xenografts) and immunocompetent(syngeneic) mice models. The successful completion of the proposed project will lead to potent and specific,lead-optimized LOX inhibitors to overcome chemoresistance in TNBC, the deadliest form of breast cancer.
Public Health Relevance Statement: PROJECT NARRATIVE
The proposed project is relevant to public health because the goal is to develop novel and highly potent LOX
inhibitors to overcome chemotherapy resistance in triple negative breast cancer (TNBC), a highly aggressive
subpopulation of breast cancer with worse survival. Once we develop LOX inhibitors with excellent drug-like
properties, there is a significant potential to improve the treatment of chemotherapy-resistant TNBC patients with
high LOX expression. Thus, the proposed project is relevant to the part of the NIH's mission that pertains to
reducing illness and disability.
Project Terms: <14-Hydroxydaunomycin> | | | | 