Direct and indirect MCL1 targeting for high-efficiency therapy of lung metastasis in-vivo and on-a-chip

About This Grant

ABSTRACT Lung metastasis is the primary cause of death in osteosarcoma (OSA) patients, with 5-year survival rates of approximately 20% using current treatments. Our recent findings highlight the need to target both tumor and microenvironment-derived factors, revealing that resident lung and immune cells released growth factors that activated tumor survival pathways upon metastasis, particularly prosurvival gene, MCL1. Inhibiting MCL1, especially when combined with cyclophosphamide, showed promising results in our preclinical model studies, eradicating metastatic lesions in some cases. However, several questions remain as to the specificity of MCL1 as a target and the feasibility of targeting this prosurvival pathway for osteosarcoma treatment. To this end, in Aim 1, we will deploy a novel bioengineered bone and lung model for real-time cell tracking to definitively establish the role of MCL1 in lung metastasis and validate these findings in vivo. We will then identify MCL1 inhibitors most able to eliminate metastases in our engineered model, in vivo, and test their safety in preclinical models. In Aim 2, we will identify mechanisms linking microenvironment-driven osteosarcoma signaling and MCL1 regulation in the lung. By using ex vivo and in vivo approaches, we will pinpoint critical ligand-receptor interactions and test receptor-level inhibitors, aimed at blocking the effects, to reduce metastatic osteosarcoma MCL1 protein levels. Promising inhibitors will then be evaluated for their effectiveness in combination with low- dose MCL1 inhibitors to eliminate lung metastasis and safety in preclinical models. Overall, this proposal aims to fully validate the potential of MCL1 inhibitors and explore combinatorial therapies to enhance efficacy and reduce toxicity, using innovative tumor-host interaction models, paving the way for future clinical trials.