138
Monoamine Oxidase Blockade Therapy for Treating Cancer
University of California - Los Angeles
Small molecule
Oncology
Hit To Lead or Lead Optimization
• MAO-A acts as an inhibitor of antitumor CD8 T Cell response, and also polarizes tumor-associated macrophages (TAMs) for immune suppression in a solid tumor.
• Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Mono-amineoxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders.
• MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models.
• Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intra-tumoral MAO-A expression with poor patient survival in a broad range of cancers.
• MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.
WO2022087361A1
Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy, Nature Communications. (2021)
