SUMMARY
UCLA researchers in the Department of Microbiology, Immunology, and Molecular Genetics identified MAO-A as a drug target and demonstrated repurposing an old antidepressant MAOI for use in combination with cancer immunotherapy methods.
BACKGROUND:
Monoamine Oxidase A (MAO-A) is a protein of myriad functions relating to neurotransmitter homeostasis and function in the brain and has been extensively studied for its role in guarding against neurological disorders. Recently the protein has also been implicated as having a role in promoting tumor progression through inhibition of immune cells involved in antitumor response. More specifically, MAO-A has been identified as an immune checkpoint that blocks T cell reaction and polarizes tumor-associated macrophages (TAMs) for immune suppression in a solid tumor. T cells and TAMs are critical immune cells in a patient’s immune battle against cancer.
Immune checkpoint blockade (ICB) therapy, such as the PD-1/PD-L1 and CTLA-4 blockade therapies, has achieved remarkable clinical responses and revolutionized the treatment of many cancers. However, only a fraction of patients with cancer respond to CTLA-4 and PD-1/PD-L1 blockade therapies, and most responders suffer tumor recurrence due to the development of tumor immune evasion. These limitations of existing ICB therapies are thought to be largely caused by the presence of multiple immune checkpoint pathways, as well as the different roles of individual immune checkpoint pathways in regulating specific cancer types and disease stages. Thus, the identification of new immune checkpoints and the development of new combination treatments are a major focus of current cancer immunotherapy studies.
In the expanding family of immune checkpoint molecules, MAO-A is unique because it is already a well-established drug target due to its known function in the brain. Small-molecule MAO inhibitors (MAOIs) have been developed and clinically used to treat neurological disorders including depression and Parkinson’s disease. In fact, MAOIs is the first major class of antidepressants being marketed in the 1950s. The UCLA research-tested multiple clinically approved MAOIs (phenelzine, moclobemide, and clorgyline) and demonstrated their enhancement of antitumor immune responses, pointing to the possibility of repurposing these old antidepressants for cancer immunotherapy. Developing new cancer drugs is extremely costly and time-consuming; drug repurposing offers an economic and speedy pathway to additional cancer therapies.
INNOVATION:
UCLA researchers in the Department of Microbiology, Immunology, and Molecular Genetics have discovered a novel role of MAO-A that implicates it in tumor immunology. They found that 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. They found that by genetically ablating the gene in mice, there was improved tumor clearance, and pharmacological inhibition of MAO-A in mice improved antitumor response and tumor suppression as well. This effect was comparable to what is seen with checkpoint inhibitors such as PD-1/PD-L1 blockade, but combination therapy of MAO-A inhibition and PD-1/PD-L1 blockade resulted in a synergistic tumor suppression response. These results indicate that MAOA inhibitors could be effective for combination cancer immunotherapies where controlling immunosuppressive tumor environments is crucial.
POTENTIAL APPLICATIONS:
- Use as a novel drug target in cancer immunotherapy.
- Development of small-molecule inhibitors of MAOA for treatment of tumors.
- Combination immunotherapy with PD-1/PD-l1 blockade
- Dual therapy benefits to cancer patients i.e., anti-depression and anti-tumor activity of MAOI
ADVANTAGES:
- MAOA inhibitors had comparable efficacy with the current standard of care (checkpoint inhibitors).
- Novel target provides diversity to cancer treatment options/biomarkers.
- When used in combination with checkpoint inhibitors synergistic antitumor response was observed.
DEVELOPMENT-TO-DATE:
Researchers have demonstrated the efficacy of pharmacological MAOA inhibition for promoting antitumor response in B16-OVA melanoma and MC38 colon cancer syngenic mouse tumor models. They also demonstrated drug synergies of MAOA inhibitors with checkpoint inhibitors (e.g., anti-PD-1).
Related Papers (from the inventors only)
- Wang, Xi, et al. “Targeting Monoamine Oxidase A for T Cell–Based Cancer Immunotherapy.” Science Immunology, vol. 6, no. 59, 2021, p. eabh2383, doi:10.1126/sciimmunol.abh2383.
- Wang, Yu-Chen, et al. “Targeting Monoamine Oxidase A-Regulated Tumor-Associated Macrophage Polarization for Cancer Immunotherapy.” Nature Communications, vol. 12, no. 1, Springer US, 2021, pp. 1–17, doi:10.1038/s41467-021-23164-2.