CM-1315-P60. Inhibitors of FOXP3 transcription factor for cancer therapy
Cáncer
Target:
Disruption of FOXP3 dimerization
- Introduction:
Identification of P60 peptide and P60-derived peptides as novel agents for tumor immunotherapy capable of inhibiting FOXP3 homodimerization and FOXP3/AML1 interaction.
- Results:
P60/P60 peptides affect the immunosuppressive activity of Treg cells, increase T cell proliferation and cytokine production after TCR stimulation and exert antitumoral effects in vivo in tumor murine models.
- Keywords:
- Cáncer ,
- Infecciones crónicas virales ,
- Inmunoterapia ,
- Inmunorregulación
- Early Discovery
- Discovery
- Preclinical
- Clinical
- Diagnostics
Approach
- There are no available compounds able to inhibit Treg activity. We found that P60 derived peptides are able to inhibit Foxp3 dimerization and its interaction with AML1/Runx1 transcription factor.
- P60 derived peptides impair the immunosuppressive activity of Tregs and constitute a strategy to enhance antitumor and antiviral immunotherapies.
Key concepts and Target Identification
- Dimerization of FOXP3 is required for its function as a transcriptional regulator and it has been described that the leucine zipper region is necessary and sufficient to mediate homo-dimerization.
- AML1 is required for IL-2 and IFN-γ gene expression in conventional CD4+ T cells and its interaction with Foxp3 is needed for the immunosuppressive activity of Tregs.
- P60 derived peptides inhibit FOXP3 homodimerization and FOXP3/AML1 interaction impairing the immuno-suppressive activity of Treg cells and enhancing T cell proliferation and cytokine production upon TCR stimulation.
- P60/P60 peptides derived are identified as regulators of Treg and synergizes with anti-PD1 to cure colon cancer tumors in a murine model. P60/P60 peptides derived can be considered as new agents for tumor immunotherapy.
Target Validation
- Treg inhibitory peptide P60 interacts with the intermediate region of FOXP3 inhibiting homodimerization and its association with AML1. Key residues implicated in the interaction of P60 with FOXP3 have been identified and allowed us to identify P60 derived peptides with higher Treg inhibitory capacity and anti-tumor activity.
Intellectual Property
New Patent application filed (WO2018077716A1).
(More information in Lozano et al, Oncotarget, 2017)