Development of Novel Small-Molecule Rb Protein Modulator for Ovarian Cancer Immunotherapy
Abstract
This pilot proposal stems from our discovery that novel small molecule that interact with the retinoblastoma (Rb) protein domain C, AP-3-84, can induce myeloid-preferential apoptosis. Our data indicate that treatment with AP-3-84 can lead to myeloid cell depletion (in ex vivo cultures of human myeloid cells derived from ovarian tumors, as well as in a murine in vivo model). We will test the hypothesis that treatment with Rb modulators AP-3-84 will result in ovarian tumor regression and/or improved survival by increasing myeloid cell death and increasing anti-tumor cell-mediated responses. Specific aims will address: (1) To establish the impact of exposure to AP-3-84 on gene expression, viability and function of myeloid and lymphoid cell subsets isolated from fresh human ovarian cancer tissue. (2) A-To define the efficacy of treatment with AP-3-84 in achieving tissue and tumor myeloid cell depletion (TAM, MSDCs, rDCs) at different points of ovarian tumor progression in murine models and its effect on overall survival. B-in the same model, to assess the changes in anti-tumor cellular immunity induced by AP-3-84 treatment. The proposed studies seeks to establish that the Rb protein can serve as a new molecular target in immunosuppressive myeloid cells in ovarian cancer models, and that its blockage results in myeloid cell death within the tumor microenvironment, leading to a decrease in local immunosuppression, and enhanced T-cell control.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2021
- Accession Number
- AD1139908
Entities
People
- Luis J. Montaner
Organizations
- Wistar Institute