Development of Novel Small-Molecule Rb Protein Modulator for Ovarian Cancer Immunotherapy
Technical Report,01 Mar 2019,29 Feb 2020
The Wistar Institute of Anatomy and Biology Philadelphia United States
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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 andor 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.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research