Targeting PLK-1 for Treating MYC-Driven Lymphomas
Abstract
The overall aim of the project is to determine the therapeutic value of targeting PLK-1 in the treatment of MYC-driven lymphomas. Polo like kinase (PLK)-1 selective inhibitor, Volasertib (BI 6727), has been known to have a potent anti-tumor effect in various cancer cells,including B cell lymphomas. Unfortunately, Volasertib was withdrawn in Phase III clinical trials due to its adverse effects, including myelosuppression. In this study, we developed an Antibody-drug conjugates (ADC), which is anti-CD19 antibody (Inebilizumab)-Volasertib conjugate (V-ADC) to increase the target specificity for B-cell lymphoma cells and minimize the toxic effects of Volasertib. We will test the efficacy of V-ADC treatment in B-cell lymphomas in vitro and in vivo. We found, unexpectedly, that V-ADC exhibited little cytostatic/cytotoxic effects in Z138, a mantle cell lymphoma (MCL) cell line. We hypothesized that the expression level of CD19 as wellits gene mutation may affect the binding affinity which required for V-ADC endocytosis. In addition, lysosomal enzymatic activity might also be involved in regulating V-ADC therapeutic effect because lysosomal enzymes cleave the linker between Volasertib andInebilizumab, which releases free Volasertib into the cells. In this study, we have shown that overexpression of wild type or mutant CD19in Z138 cells exhibited increased cytotoxicity of Volasertib in a dose-dependent manner. Furthermore, we found V-ADC induced significant cell death after cell starvation in CD19-overexpressing Z138 cell line. Moreover, the combination of V-ADC and rapamycin which is an inhibitor of mammalian target of rapamycin complex 1 (mTORC1) induced a reduction of cell viability significantly. We are in the process of confirming whether lysosome enzymes activity might be involved in V-ADC therapeutic effect in B cell lymphoma cell lines, and we will further investigate the effects of V-ADC in xenograft models of aggressive B-cell lymphoma in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1189828
Entities
People
- Chieko Saito
- Kai Fu
Organizations
- Health Research, Incorporated