Huising, Dianne (2020) Combining daratumumab and BH3 mimetics to target T-cell acute lymphoblastic leukemia: a possible powerful combination Search and research to an improved treatment regimen for T-cell acute lymphoblastic leukemia patients. thesis, Medicine.
Full text available on request.Abstract
New, specifically targeting therapy for T-cell lymphoblastoid leukemia (T-ALL) is needed because of short- and long-term effects of chemotherapy, the poor prognosis of early thymocyte precursor ALL and the poor prognosis of refractory and relapsed T-ALL when treated with chemotherapy. We focused on two possible targets: CD38 and different antiapoptotic proteins (Bcl-2, Bcl-XL and Mcl-1), both known to be highly expressed in T-ALL. Daratumumab, an anti-CD38 monoclonal antibody for treatment of multiple myeloma, has already shown its efficacy in off-label treated T-ALL patients. One of the BH3 mimetics, targeting antiapoptotic proteins, is venetoclax, a Bcl-2 inhibitor, already used for treatment of chronic lymphoid leukemia. We hypothesized a synergistic action of daratumumab and a BH3 mimetic to treat T-ALL, since both act via the intrinsic pathway of apoptosis. We used T-ALL cell lines CEM, Jurkat and Molt-4. All of them expressed CD38 and one or more antiapoptotic proteins. Results of monotherapy with daratumumab, venetoclax (Bcl-2 inhibitor), A1155463 (Bcl-XL inhibitor) or S63845 (Mcl-1 inhibitor) were compared to results of combination treatment. No relevant cell death could be induced in vitro by daratumumab or venetoclax monotherapy. The Bcl-XL inhibitor induced cell death up to 90% at clinically relevant concentrations. Addition of daratumumab did not increase cell death. Immunohistochemical staining of bone marrow biopsies of T-ALL patients all showed clear expression of Bcl-2 or Bcl-XL and justifies use of BH3 mimetics in T-ALL. Despite we could not establish any effects on cell viability in our T-ALL cell lines in vitro with daratumumab, we still believe it to be a powerful drug in treatment of T-ALL. Other mechanisms of action of drat should be tested, as well as in vivo experiments should be performed. BH3 mimetics have shown very promising results in T-ALL cell lines. If daratumumab and BH3 mimetics do not work synergistically, they can still be a strong addition to each other for treatment of T-ALL.
| Item Type: | Thesis (UNSPECIFIED) |
|---|---|
| Supervisor name: | Dr. Bellido, M. and Dr. van Meerten, T. |
| Faculty: | Medical Sciences |
| Date Deposited: | 25 Oct 2023 11:08 |
| Last Modified: | 25 Oct 2023 11:08 |
| URI: | https://umcg.studenttheses.ub.rug.nl/id/eprint/3714 |
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