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Enhancing the therapeutic effects of in vitro targeted radionuclide therapy of 3D multicellular tumor spheroids using the novel stapled MDM2/X-p53 antagonist PM2.
Mortensen, Anja C L; Morin, Eric; Brown, Christopher J; Lane, David P; Nestor, Marika.
Afiliación
  • Mortensen ACL; Department of Immunology, Genetics, and Pathology, The Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden. anja.mortensen@igp.uu.se.
  • Morin E; Department of Immunology, Genetics, and Pathology, The Rudbeck Laboratory, Uppsala University, SE-751 85, Uppsala, Sweden.
  • Brown CJ; p53Lab, A*STAR, 8A Biomedical Grove, #06-04/05 Neuros/Immunos, Singapore, 138648, Singapore.
  • Lane DP; p53Lab, A*STAR, 8A Biomedical Grove, #06-04/05 Neuros/Immunos, Singapore, 138648, Singapore.
  • Nestor M; Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
EJNMMI Res ; 10(1): 38, 2020 Apr 16.
Article en En | MEDLINE | ID: mdl-32300907
ABSTRACT

BACKGROUND:

Precision therapeutics continuously make advances in cancer therapy, and a field of growing interest is the combination of targeted radionuclide therapy (TRNT) with potential radiosensitizing agents. This study evaluated whether the effects of in vitro TRNT, using the 177Lu-labeled anti-CD44v6 antibody AbN44v6, were potentiated by the novel stapled MDM2/X-p53 antagonist PM2. MATERIALS AND

METHODS:

Two wt p53 cell lines, HCT116 (colorectal carcinoma) and UM-SCC-74B (head and neck squamous cell carcinoma), expressing different levels of the target antigen, CD44v6, were used. Antigen-specific binding of 177Lu-AbN44v6 was initially verified in a 2D cell assay, after which the potential effects of unlabeled AbN44v6 on downstream phosphorylation of Erk1/2 were evaluated by western blotting. Further, the therapeutic effects of unlabeled AbN44v6, 177Lu-AbN44v6, PM2, or a combination (labeled/unlabeled AbN44v6 +/- PM2) were assessed in 3D multicellular tumor spheroid assays.

RESULTS:

Radiolabeled antibody bound specifically to CD44v6 on both cell lines. Unlabeled AbN44v6 binding did not induce downstream phosphorylation of Erk1/2 at any of the concentrations tested, and repeated treatments with the unlabeled antibody did not result in any spheroid growth inhibition. 177Lu-AbN44v6 impaired spheroid growth in a dose-dependent and antigen-dependent manner. A single modality treatment with 20 µM of PM2 significantly impaired spheroid growth in both spheroid models. Furthermore, the combination of TRNT and PM2-based therapy proved significantly more potent than either monotherapy. In HCT116 spheroids, this resulted in a two- and threefold spheroid growth rate decrease for the combination of PM2 and 100 kBq 177Lu-AbN44v6 compared to monotherapies 14-day post treatment. In UM-SCC-74B spheroids, the combination therapy resulted in a reduction in spheroid size compared to the initial spheroid size 10-day post treatment.

CONCLUSION:

TRNT using 177Lu-AbN44v6 proved efficient in stalling spheroid growth in a dose-dependent and antigen-dependent manner, and PM2 treatment demonstrated a growth inhibitory effect as a monotherapy. Moreover, by combining TRNT with PM2-based therapy, therapeutic effects of TRNT were potentiated in a 3D multicellular tumor spheroid model. This proof-of-concept study exemplifies the strength and possibility of combining TRNT targeting CD44v6 with PM2-based therapy.
Palabras clave

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: EJNMMI Res Año: 2020 Tipo del documento: Article País de afiliación: Suecia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: EJNMMI Res Año: 2020 Tipo del documento: Article País de afiliación: Suecia
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