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STAT3 as a Therapeutic Target for the Treatment of Glioblastoma Multiforme

  • Author(s): Assi, Hikmat Haizar
  • Advisor(s): Castro, Maria G
  • et al.

The STAT3 transcription factor is a central mediator of tumor growth and immune suppression. As a transcription factor, STAT3 promotes the expression of genes that allow tumor cells to proliferate, migrate and evade apoptosis. Activation of STAT3 in tumor infiltrating immune cells has also been demonstrated to be responsible for their immune-suppressive phenotype. As such, STAT3 is an attractive target for cancer therapy. In these set of studies, we evaluated the inhibition of STAT3 as a means of inducing tumor regression in mouse models of brain cancer. Inhibition of STAT3 was achieved using shRNA-mediated knockdown or small molecules (CPA-7, WP1066, or ML116) and was associated with an induction of growth arrest in glioma cells with a concomitant induction of apoptosis. Moreover, the targeting specificity of the small molecules appeared to be highly dependent on the cell line and drug concentration utilized in the assay. In addition to the in vitro studies, we evaluated the therapeutic efficacy of these compounds using peripheral and intracranial mouse glioma and melanoma models. Of these compounds CPA-7 appeared to be the most effective at inducing the regression of peripheral tumors. Furthermore, therapeutic efficacy of CPA-7 was not evident in intracranial tumors, as our data indicated limited diffusion into the CNS as a consequence of the blood-brain barrier.

In addition, we evaluated whether DC-based immunotherapies would benefit from STAT3 suppression. Using a conditional hematopoietic knockout mouse model, we assessed the impact of STAT3 deletion on the differentiation and function of dendritic cells from bone marrow precursors. Our results indicated the following pleiotropic functions of STAT3: hematopoietic cells that lacked STAT3 were unresponsive to Flt3L and failed to differentiate as DCs. In contrast, STAT3 was not required for GM-CSF induced DC differentiation. However, STAT3 null GM-CSF derived DCs did express higher levels of MHC-II, IL-12p70, IL-10, and TNFα upon TLR stimulation. STAT3 deficient DCs were also better at presenting antigen to naïve T cells. While STAT3 deficient DCs displayed an enhanced activation phenotype in culture, they elicited an equivalent therapeutic response in vivo compared to their wild type counterparts when utilized as vaccines for mice bearing intracranial gliomas.

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