S100A9: A therapeutic target in multiple myeloma and acute myeloid leukemia

Research output: ThesisPhD Thesis

Abstract

Multiple Myeloma (MM) and Acute Myeloid Leukemia (AML) are hematological cancers characterized by the uncontrolled growth of tumor cells in the blood and/or bone marrow. Despite major therapeutic advances, both cancer types remain incurable for the majority of patients which face a consistently high risk of relapse. Calcium-binding protein S100A9 was previously identified as an important regulator of immunosuppression and tumor growth in solid tumors. Since immunosuppressive cell types are key components of the bone marrow microenvironment in MM and AML, we aimed to investigate the function and potential of S100A9 as a therapeutic target in both hematological cancers.
In MM, we evaluated the therapeutic and immunomodulatory effects of the clinical tested S100A9 inhibitor tasquinimod. In vitro, tasquinimod significantly reduced MM cell proliferation by targeting of c-MYC and induction of p27 expression in human MM cell lines. Moreover, tasquinimod could significantly reduce myeloid-mediated immunosuppression, leading to enhanced T-cell proliferation in vitro. Using the immunocompetent 5TMM models, we could demonstrate that short-term treatment with tasquinimod significantly increased the total number of myeloid cells and shifted this population towards a more immunostimulatory state, resulting in reduced myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly decreased the tumor load and increased the trabecular bone volume, which resulted in a prolonged overall survival of MM-bearing mice.
In AML, high levels of S100A9 could be detected in primary AML cells and AML cell lines. In addition, S100A9 was significantly upregulated in AML samples compared to normal tissue. Silencing and therapeutic targeting of the S100A9 protein, with either siRNA or tasquinimod, resulted in reduced AML cell proliferation and viability, which was associated with a decrease in mammalian target of rapamycin (mTOR) and endoplasmic reticulum stress signaling. Inhibition of S100A9 also affected the cell metabolism, modulating glycolysis and/or the mitochondrial function of AML cell lines. Lastly, using AML cell lines and primary AML samples, we could demonstrate that targeting of S100A9 could significantly increase sensitivity towards standard of care agent venetoclax. This increase in drug sensitivity could be linked to a downregulation of BCL-2 and c-MYC after combination therapy compared to single agent therapy.
In conclusion, this thesis provided new insights into the function of S100A9 and the mode of action of tasquinimod in hematological cancers. Moreover, our findings foster the clinical evaluation of tasquinimod in combination with other compounds such as BCL2 inhibitors for the treatment of AML and MM patients.
Original languageEnglish
Awarding Institution
  • Vrije Universiteit Brussel
Supervisors/Advisors
  • De Veirman, Kim, Supervisor
  • Maes, Ken, Co-Supervisor
  • Breckpot, Karine, Co-Supervisor
Award date20 Oct 2023
Publication statusPublished - 2023

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