Investigating the role of STAT3 in macrophage driven therapy resistance in Acute Myeloid Leukaemia and Multiple Myeloma

Acute Myeloid Leukaemia (AML) and Multiple Myeloma (MM) cell lines and primary cells exhibit constitutive STAT3 activation as evidenced by an increase in phosphorylated STAT3 protein levels, which correlates with poor clinical parameters in MM patients. Furthermore, macrophages (a type of immune cell) when cultured with AML and MM cells upregulate the expression and activation of STAT3, and this correlates with the ability of macrophages to shield AML and MM cells from the killing effects of anti-cancer drugs. In Murine models of Acute Myeloid Leukemia (AML) and Lymphoma, Bai et al., 2019 demonstrated preclinical efficacy of the STAT3 PROteolysis TArgeting Chimera (PROTAC), and thus provided a rationale for potential clinical use of this degrader. However, the therapeutic potential of SD-36 to overcome macrophage driven cancer drug resistance has yet to be investigated. Consequently, there is a crucial need to investigate selective and efficacious STAT3 degraders in AML and MM. The proposed project will capitalize on a novel selective STAT3 PROTAC/degrader SD-36, synthesized and provided to us by Prof Shaomeng Wang (Director of the Michigan Center for Therapeutic Innovation, University of Michigan). SD-36 exhibits selectivity for STAT3 over closely related STAT proteins. Furthermore, SD-36 has additional advantages over conventional small-molecular inhibitors (SMIs) of STAT3, in which degradation of STAT3 by SD-36 will block all the known functions associated with this protein, which cannot be currently achieved with traditional STAT3 inhibitors. Thus, SD-36 possesses properties consistent with a highly selective and effective compound, favouring potential future clinical applicability.