CHI3L1-targeted small molecules for glioblastoma

PROJECT SUMMARY/ABSTRACT: Glioblastoma (GBM), the most common malignant primary brain tumor, is the most aggressive diffuse glioma of the astrocytic lineage. Despite recent advances in multimodality therapy for GBM incorporating surgery, radiotherapy, chemotherapy, and supportive care, the overall prognosis remains poor, and long-term survival is rare. Immunotherapy has the potential to harness the immune system to kill brain tumor cells; however, the outcome of ongoing clinical trials with immunotherapies for GBM has been unsatisfactory. The highly immunosuppressive nature of GBM represents a key resistance mechanism to immunotherapy as glioma cells escape effective antitumor immunity by programming the tumor microenvironment (TME). The inability of immune-based therapies to cross the blood-brain barrier (BBB) represents another roadblock to the success of immunotherapy in the treatment of GBM. Therefore, there is an unmet need for the development of immunomodulators of the GBM TME that can cross the BBB. Chitinase-3 like-protein-1 (CHI3L1) is a key mediator of an immunosuppressive GBM microenvironment by reprogramming tumor-associated macrophages (TAMs). The binding of CHI3L1 to galectin-3 (Gal-3) selectively promotes TAM migration and infiltration with a protumor M2-like, but not an antitumor M1-like, phenotype in vitro and in vivo. Silencing CHI3L1 in syngeneic GBM mouse models results in increased tumor-infiltrating lymphocytes (TILs), tumor size reduction, and improved animal survival, which is reversed by the overexpression of CHI3L1. However, there are no drug candidates in existence that can block the immunosuppressive function of CHI3L1 in GBM. We aim to establish a new immunotherapeutic strategy for GBM based on targeting CHI3L1/Gal-3 interaction with small molecules, which may synergize with immune checkpoint inhibitors to effectively promote tumor regression for GBM patients. We hypothesize that small molecule-based blockade of CHI3L1/Gal-3 will reverse immune suppression and attenuate tumor progression in preclinical models of GBM. Our hybrid expertise in the development of small molecule immunomodulators, hit-to-lead optimization, translational drug discovery research, and immunopharmacology uniquely positions us to achieve this goal. We propose to perform optimization studies of a small molecule inhibitor of CHI3L1/Gal-3 interaction to develop optimized leads with single-digit nanomolar potency in cell-based assays (Aim 1). Subsequently, we will perform in vitro and in vivo pharmacokinetic (PK) evaluation of the optimized leads in order to select the top three lead compounds for further assessment of their therapeutic potential using two mouse models of GBM (Aim 2). The proximal expected outcome of this work is the introduction of clinically translatable small molecule inhibitors of CHI3L1/Gal-3 interaction that can be further implemented in combination therapy approaches to overcome the immunosuppressive nature of GBM.