ABSTRACT
Immune checkpoint inhibitors are emerging as a therapeutic approach for patients with advanced or metastatic gastrointestinal malignancies following the recent Food and Drug Administration and Asian approvals for colorectal, gastric, and hepatocellular carcinoma. As discussed in earlier articles, phase I-II trials demonstrate quite positive clinical activity, particularly in patients with immunogenic cancer subtypes. This outreach paper discusses some of the next innovative immunotherapy strategies under development. Here, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells are increasingly coming into focus as new targets. Besides the well described use of checkpoint inhibitors, blockade of 'Wnt' or Csf1R signaling pathways as well as combinatorial treatment strategies offer promising examples for overcoming immune silencing within the resistant tumor microenvironment.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Carcinoma/therapy , Gastrointestinal Neoplasms/therapy , Immunotherapy/methods , Tumor Microenvironment/immunology , Antineoplastic Agents, Immunological/pharmacology , Carcinoma/immunology , Carcinoma/pathology , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Costimulatory and Inhibitory T-Cell Receptors/antagonists & inhibitors , Costimulatory and Inhibitory T-Cell Receptors/immunology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/immunology , Gastrointestinal Neoplasms/immunology , Gastrointestinal Neoplasms/pathology , Humans , Macrophages/drug effects , Macrophages/immunology , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/immunology , Oncolytic Viruses/immunology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Treatment Outcome , Tumor Microenvironment/drug effectsABSTRACT
3-Indolyl and 3-azaindolyl-4-aryl maleimide derivatives, called moguntinones (MOG), have been selected for their ability to inhibit protein kinases associated with angiogenesis and induce apoptosis. Here, we characterize their mode of action and their potential clinical value in human colorectal cancer in vitro and in vivo. MOG-19 and MOG-13 were characterized in vitro using kinase, viability, and apoptosis assays in different human colon cancer (HT-29, HCT-116, Caco-2, and SW480) and normal colon cell lines (CCD-18Co, FHC, and HCoEpiC) alone or in combination with topoisomerase I inhibitors. Intracellular signaling pathways were analyzed by Western blotting. To determine their potential to inhibit tumor growth in vivo, the human HT-29 tumor xenograft model was used. Moguntinones prominently inhibit several protein kinases associated with tumor growth and metastasis. Specific signaling pathways such as GSK3ß and mTOR downstream targets were inhibited with IC(50) values in the nanomolar range. GSK3ß signaling inhibition was independent of KRAS, BRAF, and PI3KCA mutation status. While moguntinones alone induced apoptosis only in concentrations >10 µmol/L, MOG-19 in combination with topoisomerase I inhibitors induced apoptosis synergistically at lower concentrations. Consistent with in vitro data, MOG-19 significantly reduced tumor volume and weight in combination with a topoisomerase I inhibitor in vivo. Our in vitro and in vivo data present significant proapoptotic, antiangiogenic, and antiproliferative effects of MOG-19 in different human colon cancer cells. Combination with clinically relevant topoisomerase I inhibitors in vitro and xenograft mouse model demonstrate a high potency of moguntinones to complement and improve standard chemotherapy options in human colorectal cancer.