NR4A1 Antagonists Inhibit Colorectal Cancer Growth and Enhance Immune Surveillance
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abstract
In 2021, it is estimated that there will be 149,480 new cases of colon cancer diagnosed in the United States and 52,980 CRC patients will die from this disease in which the incidence and death are only slightly lower in women compared to men. Early diagnosis and improved treatments have decreased the incidence of CRC in the United States; however, global rates of this disease are increasing, particularly in developing countries. Individuals with a family history of colon cancer or inherited genetic mutations have a high risk for developing CRC, however, it is estimated that 60-65% of all cases are “sporadic” with no inherited or genetic risk factors in their background. Some of the risk factors for the sporadic CRCs are shared by many other cancers and this includes age but also other preventable factors such as obesity, sedentary lifestyle, smoking, low fiber/high fat diets, alcohol consumption and high intakes of red meat. Another sub-class of CRC patients are young adults and the incidence of disease among this group has been increasing particularly in high income developed countries. Surgery is a major first option for many colon cancer patients and this can also be accompanied or preceded by radiation and neoadjuvant therapy. High risk patients with stage III and IV colon cancer are treated with various drug combinations including fluorouracil, leucovorin, folinic acid, oxaliplatin and capecitabine which inhibit the risk of disease recurrence. In addition to cytotoxic drug therapies more precision medicine approaches that target specific genes such as EGFR and pathways (angiogenesis) are being developed along with immunotherapies. The proposed research will focus on potential mechanisms and clinical applications of bis-indole derived (CDIMs) agents that bind the orphan nuclear receptor 4A1 (NR4A1, Nur77). NR4A1 is overexpressed in colon cancer patients and regulates expression not only of pro-oncogenic genes and pathways but also PD-L1 and genes associated with T-cell exhaustion that can be identified in tumor infiltrating lymphocytes. Preliminary studies confirm that CDIM/NR4A1 antagonists exhibit both chemotherapeutic activity but also downregulate PD-L1 and reverse T-cell exhaustion and proposed studies in Aim 1 will determine the underlying mechanisms using in vitro cell culture and syngeneic mouse models (Aim 1). In Aim 2 the chemotherapeutic and immunologic effects of CDIM/NR4A1 antagonists will be investigated in an inducible APC knockout mouse model and in mice crossed with whole body and intestinal specific NR4A1 deletion. These studies, coupled with histological analysis of cycling stem cells and single cell analysis of the tumor microenvironment and immune system will confirm the role of NR4A1 as an important emerging drug target for both colon cancer chemo- and immune therapies.
