Orphan Nuclear Receptor as Novel Drug Discovery Target for Cancer Immunotherapy

DESCRIPTION provided by applicant The immune system is activated by expression of novel antigens on the surface of cancer cells leading to the elimination of tumor cells by a process referred to as immune surveillance Over time additional genetic changes allow selected cells to circumvent the immune response and develop into a fully cancerous state This escape from immune surveillance is now considered a principle hallmark of cancer Recently antibodies that block the T cell inhibitory receptors CTLA and PD have been shown to boost anti tumor immunity improving survival in some cancer patients Response rates to these extraordinary therapies are low however and serious immune related side effects can complicate treatment The goal of this Phase I SBIR proposal is to identify small molecule antagonist ligands to a transcription factor an orphan nuclear receptor that normally suppresses production of cytokines such as IL and IL in effector T cells Accordingly T cells from mice deficient in this receptor are hyper responsive to stimulation and the knockout mouse is unusually susceptible to induction of autoimmune disease Importantly these mice also exhibit powerful anti tumor effects To date no valid ligands have been described for this target However structural analysis and biochemical characterization at Orphagen indicates that the target is likely to function like other members of the nuclear receptor family where binding of a small molecule ligand to a conserved pocket regulates the affinity for transcriptional coregulators on the receptor surface through allosteric modulation Next we developed a high throughput screening HTS assay for this receptor based on its interaction with a transcriptional coregulator An antagonist to this receptor which releases the coregulator is predicted to overcome its trans repressive effect lowering the threshold for T cell activation and enhancing immune activation Thus our long term objectives are to identify small molecules that reverse transcriptional suppression by this target and explore whether these molecules can stimulate T cell activation and improve tumor immunity In Specific Aim we will screen diverse compound libraries using the HTS assay to identify small molecule ligands that disrupt the interaction between the orphan receptor and a peptide derived from its coregulator at a biochemical level We will then determine in Specific Aim whether the ligands identified in Specific Aim also activate gene transcription from the target receptor in a cellular assay We also propose to increase ligand affinity IC andlt M by purchase of analogues to initial hits Finally in Specific Aim we will test the ability of the identified ligands to activate IL and IL production in effector T cells cultured in vitro This pharmacological evaluation will enable more intensive drug discovery with SBIR Phase II support leading to testing of lead compounds in animal models cancer immunotherapy PUBLIC HEALTH RELEVANCE Despite a steady decline in cancer mortality over the past two decades more than half a million Americans will die of cancer in Existing therapies are often poorly tolerated and inadequate for most patients New andquot cancer immunotherapies andquot developed to mobilize the immune system against tumors have produced striking results in metastatic melanoma lung and renal cancer We propose here to identify small molecule ligands to a previously unexplored drug target that normally suppresses the immune response Our goal is to find drug like molecules that will reverse this suppression creating a powerful and potentially safer therapeutic tool to enhance clinical cancer immunotherapy and improve patient survival