reported (https://clinicaltrials.gov/ct2/show/NCT00392080?term=CJ-023%2C423&rank=1) and is currently being tested in the recruitment step for a phase 2 clinical trial to treat prostate, non-small cell lung, and breast cancers (https://clinicaltrials.gov/ct2/show/NCT02538432?term=CJ-023%2C423&rank=2). The EP4 selective antagonist, BGC20-1531, is being tested for its ability to block PGE2-induced headaches in health volunteers to determine if it is a potentially useful candidate for testing its effectiveness on clinical headaches (https://clinicaltrials.gov/ct2/show/NCT00957983?term=EP4&rank=1). Grapiprant, a highly selective and potent EP4 antagonist, is approved by the Food and Drug Administration for use in canine medicine to treat pain caused by inflammation such as that occurring in osteoarthritis; it is currently also under investigation for use in humans. Genomic Studies Single nucleotide polymorphism (SNP) A/G variant rs10440635 close to the PTGER4 gene on human chromosome 5 has been associated with an increased incidence of Ankylosing spondylitis in a population recruited from the United Kingdom, Australia, and Canada. Ankylosing spondylitis is a chronic inflammatory disease involving excessive bone deposition in the Vertebral column and increased expression of EP4 at vertebral column sites of involvement. Thus, excessive EP4 activation may contribute to the pathological bone remodeling and deposition found in ankylosing spondylitis and the rs10440635 variant may predispose to this disease by influencing EP4's production or expression pattern. The GG genotype at -1254G>A in PTGER4 is associated with the non-steroidal anti-inflammatory drug (NSAID)-exacerbated cutaneous disease (NECD). NECD is a non-allergic hypersensitivity reaction involving the acute development of wheals and angioedema in response to NSAID consumption in individuals with a history of chronic urticarial. The G allele at the -1254 position leads to lower PTGER4 gene promoter function, lower levels of EP4, and presumably thereby less of the anti-inflammatory effects of EP4. Several PTGER4 gene variations have been associated with inflammatory bowel disease: a) Meta-analysis of Genome-wide association studies found that SNP variant rs11742570 containing a C/T single-nucleotide variation in PTGER4 is associated with an increased incidence of Crohn's disease; b) rs4495224, an A/C SNP variant, and rs7720838, both of which are projected to be binding sites in PTERG4 for the transcription factor, NF-κB, have been associated with Crohn's disease in three independent cohorts with the association between rs7720838 and Crohn's disease being replicated in other populations; and c) certain alleles in 5p13.1, a Gene desert close to PTGER4, correlate with the expression levels of EP4 as well as with the development of Crohn's disease. The A/T SNP variant, rs4434423, in the 5'-untranslated region of PTGER4