632PPatient-derived xenografts (PDX) identify JMJD6 inhibitor as an effective therapeutic medicine in colorectal cancer

Abstract Background The Jmjc-domain-containing protein 6 (JMJD6) is a member of JmjC oxygenases that contain both arginine demethylase and lysine hydroxylase activities. Overexpression of JMJD6 has been reported to be associated with the development of various types of cancers, such as breast, lung, liver, and colon cancer. The present study aimed to explore the inhibitory effect of the small-molecule JMJD6 inhibitor named WL8 obtained by virtual screening on the progression of colorectal cancer. Methods WL8 was administered to a mouse bearing xenografts of human colorectal cancer tissue, once every 7 days for 3 times. We analyzed the response of tumors from three patients to the JMJD6 inhibitor (11.5mg/kg, intrapertoneally, i.p.), and to FOLFOX (oxaliplatin 12mg/kg, calcium levifolinate 30mg/kg, 5-fluorouracil 55mg/kg, i.p.) or FOLFIRI (irinotecan 40mg/kg, calcium levifolinate 30mg/kg, 5-fluorouracil 55mg/kg, i.p.), as well as to combined usage of JMJD6 inhibitor and FOLFOX or FOLFIRI in PDX models by recording the tumors sizes every 3 or 4 days for 7 times. The differences between groups were analyzed using one-way ANOVA. (i.p. stands for intraperitoneal.). Results Compared with FOLFOX or FOLFIRI, WL8 inhibited tumor growth more effectively in the PDX models of three patients (One patient’s partial results are shown in the table). Combinatorial therapies using both JMJD6 and FOLFOX (or FOLFIRI) could further reduced the tumour size. Table: 632P . Group 8 Days 15 Days 22 Days Control 1.8075±0.3950 $^@ 2.5706±0.2900 #%$^@ 2.6834±0.0416 #%$^@ FOLFOX 1.4184±0.2067 1.3639±0.2381 *@ 1.3867±0.4155 *^@ FOLFIRI 1.4712±0.1568 1.3894±0.4543 *@ 1.7474±0.0705 *$^@ WL8 0.9656±0.4456 * 1.1069±0.4376 * 1.1655±0.2884 *%^@ WL8+ FOLFOX 0.7125±0.0410 *#% 0.7767±0.4359 * 0.4833±0.0503 *#%$ WL8+ FOLFIRI 1.0325±0.3903* 0.6367±0.1436 *#% 0.3900±0.0265 *#%$ Relative tumor volumn (on days after first administration, notes: P values are indicated with symbols as follows, * P Conclusions We found an small-molecule inhibitor of JMJD6 with impressive therapeutic effects on colorectal cancer in pre-clinical study. Legal entity responsible for the study The First Affiliated Hospital of Xiamen University. Funding National Natural Science Foundation of China, Fujian Provincial Department of Science and Technology, Fujian Provincial Health and Family Planning Commission Foundation of Youth Scientific Research Project, Xiamen Science and Technology Bureau Foundation of Science and Technology Project for the Benefit of the People. Disclosure All authors have declared no conflicts of interest.