Abstract 1317
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<0.05 v.s. ctrl; # P<0.05 v.s. FOLFOX; % P<0.05 v.s. FOFIRI; $ P<0.05 v.s. WL8; ^ P<0.05 v.s. WL8+FOLFOX; @ P<0.05 v.s. WL8+FOLFIRI)
Conclusions
We found an small-molecule inhibitor of JMJD6 with impressive therapeutic effects on colorectal cancer in pre-clinical study.
Clinical trial identification
Editorial acknowledgement
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.
Resources from the same session
3266 - Morphology of tumor-associated macrophages dictates the prognosis of patients with colorectal liver metastases.
Presenter: Matteo Donadon
Session: Poster Display session 2
Resources:
Abstract
1694 - Pembrolizumab (pembro) Plus mFOLFOX or FOLFIRI in Patients With Metastatic Colorectal Cancer (mCRC): KEYNOTE-651 Cohorts B and D
Presenter: Richard Kim
Session: Poster Display session 2
Resources:
Abstract
908 - Romidepsin (FK228) Regulates the Expression of the Immune Checkpoint Ligand PD-L1 and Exerts Synergistic Anti-Tumor Activity with an Anti-PD-1 Antibody in Colon Cancer
Presenter: Hui Li
Session: Poster Display session 2
Resources:
Abstract
3127 - Prognostic significance of circulating regulatory T lymphocytes (Tregs) in patients with metastatic colorectal cancer (mCRC) under treatment with first line chemotherapy.
Presenter: Zafeiris Zafeiriou
Session: Poster Display session 2
Resources:
Abstract
5416 - The SAFFO study: Sex-related prognostic role And cut-oFf deFinition of monocyte-to-lymphocyte ratio (MLR) in metastatic colOrectal cancer
Presenter: Camilla Lisanti
Session: Poster Display session 2
Resources:
Abstract
2518 - SPICE, a phase I study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: analysis of the metastatic colorectal cancer patients in the dose escalation phase
Presenter: Marwan Fakih
Session: Poster Display session 2
Resources:
Abstract
4000 - Phase 1/2 study with CXCL12 inhibitor NOX-A12 and pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer
Presenter: Niels Halama
Session: Poster Display session 2
Resources:
Abstract
2223 - Microsatellite Instability Status in Metastatic Colorectal Cancer and Effect of Immune Checkpoint Inhibitors on Survival in MSI-High Metastatic Colorectal Cancer
Presenter: Wataru Okamoto
Session: Poster Display session 2
Resources:
Abstract
2569 - Phase II trial of Trametinib (T) and Panitumumab (Pmab) in RAS/RAF wild type (wt) metastatic colorectal cancer (mCRC)
Presenter: Kanan Alshammari
Session: Poster Display session 2
Resources:
Abstract
5402 - Microsatellite instability and immunogenicity in colorectal cancer – do resident memory Tcells (Trm) play a role in colorectal cancer
Presenter: Wei Toh
Session: Poster Display session 2
Resources:
Abstract