New Biomarker Opens Doors for Novel Treatments in CRC

Cell Reportsby researchers at the UNC Lineberger Comprehensive Cancer Center.

According to the study, which was conducted using mice models, significantly low levels of NLRX1 may portend a diagnosis of CRC, since key cancer-promoting pathways are increased in the absence of NLRX1, including nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and interleukin 6 (IL-6).

These findings suggest that STAT3 and IL-6 inhibitors could prove useful in patients with low expression of NLRX1; however, further testing still needs to be performed on samples of human tissue.

“What we’re proposing is, if you can profile people with low NLRX1 in their colorectal cancer, you could consider using this therapy that we identified,” said senior author Jenny P. Ting, PhD, William R. Kenan Jr. Professor of Microbiology and Immunology, UNC School of Medicine, in a press release. “We have identified a critical biomarker for this disease."

Previous research has indicated that NLRX1 does not correlate to the carcinogenesis of CRC. Prior trials employed either single-agent azoxymethane, or a combination of azoxymethane and dextran sodium sulfate over the course of 3 days, to induce NLRX1 low expression tumorigenesis without success. In the current findings, researchers directly monitored the levels of NLRX1 in mouse models, without inducing an NLRX1-low state.

Overall, a lack of NLRX1 resulted in IL-6 being produced in far greater quantities and STAT3 becoming activated, both of which are known to be cancer-promoting pathways. In order to monitor this, researchers then implanted CRC tumors in mice models with mutations in the APC (Adenomatous polyposis coli) gene and subsequently deleted NLRX1, a receptor found in roughly 80% of human CRC tumors.

“This report finds that the presence of NLRX1 limits activation of key signaling pathways leading to NF-κB, MAPK, IL-6, and STAT3 activation, which promote various aspects of tumor development,” said A. Alicia Koblansky, PhD, postdoctoral research fellow, UNC Lineberger, and lead author in the study. “The loss of NLRX1 creates a microenvironment that potentiates the development of tumors in both colitis-associated and sporadic models of CRC. A possible impact is that NLRX1 affects tumor-promoting signals via changes in the microbiome, which would be an important future investigation.”

According to the findings, an IL-6-targeted treatment currently approved for arthritis may be effective as a therapy for patients with CRC. The treatment blocks a pathway usually down regulated by NLRX1.

“We’re arguing that clinicians could analyze NLRX1 expression, and provide them with a more targeted treatment based on that finding,” Koblansky said. “We want to help clinicians to drive precision medicine for patients as much as possible.”

References

1. Koblansky A, Truax A, Liu R et al. The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals.Cell Reports. 2016. doi:10.1016/j.celrep.2016.02.064.