Biomarker Leads to New Potential CRC Treatment

A. Alicia Koblansky, PhD

Deficiency in the protein NOD-like receptor X1 (NLRX1) could represent a potential biomarker to predict response to therapies in patients with colorectal cancer (CRC), according to a study published in Cell Reports.

According to the study, which was conducted by researchers at the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center using mice models, significantly low levels of NLRX1 may predict a CRC diagnosis, as key cancer-promoting pathways are increased in the absence of NLRX1, including nuclear factor κB (NF-κB), MAPK, STAT3, and interleukin-6 (IL-6).

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

“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 lead study author A. Alicia Koblansky, PhD, postdoctoral research fellow, UNC Lineberger Comprehensive Cancer Center. “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.”

Earlier research has indicated that NLRX1 does not correlate to the carcinogenesis of CRC. Additionally, prior clinical trials investigated 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 preclinical models, without inducing a low state of NLRX1.

Overall, a lack of NLRX1 resulted in greater production of IL-6 and activation of STAT3, both of which are known to be cancer-promoting pathways. The loss of NLRX1 also creates a microenvironment that potentiates the development of tumors in both colitis-associated and sporadic CRC models, the authors stated.

In order to monitor this, researchers then implanted CRC tumors in preclinical models with mutations in the APC gene and subsequently deleted NLRX1, a receptor found in approximately 80% of human CRC tumors.

“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.”

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The findings show that an IL-6targeted treatment currently approved for arthritis may be effective as a therapy for patients with CRC. The treatment blocks a pathway usually downregulated by NLRX1.

Additionally, a possible impact of these findings is that NLRX1 affects tumor-promoting signals via changes in the microbiome, which would be an important future investigation, the authors state.

Elevated NF-kB signaling can de-differentiate intestinal epithelial cells that eventually acquire stem-like properties and tumor-initiating capacity, the authors stated. NF-kB also facilitates Wnt-driven proliferation of intestinal stem cell. MAPK regulates intestinal cell proliferation and epithelial differentiation and promotes progression and oncogenesis of human CRC, while NF-kB and STAT3 regulate several target genes regulating cell cycle and proliferation. This work shows that NLRX1 serves as a checkpoint of these multiple critical cancer-promoting pathways to maintain a homeostatic, noncancerous state, the authors added.

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

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 Rep. 2015;14: 2562-2572.