Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial.

BACKGROUND: To assess the predictive value of early metabolic response (ΔSUV) after short-term treatment with first-line cetuximab in patients (pts) with RAS-wt metastatic colorectal cancer (mCRC). METHODS: In this prospective phase II study, RAS-wt mCRC pts received a single-agent cetuximab run-in therapy of 2 weeks. ΔSUV was assessed with FDG-PET/CT on days 0 and 14. Early clinical response (ECR) was evaluated with CT on day 56 after treatment with FOLFIRI-cetuximab. Primary endpoint was the predictive significance of ΔSUV for ECR. Secondary endpoints were PFS (progression free survival), OS and the influence of ΔSUV on survival. RESULTS: Forty pts were enroled and 33 pts were evaluable for the primary endpoint. The CT response rate was 57.6%. For responders, ΔSUV was significantly higher (p = 0.0092). A significant association of ΔSUV with ECR was found (p = 0.02). Median PFS was 11.7 months and median OS was 33.5 months with a 1-year survival rate of 87.9%. ΔSUV was found to significantly impact the hazard for OS (p = 0.045). CONCLUSIONS: We demonstrate that cetuximab induces metabolic responses in mCRC pts. The study endpoint was met with the ΔSUV discriminating between responders and non-responders. However, these data should be validated in larger patient cohorts.

The transcription factor c-Jun protects against liver damage following activated ß-Catenin signaling.

BACKGROUND: The Wnt/ß-Catenin signaling pathway is central for liver functions and frequently deregulated in hepatocellular carcinoma (HCC). Analysis of the early phenotypes and molecular events following ß-Catenin activation is therefore essential for better understanding HCC pathogenesis. The AP-1 transcription factor c-Jun is a putative ß-Catenin target gene and promotes hepatocyte survival, proliferation, and liver tumorigenesis, suggesting that c-Jun may be a key target of ß-Catenin signaling in the liver. METHODOLOGY/PRINCIPAL FINDINGS: To address this issue, the immediate hepatic phenotypes following deletion of the tumor suppressor Apc and subsequent ß-Catenin activation were analyzed in mice. The contribution of c-Jun to these phenotypes was dissected in double mutant animals lacking both, Apc and c-Jun. ß-Catenin was rapidly activated in virtually all Apc mutant hepatocytes while c-Jun was induced only after several days, suggesting that its expression was rather a secondary event following Apc deletion in the liver. Loss of Apc resulted in increased hepatocyte proliferation, hepatomegaly, deregulated protein metabolism, and premature death. Interestingly, additional deletion of c-Jun did not affect hepatocyte proliferation but resulted in increased liver damage and mortality. This phenotype correlated with impaired expression of hepatoprotective genes such as Birc5, Egfr Igf1 and subsequently deregulated Akt signaling. CONCLUSIONS/SIGNIFICANCE: These data indicate that c-Jun is not a primary target of ß-Catenin signaling in the liver, but rather protects against liver damage, which in turn may promote liver tumorigenesis.