Clinical translation for improved prognosis, prediction and restriction of tumor progression and metastasis
We demonstrated MACC1 as metastasis inducer, prognostic biomarker for CRC and as a target for metastasis inhibition. MACC1 outperforms KRAS, BRAF, and MMR mutation status, but improves prognosis in combination with KRAS13 mutation. We showed highest prognostic value of MACC1 at the CRC tumor invasion front (V. Kölzer, Uni Bern). We established a novel, non-invasive liquid biopsy test demonstrating the prognostic value of circulating MACC1 transcripts in patient blood in prospective studies. We identified novel MACC1-regulated genes, demonstrated their metastasis-inducing potential in mice and their prognostic value for CRC patient survival. We confirmed MACC1 as prognostic biomarker and driver for progression and metastasis in tumors and blood from hepatobiliary, gastric, pancreatic, breast cancer and glioblastoma patients (A. Lederer, C. Denkert, K. Detjen, all Charité, C. Hagemann, Uni Würzburg). We recently completed a clinical study demonstrating MACC1 as predictive marker for patient stratification for adjuvant treatments in CRC stage II (in cooperation with Hoffmann La Roche Pleasanton CA and Ventana Tucson AZ).
We showed the importance of S100A4 for CRC in the context of its receptor RAGE. RAGE itself and combined with S100A4 serves as prognostic biomarker for metastasis and patient survival.
Therapeutic translation is done in prospective clinical phase II trials treating CRC patients for metastasis growth inhibition with the FDA-approved small molecules niclosamide which we identified via HTS as transcriptional S100A4 inhibitor (S. Burock, Charité Comprehensive Cancer Center). Therapeutic outcome is monitored by imaging (CT, MRT) paralleled by determination of circulating S100A4 transcripts in patient blood.