A new therapeutic strategy to target liver metastasis in colon cancer

Colon cancer (CC) is one of the leading causes of cancer-related death in the world. Hepatic or liver metastasis (LM) is the primary cause of death in colon cancer patients. Unfortunately, many CC patients develop LM despite surgery with lymph node removal, and many die. Therefore, identifying novel therapeutic approaches is necessary to prevent LM in these patients. COAD (GDC TCGA CRC) and our preliminary data show that VEGF-C/FLT4 (VEGF-C and VEGF-A are different cytokines with distinct functions) axis might be a major driver of LM in many CC patients. As we further showed that dopamine D4 receptors (DRD4) could regulate this axis, we hypothesized that DRD4-mediated therapy alone or in combination with the currently used anti-cancer chemotherapeutic drugs might prevent LM in colon cancer. There are three aims in this proposal. The first aim will determine the therapeutic efficacy of selective DRD4 agonists, either alone or in combination with the anti-cancer drugs, to prevent or significantly lower the incidence of liver metastasis in preclinical animal models simulating human cancer patients. The second aim will elucidate the molecular mechanisms by which DRD4 acts. The third aim will elucidate the molecular mechanisms by which DRD4 inhibits VEGF-C expression in the cells producing VEGF-C in the liver premetastatic niche.