| Colorectal cancer (CRC) the third leading causes of cancer-related death worldwide with an estimated 639,000 deaths each year. In the United States, CRC is the second leading cause of cancer-related death, resulting in approximately 49,920 deaths in 2009. Despite significant advances in research and development in CRC and gastric cancer, the current response rate for 1st line treatment of mCRC remains ~50% and dramatically decreases for 2nd line therapy. In addition, the five-year survival rate for patients diagnosed with mCRC is approximately 10%. While, molecularly targeted therapies have improved treatment outcomes for patients with cancer, these benefits are modest and in only select patient populations. It is clear that the new chemotherapeutic options and novel drug combinations must be developed to provide benefit for the approximately half of patients that fail to response to current chemotherapeutic options that are available. We hypothesize that combining novel agents that target alternative tumor associated pathways will result in additive to synergistic interactions with standard of care chemotherapy, leading to new treatment options for those patients who fail to respond to current therapy.;The following body of work focuses on the integration and evaluation of a dual EGFR/HER2 targeted TKI, lapatinib, and the novel HDACi, vorinostat and LBH589, into CRC cancer combination chemotherapies utilizing in vitro and in vivo models. The HER receptor family plays an important role in driving the growth and progression of many types of solid tumors. In this body of work, it is demonstrated that the dual EGFR/HER2 TKI, lapatinib, enhances the antitumor activity of two anticancer agents with markedly differing mechanisms of action. Lapatinib in combination with the DNA-damaging agent irinotecan or in combination with the HDACi LBH589 resulted in synergistic increases in tumor growth inhibition both in vitro and in vivo models.;The HDACi's are emerging as a highly useful class of anticancer agents that inhibit HDAC enzymes that are involved in the deacetylation of histone and non-histone cellular proteins. The pan-HDACi's vorinostat and panobinostat (LBH589), achieve potent inhibition of all HDAC enzymes implicated in cancer and have demonstrated potent antitumor activity in preclinical models and promising clinical efficacy in cancer patients. In this study, we focused on the effect of these HDACi on global transcription profiles in CRC models and evaluated the effect of panobinostat on the HER family members expression and signaling in CRC, as well as further evaluated the antitumor effects when utilized in combination with lapatinib.;The results from these studies provide valuable information on promising new strategies and warrant further evaluation in the treatment of gastrointestinal cancers. Ongoing clinical investigations with these agents and others currently in development along with the identification of clinically relevant biomarkers that are both prognostic and predictive will provide further advances to improve outcomes in the treatment of gastrointestinal malignancies. |
