The current 5-year survival rate for patients with metastatic colorectal cancer (CRC) is only about 8%. The vast majority of CRC mortality is due to cancer cell resistance to existing therapeutic agents. Therefore, development of novel agents that can suppress drug-resistant metastatic CRC is in urgent need. We have purified from wild mushroom a compound with potent anti-tumor activity. This compound was identified as Verticillin A. We demonstrated that Verticillin A modifies the BNIP3 promoter chromatin histone structure to over-ride the silencing effect of DNA methylation to activate BNIP3 transcription in metastatic human CRC cells. Interestingly, our preliminary studies revealed that Verticillin A is effective in suppression of drug- resistant CRC stem cell growth. Our long-term objective is to develop Verticillin A as a therapeutic agent for treatment of human patients with metastatic CRC. The objectives of this project are to elucidate the underlying molecular mechanisms of Verticillin A action and to determine whether Verticillin A can effectively suppress MDSC and drug-resistant CRC stem cells in vivo. We propose to pursue the following three aims: 1) determine the network of DNA and H3K9 methylation in the BNIP3 promoter chromatin that mediates BNIP transcriptional repression in human CRC cells;2) test the hypothesis that Verticillin A targets histone methylation to activate BNIP3 transcription and suppress spontaneous metastasis of 5-FU- resistant CRC stem cells in vivo;and 3) test the hypothesis that Verticillin A and 5-FU cooperate to induce MDSC apoptosis and suppress MDSC accumulation. Successful completion of these proposed studies has the potential to develop Verticllin A as an effective drug for treatment of human patients with 5-FU-resistant metastatic colorectal cancer.
On a national basis, the relative five year survival with colorectal cancer was estimated at only approximately 40% among Veterans, substantially lower than the 60% survival rate among the general population. Spreading of the cancer cells to distal organ is the primary cause of death among colorectal cancer patients. According to the American Cancer Society, the 5-year survival rate for colorectal cancer patients is 92% if the cancers have not spread. However, the 5-year survival rate drops to 8% once the cancer has spread to the liver. There is no effective therapy for metastatic colorectal cancer and prospects for cure remain poor. Therefore, development of novel agents that can effectively suppress drug-resistant metastatic colorectal cancer is critical for colorectal cancer management. Our proposed studies will provide the basis for molecular mechanism-based therapy against the deadly metastatic colorectal cancer, which is one of the greatest threats to Veterans'health.
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