The main drug for colorectal cancer (CRC) treatment is 5-FU. It inhibits a pivotal enzyme in DNA replication pathway via TS. Thus 5-FU stops cell survival and proliferation. Increases in TS level render the 5-FU treatment ineffective. Development of chemoresistance is a major reason for treatment failure. We have demonstrated that ATO sensitized 5-FU resistant CRC cells by inhibiting TS mRNA expression both in vitro and in clinic. However, the mechanism of TS reduction by ATO is not known. Except for ATO regulating Gli, only correlative evidences are available regarding ATO-TS and Gli-TS interaction. The association among these three moieties has not been experimentally demonstrated. We hypothesize 1. Gli is a transcriptional regulator of TS; 2. ATO inhibits Gli thereby down regulates TS expression. Therefore, we propose to study Gli as a transcriptional regulator of TS and the role ATO plays in reversing 5-FU resistance in CRC. We will achieve these objectives using:
Aim 1 : To investigate the role of the transcription factor Gli in regulatin TS expression and development of 5-FU resistance.
Aim 2 : To understand the role of ATO in regulating TS through the transcription factor Gli. The significance of the study is the opportunit to explain the molecular mechanism of reversal of 5-FU resistance by ATO. The innovation is the use of ATO to inhibit Gli activity thereby TS expression. Relevance to Human Health: Due to poor access to health care, minorities are diagnosed with late stage cancer and reported to have poor quality of life. My research focuses on developing better treatment options that will benefit CRC patients who are diagnosed with late stages of disease as well as those who have exhausted all the existing treatment options.
The proposed study aims to investigate the mechanisms of arsenic trioxide regulating the enzyme thymidylate synthase and the reversal of 5-FU resistance in colorectal cancer patients. The second objective is to develop combination therapies that incorporate our discoveries. This research is relevant to the mission of NIH, because upon successful completion of the study objectives, a new treatment regimen could be made available for about 12,000 - 18,000 end stage colorectal cancer patients who had exhausted all the available standard chemotherapy options.
