Cycloxygenase's role in radiation and chemo-resistance
Research in my laboratory is focused on developing the molecular basis of combinatorial therapeutic strategies involving radiation, chemotherapeutic agents and small molecule inhibitors. We have initiated two programs that address tumor resistance to radiation and/or chemotherapy: (1) Pre-clinical evaluation of chemotherapeutic agents and small molecule inhibitors as potential radio-sensitizers (2) Basic research program to analyze the effect of small molecule inhibitors on Cycloocygenase-2 (COX-2) expression induced by radiation and chemotherapeutic agents in lung carcinoma cells.
We are currently investigating two lead chemotherapeutic agents, oxaliplatin and docetaxel in combination with radiation. Our objective is to evaluate the potential of oxaliplatin as a radiation sensitizer and determine the appropriate dose and schedule of oxaliplatin when applied during and/or following a course of docetaxel and radiation therapy in pre-clinical human lung carcinoma model. We are also investigating the effect of several small molecule inhibitors (Terceva, Iressa, Flavopiridol, BMS387032) as potential radio-sensitizers and their effect on COX-2 expression.
An increase in COX-2 expression is associated with tumor progression and plays a critical role in the acquisition of an invasive and metastatic phenotype that may leads to the resistance to radiation and chemotherapy. Ionizing radiation and chemotherapeutic agents including docetaxel have been shown to induce COX-2 expression in lung carcinoma cells. In our current study we are using a novel class of compounds known as cyclin dependent kinase inhibitors (cdk-I) to arrest the signaling pathways that induce COX-2 gene expression in response to (i) radiation, (ii) chemotherapy and (iii) cytokines. A primary objective of this investigation is to elucidate the role of Cdk2 in the transcriptional activation of COX-2 gene expression.
A second component of this study will analyze cellular and tissue proteomic patterns in response to the combined treatment of chemo-radiation and cdk-inhibitors. Comparison of the proteomic profiles between the different treatments may identify a novel characteristic proteomic pattern especially in the radio-and chemo-resistant samples. These proteomic patterns are of special interest to differentiate the drug and/or radiation induced markers.