Despite many recent advances in cancer therapy, it is apparent that with the high rate of treatment failures in gastrointestinal cancers new therapeutic approaches are necessary. An understanding of the cell cycle has provided the opportunity for the identification of new therapeutic targets. Cell cycle checkpoints at the G1/S and the G2/M interface are tightly regulated by a broad range of cell cycle proteins called cyclin dependent kinases (CDK's). In the NCI drug screen the drug flavopiridol has been identified that inhibits CDK1, 2, 4, and 6. However, despite promising preclinical activity, phase II single agent trials with flavopiridol in colon and gastric cancers have been disappointing. In view of this, R01 CA67819-04A1 had been devoted to developing a different therapeutic strategy in the development of flavopiridol for the treatment of gastrointestinal cancers. Our laboratory studies have indicated that flavopiridol enhances the induction of apoptosis by chemotherapy, especially paclitaxel, in human gastroesophageal cancer cell lines. This has been translated into a phase I clinical trial of sequential paclitaxel followed by flavopiridol (MSKCC IRB#96-77 and NCI#T96-0091). The clinical results have been remarkable for major responses in patients with chemotherapy refractory malignancies, especially in patients with esophagus cancer who have received prior paclitaxel therapy. Proving that flavopiridol restores the activity of a paclitaxel in patients with paclitaxel-refractory esophageal cancer would have extraordinary clinical implications. This hypothesis will be tested in a phase II trial. Patients with metastatic esophagus cancer who have demonstrated unequivocal disease progression on prior paclitaxel will receive paclitaxel with flavopiridol. In addition, we plan a phase I clinical trial combining flavopiridol with irinotecan (CPT-11). CPT-11 is a major new drug in the treatment of colon cancer. However, response rates with this agent remain quite low. The basis for treatment failure is unknown. Preliminary clinical results from our Center indicate that increased expression of the CDK inhibitor p21 is associated with CPT-11 resistance. Our laboratory data indicates that flavopiridol significantly potentiates the induction of apoptosis by CPT-11 in colon cancer cell lines and this is associated with the suppression of p21 protein. Therefore, in this phase I clinical trial we propose examining the expression of p21 relative to treatment response and determining whether p21 is suppressed with the drug combination. In addition, we will use representational differential analysis (RDA) to identify new biomarkers of response for this drug combination. The long-term goal of this phase I study will be to increase the therapeutic benefit of CPT-11 and to identify those patients who would most benefit from the drug combination.
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