Cell cycle mediated drug resistance is an emerging concept in which intrinsic cell cycle checkpoints that remain functional within the malignant cell are able to induce cell cycle arrest and DNA repair mechanisms in response to DNA damage by cytotoxic therapy. One of the key regulators of cell cycle mediated drug resistance is p53, the DNA binding transcription factor that is activated upon genotoxic stress of various types. The applicant has observed in pre-clinical models and in early phase clinical studies that tumor cells wildtype for p53 (p53wt) are relatively refractory to irinotecan based therapy when compared with tumor cells that have non-functional, mutant p53 (p53mut). Furthermore, they have demonstrated that the sequential administration of irinotecan followed by flavopiridol can overcome this p53 mediated cell cycle drug resistance. Gastric cancer is an aggressive neoplasm associated with an extremely poor prognosis. Median survival for metastatic or unresectable disease is approximately 8 to 10 months. Unfortunately, despite its enormous global impact, little progress has been made in the treatment of this disease. Conventional chemotherapy for metastatic gastric cancer remains palliative, with few patients ever demonstrating long term survival. Irinotecan and irinotecan based combinations are moderately active in the treatment of advanced gastric cancer, with response rates to single agent treatment only 14-20%. A proposed mechanism of resistance to irinotecan based therapy is the induction of cell cycle mediated drug resistance in p53wt tumors. In a random assignment Phase 2 clinical trial, the applicant proposes to demonstrate the presence of cell cycle mediated drug resistance in p53wt gastric cancer, and further to demonstrate that this resistance can be overcome with the sequential administration of flavopiridol following irinotecan. If successful, they will have established an important clinical signal of a new strategy to improve the care of patients with gastric cancer. Furthermore, if successful, this study could represent the first clinical evidence of overcoming cell cycle mediated drug resistance with the appropriate use of a new class of anticancer therapies, cyclin dependent kinase inhibitors (CDKI). As a result, this study may serve as a model for how one can combine CDKIs with cytotoxic treatment in cancer therapeutics that may be applied to other solid tumor malignancies.
The relevance of this grant proposal is to provide clinical evidence of a new concept on how a cancer cell may develop resistance to chemotherapy, and how we may overcome this resistance by a new class of chemotherapy drugs. The proposal introduces the concept of resistance to chemotherapy due to innate and intact mechanisms the cell has of identifying damage to its DNA, and how the cell may stop the process of DNA replication so as to provide a way for it to repair this DNA damage that was caused by chemotherapy. We defined this new mechanism of resistance to chemotherapy cell cycle mediated drug resistance. We demonstrate that this type of resistance to irinotecan chemotherapy is a function of having a normal protein, p53. We show molecular mechanisms for why this protein is central to the concept of cell cycle mediated drug resistance to irinotecan. Finally, we demonstrate how flavopiridol as a representative of a novel class of drugs called cyclin dependent kinase inhibitors (CDKIs) can overcome p53 dependent resistance to irinotecan. Stomach cancer is a common disease worldwide, but is an orphan disease within the United States. As a result, drug development in this disease has lagged. The protein, p53, is commonly expressed at normal levels in stomach cancer, and this may be why irinotecan has only marginal activity in this disease. We propose a random assignment phase II study of irinotecan versus irinotecan and flavopiridol in patients with p53 wild type stomach cancer. If successful, this project will have a major impact on our treatment and survival of gastric cancer. It will serve as a model for how to combine this new class of agents, CDKIs, in other tumor types and with other conventional chemotherapy drugs.
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