The experiments described in this proposal have been designed to provide greater understanding of the farnesyl transferase inhibitor (FTI) class of anti-cancer drugs. FTIs are currently being tested in clinical trials against a variety of cancers and the preclinical studies described here will help determine if these drugs should be tested in additional diseases. Initial studies have shown that FTIs can cause regression of tumors in a transgenic mouse model of Burkitt lymphoma (BL). This proposal aims to provide further evidence to support the testing of FTIs in BL patients by combining treatment of an FTI with components of the existing chemotherapeutic regimen used for BL. These studies will be performed using BL cells in culture and in mice transplanted with transgenic BL tumors. Additional experiments will identify the mechanism of cell death activated by FTIs in human BL tumor cells in order to further understand the mechanism of action of these drugs. The second major objective of this proposal is to determine how FTI treatment can affect the immune response involved in transplant rejection. My preliminary results show that this anti-cancer drug may have an unanticipated therapeutic application as an anti-rejection drug. This could be an improvement over current therapies that rely on immune suppression because FTI treatment does not appear to affect normal immune responses. These studies attempt to determine the cellular and molecular mechanisms blocked by FTIs during immune rejection. The results of this work should increase our understanding of this class of drugs and may extend their usefulness in the clinic as both anti-cancer and anti-rejection drugs. Patients who have received bone marrow or other transplants as an adjunct to cancer therapy may especially benefit from this application of FTIs.
This project will use preclinical mouse models to test two novel applications of the farnesyl transferase inhibitor class of anti-cancer drugs. The ability of farnesyl transferase inhibitors to improve on existing therapies in Burkitt lymphoma will be examined. Farnesyl transferase inhibitors will also be tested as anti-rejection drugs that may prevent rejection of transplanted organs by the immune system.