The Spindle Checkpoint as a Target for Cancer
The spindle checkpoint is a signaling pathway that normally promotes the proper segregation of chromosomes in M phase. If in mitosis the chromosomes are not properly aligned on the mitotic spindle, the spindle checkpoint halts cell cycle progression prior to the metaphase-to-anaphase transition. This delay allows more time for chromosomes to attach the mtitotic spindle microtubules and move to their proper positions at the midplane of the cell. Individual cells can be artificially forced to override the spindle checkpoint by the injection of antibodies to proteins of the spindle checkpoint or by transfection of cDNA's encoding mutant, dominant-negative spindle checkpoint proteins. These interventions induce massive imbalances in chromosome segregation that can be directly lethal or cause apoptosis. Tumor cells often exhibit defective checkpoint responses compared to normal somatic cells. The relative weakness of tumor cells to induce cell cycle checkpoints in response to damage may be one mechanism by which anti-cancer therapies show some selectivity for tumors. Drugs that specifically target cell cycle checkpoints may be useful in further sensitizing tumor cell population to therapy. There are currently no cell permeable drugs that can inactivate the spindle checkpoint. The project proposed here is to develop and institute a high throughput screen for drugs that can penetrate cell membranes and inactivate the spindle checkpoint. Several of the protein components of the spindle checkpoint pathway have no other functions. Thus it is reasonable that specific small molecule inhibitors of this pathway can be found. Once effective drugs have been identified, the specific proteins of the spindle checkpoint pathway that are targeted will be determined. It is anticipated that these drugs will be clinically useful for anti-cancer therapy, particularly when used in combination with chemotherapeutic anti-microtubule drugs such as the vinca alkaloids and the taxanes which are themselves potent inducers of the spindle checkpoint.