Research in the Letai lab centers on understanding how cells decide to make the commitment to apoptosis. We focus on the role of BCL-2 family proteins, as these proteins play the key roles in deciding whether cells should commit to apoptosis, and in executing the mitochondrial permeabilization that is the required hallmark of mitochondrial apoptosis.An important past and continuing interest is understanding how BH3-only proteins signal death. We proposed the concept that BH3-only proteins can play two different roles: activators, which can directly activate BAX and BAK; and sensitizers, which antagonize antiapoptotic proteins like BCL-2 and MCL-1. We are studying how some cells can be "primed for death" by possessing large amounts of activator BH3-only proteins sequestered by anti-apoptotic proteins. We can detect such cells by means of a technique we developed called BH3 profiling.
Cells that are primed are dependent on at least one antiapoptotic protein for survival. If this protein is removed, or its function antagonized, the cell will die. BH3 profiling can detect primed cells that are dependent on antiapoptotic proteins like BCL-2. This is particularly useful in identifying cells that will be sensitive to BCL-2 antagonist drugs like ABT-737. We study the molecular basis to sensitivity to BCL-2 antagonism, and how this sensitivity can be modulated.
Cancer cells, but not most normal cells, require a block in apoptosis to survive. BH3 profiling can be used to discriminate these blocks into three different classes. It is particularly interesting to us that cells in the class of primed cells appear to be more sensitive to conventional chemotherapy. We are very interested in testing how widely this predictive ability can be applied to cancer cells.
Surprisingly little is known about the details of death signaling due to chemotherapy. We would like to better understand why some cells are killed by certain chemotherapies, but not others. Why are cancer cells generally more sensitive than normal cells to chemotherapy? What are the mechanisms of multi-drug resistance. We are convinced that a better understanding of apoptotic mechanisms will be critical to answering these fundamental but poorly understood questions.
An important aim of this laboratory is to apply what we learn to the improved therapy of human cancers. We collaborate in clinical trials, and put a priority on studying primary human cancer tissues. While our interests thus far have focused on leukemia and lymphoma, it is clear the apoptosis plays an important role in the killing of nearly all cancers. Thus, we look forward to applying our strategies to other cancers, and have begun studies in ovarian, lung, colon and breast cancers.
Please see our Publications page for details of recent work.
