Our Research
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-199 (venetoclax). Our studies helped initiate studies of venetoclax in CLL and AML, which have now resulted in multiple FDA approvals. In addition, these successes led to an entirely new class of BH3 mimetic drugs that inhibit BCL-2, BCL-XL, or MCL-1. These are being tested in over 100 clinical trials worldwide in many different kinds of cancer.
Dynamic BH3 profiling (DBP) can rapidly measure if a drug induces apoptotic signaling in a cancer cell. We have shown that this signal can be used to predict in vivo efficacy of a drug. DBP works fast enough that it can be performed on primary cancer tissue within 24 hours, without need for expansion or prolonged ex vivo culture. We are testing how we can introduce DBP into clinical practice to better choose the right drugs for the right patient, in an effort we call functional precision medicine.
Recently we have expanded our efforts to study how immune-oncology agents, such as CAR T cells or checkpoint blockade inhibitors cause death of cancer cells. We are studying how manipulating the apoptotic pathways of cancer cells targeted by immune-oncology agents might increase their efficacy.
Another newer effort is a study of how programmed cell death pathways change during aging, cellular senescence, and chemotherapy induced persistence. Understanding these properties may allow us to selectively target such states, which might be beneficial to reduce aging phenotypes and reduce drug resistance in cancer cells.
Please see our Publications page for details of recent work and selected publications.
Visit our BH3 Profiling page to learn more about how to BH3 profile.
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-199 (venetoclax). Our studies helped initiate studies of venetoclax in CLL and AML, which have now resulted in multiple FDA approvals. In addition, these successes led to an entirely new class of BH3 mimetic drugs that inhibit BCL-2, BCL-XL, or MCL-1. These are being tested in over 100 clinical trials worldwide in many different kinds of cancer.
Dynamic BH3 profiling (DBP) can rapidly measure if a drug induces apoptotic signaling in a cancer cell. We have shown that this signal can be used to predict in vivo efficacy of a drug. DBP works fast enough that it can be performed on primary cancer tissue within 24 hours, without need for expansion or prolonged ex vivo culture. We are testing how we can introduce DBP into clinical practice to better choose the right drugs for the right patient, in an effort we call functional precision medicine.
Recently we have expanded our efforts to study how immune-oncology agents, such as CAR T cells or checkpoint blockade inhibitors cause death of cancer cells. We are studying how manipulating the apoptotic pathways of cancer cells targeted by immune-oncology agents might increase their efficacy.
Another newer effort is a study of how programmed cell death pathways change during aging, cellular senescence, and chemotherapy induced persistence. Understanding these properties may allow us to selectively target such states, which might be beneficial to reduce aging phenotypes and reduce drug resistance in cancer cells.
Please see our Publications page for details of recent work and selected publications.
Visit our BH3 Profiling page to learn more about how to BH3 profile.