BBS Faculty Member - Anthony Letai

Anthony Letai

Department of Medical Oncology

Dana Farber Cancer Institute
Mayer Building, Room 430
450 Brookline Ave.
Boston, MA 02215
Tel: 617-632-2348
Fax: 617-582-8160
Email: anthony_letai@dfci.harvard.edu
Lab Members: 5 postdoctoral fellows, 2 technicians, 1 graduate student
Visit my lab page here.



My laboratory investigates how cells make the decision to commit to programmed cell death. The BCL-2 family of proteins contains both pro-and anti-apoptotic members which interact to determine cell fate. We would like to understand in detail why different cells make different life/death decisions when confronted with the same initial perturbation. We are examining this question using protein biochemistry and proteomics, mouse modeling, cell biology and molecular biology.

Specific areas of study include:
1) We are studying ways to identify systematically how insults like chemotherapy and growth factor withdrawal are communicated to the intrinsic (or mitochondrial) pathway of programmed cell death.

2) It is a well-known biological phenomenon that some cells seem readier to die than others. Can we define the biochemical basis for this predilection to die? Our recent work shows that “priming” of anti-apoptotic BCL-2 family members with certain pro-apoptotic members is responsible for certain cells being “primed” for death. We continue to study how broadly this can be applied in normal and cancer cells.

3) In general, it is poorly understood why some cells die when exposed to chemotherapy and others do not. We are investigating how the pretreatment apoptotic apparatus can govern chemosensitivity. Our ultimate goal is to apply these studies to primary cancer cells and predict chemosensitivity in the clinical setting. Key to these studies is a tool we have developed called “BH3 profiling”. We have converted BH3 profiling recently to a FACS-based assay so that we can now study complex samples like biopsy tissues. We are also investigating the role fof a differential apoptotic preset in physiologic settings like immune cell maturation.

4) Cancer cells violate many rules of normal cellular behavior, and thus often must endure tonic death signaling. Are cancer cells, but not normal cells, primed for death? Can we target this priming as a cancer selective targeted therapy?

5) Small molecule antagonists of anti-apoptotic BCL-2 proteins are in pre-clinical and clinical development. We have been studying these compounds to evaluate mechanism of action, and to determine predictors of cellular sensitivity. We have developed several assays which can accurately predict sensitivity to this class of compound. We are testing these in cell lines and primary human malignancies.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Ryan JA, Brunelle JK, Letai A. 2010. Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes. Proceedings of the National Academy of Science (USA), 107:12895-900. (PMCID: PMC2919900)

Brunelle JK, Ryan JA, Yeceis D, Opferman J, Letai A. 2009. MCL-1 dependent leukemia cells are more sensitive to chemotherapy than BCL-2 dependent counterparts. J Cell Biol 187:429-42.

Letai A. 2008. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nature Reviews Cancer, 8: 121-132.

Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A. 2007. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell, 12: 171-185.



© 2014 by the President and Fellows of Harvard College