Roya Khosravi-Far

Department of Pathology
Beth Israel Deaconess Medical Center
3 Blackfan Circle, CLS 0537
Boston, MA 02215
Tel: (617) 735-2460
Fax: (617) 735-2475
Email: rkhosrav@bidmc.harvard.edu
9 postdoctoral fellows

Normal development of multicellular organisms is controlled by a delicate balance between signals that regulate cell proliferation, differentiation and programmed cell death. Dysregulation of any of these cellular processes leads to a variety of human diseases, including cancer. A major interest of our laboratory is elucidating the mechanisms by which oncogenes promote evasion of tumor cells from apoptosis. In addition, we are investigating the signal transduction pathways that regulate cell fate, in particular ones that are involved in mediating apoptosis by members of the TNF family of ligands. Some of our current projects are described briefly:

1) A crucial aspect of tumorigenesis is the evasion of apoptosis. An understanding of how oncogenes cause resistance to apoptosis will help in the design of more suitable anti-cancer therapies, yet the mechanisms by which some of the most prominent oncogenes, such as BCR-ABL, enable protection from apoptosis are far from clear. Recently, we have observed that Bcr-Abl induces evasion of transformed cells from apoptosis by downregulating the transcription of many proapoptotic factors. We have also elucidated a key role of the Forkhead family of transcription factors/tumor suppressors in Bcr-Abl-induced evasion of apoptosis. We are currently investigating the mechanisms by which Forkhead tumor suppressors are regulated. This will allow us to identify and characterize therapeutic targets. We are also using molecular modeling and chemical library screening to target Forkhead proteins.

2) The proteasomal degradation pathway is involved in the regulation of variety of cellular functions, including apoptosis. Several downstream mediators of Bcr-Abl-induced leukemia, including the Forkhead family of transcription factors, are regulated by the proteasomal degradation pathway. In a Bcr-Abl-induced leukemia mouse model (generated by a bone marrow transduction and transplantation strategy), we have demonstrated that inhibition of the proteasomal degradation pathway results in regression of leukemia. Additionally, in patient studies, we have found complete molecular regression in a Bcr-Abl-positive leukemia patient. We are currently investigating the utility and efficacy of targeting the proteasomal degradation pathway in cancer therapy. Furthermore, we are investigating whether the inhibitors of the proteasome degradation pathway act on cancer stem cells to effect a long-lasting remission.

3) The recent finding that the TNF-related apoptosis inducing ligand, TRAIL, selectively induces apoptosis of transformed cells in vitro, has provided hope for the use of TRAIL as a cancer therapeutic. However, the signaling events that mediate the biological effects of TRAIL and its receptors are not well characterized. Recently, we have identified several proteins that interact specifically with TRAIL receptors. We are currently investigating the mechanism of function of these proteins as well as other death receptor-interacting molecules.

References:

• Ndebele K, Gona P, Jin TG, Benhaga N, Chalah A, Degli-Esposti M, Khosravi-Far R. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced mitochondrial pathway to apoptosis and caspase activation is potentiated by phospholipid scramblase-3. Apoptosis. 2008 Jul;13(7):845-56.
• Degli Esposti M, Tour J, Ouasti S, Ivanova S, Matarrese P, Malorni W, Khosravi-Far R. Fas death receptor enhances endocytic membrane traffic converging into the Golgi region. Mol Biol Cell. 2009 Jan;20(2):600-15.
• Jagani Z, Song K, Kutok J, Benhaga N, Melet A, Grassian A, Ren R, Ghaffari S, Wu K, Khosravi-Far, R. Proteasome Inhibition Abrogates BCR-ABL-Induced, FOXO3a-, TRAIL- and Bim-Mediated Evasion of Apoptosis and
  Causes Regression of CML-Like Disease. Cancer Research. In Press.
• Ren B, Song K, Jin T, Benhaga N, Parangi S, Duquette M, Zheng X, Lawler J, Khosravi-Far R. Cooperative tumor inhibition by targeting tumors and tumor associated vessels: A Molecular Basis for their Combination in Cancer Therapy. Cancer Res. 2009 May 1;69(9):3856-65