Roya Khosravi-Far, Ph.D.

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 667-8526
Fax: (617) 667-3524


rkhosrav@caregroup.harvard.edu

Roya Khosravi-Far, Ph.D.

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Associate Professor, Pathology, Harvard Medical School
  • Senior Scientist, Experimental Pathology, Beth Israel Deaconess Medical Center

DF/HCC PROGRAM AFFILIATION

Research Abstract

One of the major goals of researchers in the field of apoptosis is understanding the molecular mechanisms of the various components of the apoptotic pathways, with the hope to identify targets for novel cancer therapies. However, most cancer cells are resistant to many apoptosis-inducing agents such as most cytokines and radiation. Tumor necrosis factor has been used in some cancer therapies in an effort to eliminate tumor cells, but its administration results in a severe inflammatory response. Similarly, Fas can kill tumor cells but will also cause a sever hepatotoxicity. Recent discovery of a TNF related ligand, TRAIL, that kills transformed cells with great specificity in vitro, has provided further hope that TRAIL may be used to induce cell death in tumor cells without affecting normal tissue. However, the biological function of TRAIL and what pathways are involved in mediating its function is not yet clear. We are currently studying the biological function and tumor specificity of TRAIL-induced killing by analyzing the effect of TRAIL in inhibiting chronic myelogenous leukemia.

Death Receptors (DR) 4 and 5 are activated by TRAIL. The signaling events that mediate the biological effects of TRAIL, DR4 and DR5 are not well characterized. By phage display peptide library screening, we have identified several peptides that directly and specifically interact with DR4 and DR5 receptors. One of the DR5-interacting peptides possesses an inhibitory effect in DR5 and TRAIL-induced cell killing and may provide the mechanism for tumor specificity of TRAIL-induced killing. Identification of pathways that inhibit TRAIL-induced apoptosis in TRAIL-resistant tumor cells will provide valuable targets for cancer therapy. Inhibition of such pathways will convert the TRAIL-resistant tumor cells to TRAIL-sensitive. These cells can then be specifically eliminated by TRAIL-induced apoptosis.

Publications

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  • Bucur O, Pennarun B, Stancu AL, Nadler M, Muraru MS, Bertomeu T, Khosravi-Far R. Poor antibody validation is a challenge in biomedical research: a case study for detection of c-FLIP. Apoptosis 2013; 18:1154-62. PubMed
  • Bucur O, Stancu AL, Goganau I, Petrescu SM, Pennarun B, Bertomeu T, Dewar R, Khosravi-Far R. Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells. PLoS ONE 2013; 8:e77390. PubMed
  • Plati J, Bucur O, Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb) 2011; 3:279-96. PubMed
  • Singh A, Plati J, Khosravi-Far R. Harnessing the Tumor Suppressor Function of FOXO as an Alternative Therapeutic Approach in Cancer. Curr Drug Targets 2011. PubMed
  • Dewar R, Chen ST, Yeckes-Rodin H, Miller K, Khosravi-Far R. Bortezomib treatment causes remission in a Ph+ALL patient and reveals FoxO as a theranostic marker. Cancer Biol Ther 2011; 11:552-8. PubMed
  • Kazerounian S, Duquette M, Reyes MA, Lawler JT, Song K, Perruzzi C, Primo L, Khosravi-Far R, Bussolino F, Rabinovitz I, Lawler J. Priming of the vascular endothelial growth factor signaling pathway by thrombospondin-1, CD36, and spleen tyrosine kinase. Blood 2011. PubMed
  • Weisberg E, Choi HG, Ray A, Barrett R, Zhang J, Sim T, Zhou W, Seeliger M, Cameron M, Azam M, Fletcher JA, Debiec-Rychter M, Mayeda M, Moreno D, Kung AL, Janne PA, Khosravi-Far R, Melo JV, Manley P, Adamia S, Wu C, Gray N, Griffin JD. Discovery of a small molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFR{alpha}, Kit, and Src kinases. Blood 2010; 115:4206-16. PubMed
  • Singh A, Ye M, Bucur O, Zhu S, Santos MT, Rabinovitz I, Wei W, Gao D, Hahn WC, Khosravi-Far R. Protein Phosphatase 2A Reactivates FOXO3a through a Dynamic Interplay with 14-3-3 and AKT. Mol Biol Cell 2010; 21:1140-52. PubMed
  • Jagani Z, Song K, Kutok JL, Dewar MR, Melet A, Santos T, Grassian A, Ghaffari S, Wu C, Yeckes-Rodin H, Rodin HY, Ren R, Miller K, Khosravi-Far R. Proteasome inhibition causes regression of leukemia and abrogates BCR-ABL-induced evasion of apoptosis in part through regulation of forkhead tumor suppressors. Cancer Res 2009; 69:6546-55. PubMed
  • Ren B,Song K,Parangi S,Jin T,Ye M,Humphreys R,Duquette M,Zhang X,Benhaga N,Lawler J,Khosravi-Far R. A double hit to kill tumor and endothelial cells by TRAIL and antiangiogenic 3TSR. Cancer Res 2009; 69:3856-65. PubMed
  • 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 2008; 20:600-15. PubMed
  • Matarrese P, Manganelli V, Garofalo T, Tinari A, Gambardella L, Ndebele K, Khosravi-Far R, Sorice M, Degli Esposti M, Malorni W. Endosomal compartment contributes to the propagation of CD95/Fas-mediated signals in type II cells. Biochem J 2008; 413:467-78. PubMed
  • Plati J, Bucur O, Khosravi-Far R. Dysregulation of apoptotic signaling in cancer: Molecular mechanisms and therapeutic opportunities. J Cell Biochem 2008; 104:1124-49. PubMed
  • 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; 13:845-56. PubMed
  • Chalah A, Khosravi-Far R. The mitochondrial death pathway. Adv Exp Med Biol 2008; 615:25-45. PubMed
  • Jagani Z, Khosravi-Far R. Cancer stem cells and impaired apoptosis. Adv Exp Med Biol 2008; 615:331-44. PubMed
  • Melet A, Song K, Bucur O, Jagani Z, Grassian AR, Khosravi-Far R. Apoptotic pathways in tumor progression and therapy. Adv Exp Med Biol 2008; 615:47-79. PubMed
  • Jagani Z, Singh A, Khosravi-Far R. FoxO tumor suppressors and BCR-ABL-induced leukemia: a matter of evasion of apoptosis. Biochim Biophys Acta 2007; 1785:63-84. PubMed
  • Zhang X, Zhang L, Yang H, Huang X, Otu H, Libermann TA, DeWolf WC, Khosravi-Far R, Olumi AF. c-Fos as a proapoptotic agent in TRAIL-induced apoptosis in prostate cancer cells. Cancer Res 2007; 67:9425-34. PubMed
  • Brown L, Ongusaha PP, Kim HG, Nuti S, Mandinova A, Lee JW, Khosravi-Far R, Aaronson SA, Lee SW. CDIP, a novel pro-apoptotic gene, regulates TNFalpha-mediated apoptosis in a p53-dependent manner. EMBO J 2007; 26:3410-22. PubMed
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