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Scientist Profile

Avi Ashkenazi

Senior Staff Scientist and Director
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"I believe that the most important purpose of science is to advance human knowledge toward practical applications that can transform or save human lives."

I received his PhD in Biochemistry from the Hebrew University of Jerusalem, Israel in 1986. I trained as a postdoctoral fellow from 1986 to 1989 at the University of California, San Francisco, and at Genentech, studying novel G protein-coupled receptors. In 1989 I was appointed to Research Scientist at Genentech and progressed through the scientific ranks of the Research division to become Senior Staff Scientist and Director of the Molecular Oncology department. In the early 1990’s I was involved in the development and translation of the immunoglobulin Fc-fusion protein technology, which is now used in numerous research laboratories around the world and in several major biotechnology drugs. Subsequently, my laboratory discovered several novel members of the tumor necrosis factor (TNF) superfamily, most notably, the apoptosis-inducing ligand Apo2L/TRAIL and its "death" and "decoy" receptors.

Our basic research has helped elucidate the mechanism of apoptosis signaling by Apo2L/TRAIL, and our translational work in this area pioneered the development and clinical investigation of a class of pro-apoptotic receptor agonists (PARAs) in cancer. We also have contributed, in collaboration with Jing Qing and Ya Wu, an anti-FGFR3 antibody that is currently in clinical trials. To date, I have published 97 research papers and 30 review articles and have co-edited a book on antibody fusion proteins. Four of my top papers have been cited over 1000 times and a fifth paper has been cited over 4600 times. My discoveries in the area of apoptosis are highlighted in the textbook "The biology of Cancer" (authored by Robert A. Weinberg). I have presented over 90 lectures at scientific institutions and conferences and have been a named inventor on 53 issued US patents. In 2007 I co-chaired the international TNF conference and have been a member of the editorial boards of Current Biology, Nature Reviews Cancer, Journal of Biological Chemistry, Cancer Biology & Therapy, and Cell Death & Differentiation.

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My Focus

Our department is currently investigating strategies to kill cancer cells by harnessing their inherent stress-response mechanisms. Cancer cells frequently experience biological stress as a result of DNA damage, protein misfolding, or oxygen and nutrient imbalances. Typically, they manage to adapt to the stress and continue to grow unabated. However, if cells fail to adapt, a built-in suicide program called apoptosis kicks in to eliminate them.

Our goal is to identify the key molecular switches that control this apoptotic program and to develop drugs that manipulate them to trigger cancer cell death. We are studying this by tracing the intracellular signaling pathways that connect between sensors of biological stress at the cell surface, the nucleus, or the endoplasmic reticulum, and caspases - specialized enzymes that execute the apoptotic cell death program.

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My Interests

Professionally I am interested in understanding basic mechanisms of cell biology, cancer biology, signal transduction, and cell death, and in harnessing that knowledge to develop novel therapeutic strategies for cancer and other diseases. Personally I am interested in music, architecture and philosophy.

 
Publications & Recognition
  • NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-alpha feedforward signaling.
  • Cell. 2011 Apr 1;145(1):92-103.
  • Biton S, Ashkenazi A.
  • View Abstract on PubMed
  • An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells.
  • Cancer Cell. 2011 Jan 18;19(1):101-13.
  • Wilson NS, Yang B, Yang A, Loeser S, Marsters S, Lawrence D, Li Y, Pitti R, Totpal K, Yee S, Ross S, Vernes JM, Lu Y, Adams C, Offringa R, Kelley B, Hymowitz S, Daniel D, Meng G, Ashkenazi A.
  • View Abstract on PubMed
  • Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling.
  • Cell 2009 May 15; 137(4): 721-35.
  • Jin Z, Li Y, Pitti R, Lawrence D, Pham VC, Lill JR, Ashkenazi A.
  • View Abstract on PubMed
 
View All Publications & Recognition
 
 
Pipleline Contributions
 
  • University of California, San Francisco, Department of Hormone Research, and Genentech, Inc., Department of Developmental Biology
  • Postdoctoral Fellow
  • 1986-1989
  • Hebrew University, Israel, Department of Biochemistry
  • Ph.D.
  • 1986
  • Hebrew University, Israel, Department of Biochemistry
  • B.S.
  • 1983
Publications & Recognition
  • NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-alpha feedforward signaling.
  • Cell. 2011 Apr 1;145(1):92-103.
  • Biton S, Ashkenazi A.
  • View Abstract on PubMed
  • An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells.
  • Cancer Cell. 2011 Jan 18;19(1):101-13.
  • Wilson NS, Yang B, Yang A, Loeser S, Marsters S, Lawrence D, Li Y, Pitti R, Totpal K, Yee S, Ross S, Vernes JM, Lu Y, Adams C, Offringa R, Kelley B, Hymowitz S, Daniel D, Meng G, Ashkenazi A.
  • View Abstract on PubMed
  • TWEAK induces apoptosis through a RIP1-FADD-Caspase-8 signaling complex.
  • J Biol Chem 286, 21546-21554 (2011).
  • Ikner A, Ashkenazi A.
  • View Abstract on PubMed
  • Proapoptotic DR4 and DR5 signaling in cancer cells: Toward clinical translation.
  • Curr. Opin. Cell Biol. 22, 1-8 (2010).
  • Yang A, Wilson NS, Ashkenazi A.
  • View Abstract on PubMed
  • New Insights into Apoptosis Signaling by Apo2L/TRAIL.
  • Oncogene 1-14 (2010).
  • Gonzalvez F, Ashkenazi A.
  • View Abstract on PubMed
  • Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling.
  • Cell 2009 May 15; 137(4): 721-35.
  • Jin Z, Li Y, Pitti R, Lawrence D, Pham VC, Lill JR, Ashkenazi A.
  • View Abstract on PubMed
  • Phase I dose-escalation study of recombinant human (rh)Apo2L/TRAIL, a dual pro-apoptotic receptor agonist, in patients with advanced cancer.
  • J Clin Onc. 281, 2839-2846 (2010).
  • Herbst R, Eckhardt G, Kurzrock R, Ebbinghaus S, O'Dwyer P, Gordon M, Novotny W, Goldwasser M, Tohnya T, Lum B, Ashkenazi A, Jub A, Mendelson D.
  • A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies.
  • Clin Cancer Res 2010 Feb 15; 16(4): 1256-63.
  • Camidge DR, Herbst RS, Gordon MS, Eckhardt SG, Kurzrock R, Durbin B, Ing J, Tohnya TM, Sager J, Ashkenazi A, Bray G, Mendelson D.
  • View Abstract on PubMed
  • Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice.
  • J Clin Invest 2009 May; 119(5): 1216-29.
  • Qing J, Du X, Chen Y, Chan P, Li H, Wu P, Marsters S, Stawicki S, Tien J, Totpal K, Ross S, Stinson S, Dornan D, French D, Wang QR, Stephan JP, Wu Y, Wiesmann C, Ashkenazi A.
  • View Abstract on PubMed
  • Death receptor signal transducers: nodes of coordination in immune signaling networks.
  • Nat Immunol 2009 Apr; 10(4): 348-55.
  • Wilson NS, Dixit V, Ashkenazi A.
  • View Abstract on PubMed
  • Directing cancer cells to self-destruct with pro-apoptotic receptor agonists.
  • Nat Rev Drug Discov 2008 Dec; 7(12): 1001-12.
  • Ashkenazi A.
  • View Abstract on PubMed
  • Cooperation of the Agonistic DR5 Antibody Apomab with Chemotherapy to Inhibit Orthotopic Lung Tumor Growth and Improve Survival.
  • Clin Cancer Res 2008 Dec 1; 14(23): 7733-40.
  • Jin H, Yang R, Ross J, Carano R, Fong S, Totpal K, Lawrence D, Zheng Z, Koeppen H, Schwall R, and Ashkenazi A.
  • View Abstract on PubMed
  • To kill a tumor cell: the potential of proapoptotic receptor agonists.
  • J Clin Invest 2008 June; 118(6): 1979-90.
  • Ashkenazi A, Herbst RS.
  • View Abstract on PubMed
  • Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5.
  • Cell Death Differ 2008 Apr; 15(4): 751-61.
  • Adams C, Totpal K, Lawrence D, Marsters S, Pitti R, Yee S, Ross S, Deforge L, Koeppen H, Sagolla M, Compaan D, Lowman H, Hymowitz S, Ashkenazi A.
  • View Abstract on PubMed
  • Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts.
  • Blood 2007 Dec 1; 110(12): 4037-46.
  • Daniel D, Yang B, Lawrence DA, Totpal K, Balter I, Lee WP, Gogineni A, Cole MJ, Yee SF, Ross S, Ashkenazi A.
  • View Abstract on PubMed
  • Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL.
  • Nat Med 2007 Sep; 13(9): 1070-7.
  • Wagner KW, Punnoose EA, Januario T, Lawrence DA, Pitti RM, Lancaster K, Lee D, von Goetz M, Yee SF, Totpal K, Huw L, Katta V, Cavet G, Hymowitz S, Amler L, Ashkenazi A.
  • View Abstract on PubMed
  • Secreted sulfatases Sulf1 and Sulf2 have overlapping yet essential roles in mouse neonatal survival.
  • PLoSOne 6, e575, 2007.
  • Holst CR, Bou-Reslan H, Gore BB, Wong K, Grant D, Chalasani S, Carano RA, Frantz GD, Tessier-Lavigne M, Bolon B, French DM, Ashkenazi A.
  • View Abstract on PubMed
  • Delineation of the cell-extrinsic apoptosis pathway in the zebrafish.
  • Cell Death Differ 2006 Oct; 13(10): 1619-30.
  • Eimon PM, Kratz E, Varfolomeev E, Hymowitz SG, Stern H, Zha J, Ashkenazi A.
  • View Abstract on PubMed
  • Functional characterization of the Bcl-2 gene family in the zebrafish.
  • Cell Death Differ 2006 Oct; 13(10): 1631-40.
  • Kratz E, Eimon PM, Mukhyala K, Stern H, Zha J, Strasser A, Hart R, Ashkenazi A.
  • View Abstract on PubMed
  • Death-receptor activation halts clathrin-dependent endocytosis.
  • Proc Natl Acad Sci U S A 2006 Jul 5; 103(27): 10283-8.
  • Austin CD, Lawrence DA, Peden AA, Varfolomeev EE, Totpal K, De Maziere AM, Klumperman J, Arnott D, Pham V, Scheller RH, Ashkenazi A.
  • View Abstract on PubMed
  • Molecular determinants of kinase pathway activation by Apo2 Ligand/Tumor Necrosis Factor Related Apoptosis-Inducing Ligand.
  • J Biol Chem 2005 Dec 9; 280(49): 40599-608.
  • Varfolomeev E, Maecker H, Sharp D, Lawrence D, Renz M, Vucic D, Ashkenazi A.
  • View Abstract on PubMed
  • TWEAK attenuates the transition from innate to adaptive immunity.
  • Cell 2005 Dec 2; 123(5): 931-44.
  • Maecker H, Varfolomeev E, Kischkel F, Lawrence D, LeBlanc H, Lee W, Hurst S, Danilenko D, Li J, Filvaroff E, Yang B, Daniel D, Ashkenazi A.
  • View Abstract on PubMed
  • Selective knockdown of the long variant of cellular FLICE-inhibitory protein augments death receptor-mediated caspase-8 activation and apoptosis.
  • J Biol Chem 2005 May 13; 280(19): 19401-9.
  • Sharp D, Lawrence DA, Ashkenazi A.
  • View Abstract on PubMed
  • Receptor-selective mutants of Apo2L/TRAIL reveal a greater contribution of DR5 than DR4 to apoptosis signaling.
  • J Biol Chem 2005 Jan 21; 280(3): 2205-12.
  • Kelley R, Totpal K, Lindstrom S, Mathieu M, Billeci K, DeForge L, Pai R, Hymowitz S, Ashkenazi A.
  • View Abstract on PubMed
  • Apo2L/TRAIL cooperates with chemotherapy to inhibit orthotopic lung tumor growth and improve survival.
  • Canc Res 2004 Jul 15; 64(14): 4900-5.
  • Jin H, Yang R, Fong S, Totpal K, Lawrence D, Zheng Z, Ross J, Koeppen H, Schwall R, Ashkenazi A.
  • View Abstract on PubMed
  • Tumor necrosis factor: an apoptosis JuNKie?
  • Cell 2004 Feb 20; 116(4): 491-7.
  • Varfolomeev EE, Ashkenazi A.
  • View Abstract on PubMed
  • APRIL-deficient mice have normal immune system development.
  • Mol Cell Biol 2004 Feb; 24(3): 997-1006.
  • Varfolomeev E, Kischkel F, Martin F, Seshasayee D, Wang H, Lawrence D, Olsson C, Tom L, Erickson S, French D, Schow P, Grewal IS, Ashkenazi A.
  • View Abstract on PubMed
  • Targeting death and decoy receptors of the tumour-necrosis factor superfamily.
  • Nat Rev Cancer 2002 Jun; 2(6): 420-30.
  • Ashkenazi A.
  • View Abstract on PubMed
  • Tumor-cell resistance to death receptor—induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax.
  • Nat Med 2002 Mar; 8(3): 274-81.
  • LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P, Fong S, Schwall R, Sinicropi D, Ashkenazi A.
  • View Abstract on PubMed
  • Death receptor recruitment of endogenous caspase-10 and apoptosis initiation the absence of caspase-8.
  • J Biol Chem 2001 Dec 7; 276(49): 46639-46.
  • Kischkel FC, Lawrence DA, Tinel A, LeBlanc H, Virmani A, Schow P, Gazdar A, Blenis J, Arnott D, Ashkenazi A.
  • View Abstract on PubMed
  • Direct stimulation of apoptotic signaling by soluble Apo2l/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells.
  • Clin Cancer Res 2001 May; 7(5): 1362-9.
  • Pollack IF, Erff M, Ashkenazi A.
  • View Abstract on PubMed
  • Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions.
  • Nat Med 2001 Apr; 7(4): 383-5.
  • Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B, Hillan K, Totpal K, DeForge L, Schow P, Hooley J, Sherwood S, Pai R, Leung S, Khan L, Gliniak B, Bussiere J, Smith CA, Strom SS, Kelley S, Fox JA, Thomas D, Ashkenazi A.
  • View Abstract on PubMed
  • Interaction of the TNF homologues BLyS and APRIL with the TNF receptor homologues BCMA and TACI.
  • Curr Biol 2000 Jun 29; 10(13): 785-8.
  • Marsters SA, Yan M, Pitti RM, Haas PE, Dixit VM, Ashkenazi A.
  • View Abstract on PubMed
  • Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5.
  • Immunity 2000 Jun; 12(6): 611-20.
  • Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A.
  • View Abstract on PubMed
  • Safety and antitumor activity of recombinant soluble Apo2 ligand.
  • J Clin Invest 1999 Jul; 104(2): 155-62.
  • Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z, Schwall RH.
  • View Abstract on PubMed
  • Identification of a new member of the tumor necrosis factor family and its receptor, a human ortholog of mouse GITR.
  • Curr Biol 1999 Feb 25; 9(4): 215-8.
  • Gurney AL, Marsters SA, Huang RM, Pitti RM, Mark DT, Baldwin DT, Gray AM, Dowd AD, Brush AD, Heldens AD, Schow AD, Goddard AD, Wood WI, Baker KP, Godowski PJ, Ashkenazi A.
  • View Abstract on PubMed
  • Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer.
  • Nature 1998 Dec 17; 396(6712): 699-703.
  • Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, Huang A, Donahue CJ, Sherwood SW, Baldwin DT, Godowski PJ, Wood WI, Gurney AL, Hillan KJ, Cohen RL, Goddard AD, Botstein D, Ashkenazi A.
  • View Abstract on PubMed
  • Death receptors: signaling and modulation.
  • Science 1998 Aug 28; 281(5381): 1305-8.
  • Ashkenazi A, Dixit VM.
  • View Abstract on PubMed
  • Identification of a ligand for the death-domain-containing receptor Apo3.
  • Curr Biol 1998 Apr 23; 8(9): 525-8.
  • Marsters SA, Sheridan JP, Pitti RM, Brush J, Goddard A, Ashkenazi A.
  • View Abstract on PubMed
  • A novel receptor for Apo2L/TRAIL contains a truncated death domain.
  • Curr Biol 1997 Dec 1; 7(12): 1003-6.
  • Marsters S, Sheridan J, Pitti R, Gurney A, Skubatch M, Baldwin D, Huang A, Yuan J, Goddard A, Godowski P, Ashkenazi A.
  • View Abstract on PubMed
  • Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors.
  • Science 1997 Aug 8; 277(5327): 818-21.
  • Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A.
  • View Abstract on PubMed
  • Herpesvirus entry mediator, a novel member of the tumor necrosis factor receptor family, activates the NF-kB and AP-1 transcription factors.
  • J Biol Chem 1997 May 30; 272(22): 14029-32.
  • Marsters S, Skubatch M, Gray C, Ashkenazi A.
  • View Abstract on PubMed
  • Induction of apoptosis by Apo-2 Ligand, a new member of the tumor necrosis factor cytokine family.
  • J Biol Chem 1996 May 31; 271(22): 12687-90.
  • Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A.
  • View Abstract on PubMed
  • Immunoadhesins: principles and applications [review].
  • Trends Biotechnol 1996 Feb; 14(2): 52-60.
  • Chamow SM, Ashkenazi A.
  • View Abstract on PubMed
  • Interferon gamma signals via a high-affinity multisubunit receptor complex that contains two types of polypeptide chain.
  • Proc Natl Acad Sci U S A 1995 Jun 6; 92(12): 5401-5.
  • Marsters S, Penica D, Bach E, Schreiber R, Ashkenazi A.
  • View Abstract on PubMed
  • Inhibition of murine erythroid colony formation in vitro by interferon gamma and correction by interferon gamma receptor immunoadhesin.
  • Blood 1994 Feb 15; 83(4): 911-5.
  • Means R, Krantz S, Luna J, Marsters, S, Ashkenazi, A.
  • View Abstract on PubMed
  • Cloning and expression of a human CDC42 GTPase Activating Protein reveals a functional SH3-binding domain.
  • J Biol Chem 1993 Dec 15; 268(35): 26059-62.
  • Barfod L, Zheng Y, Kuang W, Hart M, Evans T, Cerione R, Ashkenazi A.
  • View Abstract on PubMed
  • Inhibition of interferon gamma by an interferon gamma receptor immunoadhesin.
  • Immunology 1993 Aug; 79(4): 594-9.
  • Haak-Frendscho M, Marsters S, Chamow S, Peers D, Simpson N, Ashkenazi, A.
  • View Abstract on PubMed
  • A single amino-acid difference confers major pharmacologic variation between human and rodent 5-HT1B receptors.
  • Nature 1992 Nov 12; 360(6400): 161-3.
  • Oksenberg D, Marsters A, O'Dowd B, Jin H, Havlik S, Peroutka S, Ashkenazi A.
  • View Abstract on PubMed
  • Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin.
  • Proc Natl Acad Sci U S A 1991 Dec 1; 88(23): 10535-9.
  • Ashkenazi A, Marsters SA, Capon DJ, Chamow SM, Figari IS, Pennica D, Goeddel DV, Palladino MA, Smith DH.
  • View Abstract on PubMed
  • Mapping the CD4 binding site for human immunodefficiency virus type 1 by alanine-scanning mutagenesis.
  • Proc Natl Acad Sci U S A 1990 Sep; 87(18): 7150-4.
  • Ashkenazi A, Presta L, Marsters S, Camerato T, Rosenthal K, Fendly B, Capon D.
  • View Abstract on PubMed
  • Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic acetylcholine receptor subtypes.
  • Nature 1989 Jul 13; 340(6229): 146-50.
  • Ashkenazi A, Ramachandran J, Capon DJ.
  • View Abstract on PubMed
  • Functionally distinct G proteins couple different receptors to PI hydrolysis in the same cell.
  • Cell 1989 Feb 10; 56: (3)487-493.
  • Ashkenazi A, Peralta EG, Winslow JW, Ramachandran J, Capon DJ.
  • View Abstract on PubMed
  • An M2 muscarinic receptor subtype coupled to both adenylyl cyclase and phosphoinositide turnover.
  • Science 1987 Oct 30; 238(4827): 672-5.
  • Ashkenazi A, Winslow J, Peralta E, Peterson G, Schimerlik M, Capon D, Ramachandran J.
  • View Abstract on PubMed
Books
  • Antibody Fusion Proteins.
  • New York; John Wiley.
  • Chamow, S, Ashkenazi, A, editors.
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Awards & Honors
  • First Prize, Boeringer Ingelheim Award -- 1988
 
Patents
  • Assays and methods using biomarkers predictive of sensitivity to Apo2L/TRAIL-induced apoptosis.
    Ashkenazi, A., Wagner, K.
    U.S. Patent 7,629,136

Avi Ashkenazi, Senior Scientist and Alex Avardo, Receipent of Free Medicine From the Genentech® Access to Care Foundation, on the cover of Genentech's 2006 Annual Report.