Apoptosis

Dysregulation of apoptosis (also known as programmed cell death) — a key process in cancer development and progression — is being evaluated for potential therapeutic targets.5,1 Apoptosis is a critical mechanism that allows multicellular organisms to maintain tissue integrity and function, and to eliminate damaged or unwanted cells.6

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Apoptosis Cell and Cancer Research
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Apoptosis (programmed cell death) may occur through 2 main signaling pathways:
The intrinsic pathway may be triggered by DNA damage and other types of severe cell stress. It may involve the release of intracellular pro-apoptotic proteins that activate caspases, a network of proteases that ultimately destroy critical structural proteins in the cell and stimulate fragmentation of the chromosomal DNA, resulting in cell death.7

The extrinsic pathway may be triggered in response to external pro-apoptotic signals, such as endogenous Apo2L/TRAIL. Binding of this molecule to pro-apoptotic cell surface transmembrane receptors DR4 and DR5 may lead to apoptosis by initiating a signaling cascade, which results in the activation of the caspase system.5,7

The intrinsic and extrinsic apoptosis pathways converge via the activated caspases that ultimately trigger cell death.5,6


Apoptosis is triggered through two main signaling mechanisms: the “intrinsic” and the “extrinsic” pathways.6,7 The intrinsic pathway is initiated from within the cell by cellular developmental cues or as a result of severe cell stress (eg, DNA damage).7 The extrinsic pathway is initiated when a pro-apoptotic ligand binds to pro-apoptotic receptors on the surface of the cell.5 Destruction of the cell is ultimately carried out by caspases — intracellular enzymes that, once activated, destroy cellular proteins that are essential for cell survival.6,7

Over the past decade, Dr Avi Ashkenazi and Genentech scientists have made important contributions toward understanding the apoptosis pathway and have identified several key genes that encode proteins associated with this process, including the endogenous ligand Apo2L/TRAIL and its receptors.8-11

Apoptosis Induction

The ability of cancer cells to avoid apoptosis and continue to proliferate is another one of the fundamental steps in cancer development.1

Genentech BioOncology, in collaboration with Amgen, is developing a pro-apoptotic ligand, recombinant human Apo2L/TRAIL (rhApo2L/TRAIL). rhApo2L/TRAIL is the first dual pro-apoptotic receptor agonist (PARA) that directly activates the extrinsic apoptotic pathway via the pro-apoptotic receptors DR4 and DR5.5,12,13 In preclinical models, binding of this molecule selectively induced apoptosis in cancer cells while sparing normal cells.12

Genentech BioOncology is also developing a fully human monoclonal antibody, Apomab. Apomab, a DR5-targeted PARA, is specifically designed using Genentech's antibody technology to induce apoptosis by directly activating the extrinsic apoptotic pathway.

1: Recombinant human Apo2L/TRAIL is engineered to mimic endogenous Apo2L/TRAIL.14

Apoptosis: 1

2: rhApo2L/TRAIL is designed to bind to pro-apoptotic cell-surface receptors DR4 and DR5, thus activating the receptors.14

Apoptosis: 2

3: Activated DR4/DR5 recruits the cell death-inducing signaling complex (DISC) and initiates the extrinsic apoptotic signaling cascade.5,14

Apoptosis: 3

The mechanisms that may allow PARAs such as rhApo2L/TRAIL and Apomab to selectively induce apoptosis in cancer cells while sparing normal cells remain to be fully characterized. Overexpression of common oncogenes, such as myc and ras, may sensitize cancer cells to PARAs.15-18 PARAs may also indirectly activate the intrinsic pathway via intracellular crosstalk that occurs naturally between the pathways.5,19

At Genentech BioOncology, recognition of apoptosis dysregulation as a fundamental element of tumor development is a major driver of cancer research. Through research and development of novel pro-apoptotic agents targeting the extrinsic and intrinsic pathways, we aspire to further understand this critical cellular process, and ultimately, to develop more effective therapies for cancer patients.

1: The fully human monoclonal antibody Apomab is a DR5-targeted pro-apoptotic receptor agonist (PARA).5,14

Apoptosis: 4

2: Apomab is designed to activate the extrinsic apoptosis pathway directly, via the pro-apoptotic receptor DR5.14

Apoptosis: 5

3: Activated DR5 recruits the cell deathinducing signaling complex (DISC) and initiates the extrinsic apoptotic signaling cascade.5,14

Apoptosis: 6

Journal Articles

  1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.

  1. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nature. 2002;2:420–430.

  1. Ghobrial IM, Witzig, TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 2005;55:178-194.

  1. Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther. 2005;4:139-163.

  1. Marsters SA, Sheridan JP, Donahue CJ, et al. Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activated apoptosis and NF-kappa B. Curr Biol. 1996;6:1669-1676.

  1. Marsters SA, Sheridan JP, Pitti RM, et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol. 1997;7:1003-1006.

  1. Pitti RM, Marsters SA, Lawrence DA, et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996;271:12687-12690.

  1. Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science. 1997;277:818-821.

  1. Ashkenazi A, Pai RC, Fong S, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 1999;104:155-162.

  1. Kischkel RC, Lawrence DA, Chuntharapai A, et al. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity. 2000;12:611-620.

  1. Fesik SW. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer. 2005;5:876-885.

  1. Drosopoulos KG, Roberts ML, Cermak L, et al. Transformation by oncogenic RAS sensitizes human colon cells to TRAIL-induced apoptosis by up-regulating death receptor 4 and death receptor 5 through a MEK-dependent pathway. J Biol Chem. 2005;280:22856-22867.

  1. Nesterov A, Nikrad M, Johnston T, Kraft AS. Oncogenic Ras sensitizes normal human cells to tumor necrosis factor-alpha-related apoptosis-inducing ligand-induced apoptosis. Cancer Res. 2005;15:1615-1616.

  1. Ricci MS, Jin Z, Dews M, et al. Direct repression of FLIP expression by c-myc is a major determinant of TRAIL sensitivity. Mol Cell Biol. 2004;24:8541-8555.

  1. Sheikh MS. Myc tagging along the TRAIL to death receptor 5. Cell Cycle. 2004;3:920-922.

  1. LeBlanc HN, Ashkenazi A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Differ. 2003;10:66-75.

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