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Directing cancer cells to self-destruct with pro-apoptotic receptor agonists

Key Points

  • Apoptosis is a mechanism of cell suicide that has evolved in multicellular animals as a means of eliminating abnormal cells that pose a threat to the organism's life.

  • Apoptosis provides an important barrier against cancer. Occasionally, a tumour cell may acquire specific mutations, such as those that inactivate the p53 tumour-suppressor protein, which allow it to escape apoptotic death and progress to full malignancy.

  • Malignant cells remain 'primed' for apoptosis, because of their underlying aberrant properties. Therefore, drugs that can overcome anti-apoptotic changes in tumour cells might lead to important advances in cancer therapy.

  • Recent discoveries about apoptosis signalling pathways have inspired several strategies to harness this cell-death mechanism for therapeutic gain.

  • There are two key signalling pathways to control apoptosis: the extrinsic pathway, initiated outside the cell, and the intrinsic pathway, triggered from inside the cell.

  • Two major types of pro-apoptotic agents have been developed: protein-based pro-apoptotic receptor agonists (PARAs), which trigger apoptosis from the cell surface, and small molecule compounds, which activate apoptosis intracellularly.

  • PARAs that activate the DR4 and/or DR5 receptors include recombinant human Apo2L/TRAIL and agonistic DR4 and DR5 antibodies.

  • Based on preclinical data, PARAs that target DR4 and/or DR5 are particularly attractive because they display a broad spectrum of anti-tumour activity with remarkable selectivity for malignant versus normal cells. They act independently of p53 and cooperate with various chemotherapeutic drugs as well as with certain biological agents.

  • Several PARAs have met the rigorous safety criteria of Phase I clinical trials successfully, with early indications of anti-cancer activity. On that basis, a number of Phase II studies are ongoing.

  • Recent discoveries have uncovered specific diagnostic biomarkers that can assist in identifying individual cancer patients who may best benefit from PARA therapy. Differences and similarities between PARAs and their implications for clinical safety and efficacy are not yet fully understood.

  • Trials are underway to identify optimal treatment regimens that combine certain PARAs with other therapies to achieve maximal anti-cancer efficacy.

Abstract

Each day, the human body eliminates billions of unwanted cells by apoptotic suicide. Apoptosis provides an important barrier against cancer; however, specific mutations enable some tumour cells to escape apoptotic death and become more malignant. Two signalling pathways initiate apoptosis: one acts through intracellular Bcl-2 proteins, the other through cell-surface pro-apoptotic receptors. New molecular insights have inspired the development of pro-apoptotic receptor agonists (PARAs), including the recombinant human protein apoptosis ligand 2/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) and agonistic monoclonal antibodies to its signalling receptors. Acting alone, or in concert with other agents, PARAs may overcome key apoptosis blocks and direct cancer cells to self-destruct.

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Figure 1: Key steps in apoptotic signalling pathways.
Figure 2: Pro-apoptotic receptor agonists.
Figure 3: Crystal structures of pro-apoptotic receptor agonists and DR5.
Figure 4: Potential modes of pro-apoptotic receptor activation by agonistic antibodies.
Figure 5: Identification of biomarkers that might predict tumour sensitivity to rhApo2L/TRAIL.

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Glossary

Apoptosis

A form of programmed cell death that serves to eliminate cells that are misplaced, no longer needed, or irreparably damaged.

Death-inducing signalling complex

(DISC). Formed upon binding of ligand to a pro-apoptotic receptor and recruitment of initiator caspases 8 and 10 through the FADD adaptor protein. The DISC activates these initiator caspases to trigger apoptosis through effector caspases 3, 6 and 7, and by engaging the intrinsic pathway via processing of the Bcl-2 family protein Bid.

Anoikis

A type of apoptosis induced by cell detachment.

Epitope

The site on a large molecule to which an antibody binds.

Antibody-dependent cell-mediated cytotoxicity

Refers to the lysis of antibody-coated target cells by immune cells.

Complement activation

Refers to the sequential activation of serum proteins, resulting in an inflammatory response.

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Ashkenazi, A. Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat Rev Drug Discov 7, 1001–1012 (2008). https://doi.org/10.1038/nrd2637

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