Targeting TRAIL Death Receptors: TRAIL from the Lab to the Clinic

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) induces apoptosis upon ligation of its death domain-containing transmembrane receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) via activation of the extrinsic apoptosis pathway. Recombinant human (rh) TRAIL induces cell death in ˜ 50% of the cancers cell lines but not in normal cells. Apoptosis by rhTRAIL can be enhanced by DNA damaging drugs. Recently, DR4 and DR5-specific agonistic antibodies have been developed. In addition, several death receptor-selective TRAIL variants were generated using computational design.

Platinum-based chemotherapy is used for the treatment of ovarian cancer and chemo-irradiation for the treatment of cervical cancer. Cisplatin strongly enhanced DR5 surface expression. Combination of rhTRAIL-DR5 with cisplatin was the most effective combination in vitro and in an intraperitoneal bioluminescent A2780 xenograft model. In HeLa cervical cancer cells irradiation induced both DR4 and DR5 surface expression. Irradiation enhanced TRAIL-DR5 and DR4 agonistic antibody-induced apoptosis and reduced viability in HeLa cells. Both TRAIL receptor targeting drugs showed a large anti-tumor effect in combination with irradiation in a bioluminescent HeLa xenograft model. These findings are clinically relevant, since phase 1 data are already available for rhTRAIL, DR4 targeting antibody and five DR5 activating antibodies. Moreover, a wide variety of phase 1b/2 studies are currently ongoing with TRAIL receptor targeting drugs in combination with chemotherapy and/or targeted drugs.

In conclusion: TRAIL receptor targeting drugs show anti-tumor activity in in vitro and in vivo models. These drugs have entered the clinic. Elucidating potential DR4 or DR5-specific effects of novel and existing chemotherapies will be crucial to fully exploit the clinical potential of TRAIL death receptor-selective agonists.