Death receptor ligands, in particular TRAIL, to overcome drug resistance

Abstract

The efficacy of chemotherapeutic drugs is hampered by the occurrence of intrinsic and acquired drug resistance. A variety of mechanisms cause drug-resistance. A final common factor, however, is the reduced capacity of drug resistant cells to go into apoptosis following treatment with DNA damaging agents. This is due to defects in apoptotic pathways, for example, changes in p53. The presence of a common factor makes it of interest to search for ways that facilitate the cell to go into apoptosis following exposure to chemotherapeutic drugs. The death receptor ligands tumor necrosis factor (TNF), Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) are able to induce apoptosis by binding to their cell membrane receptors. Recombinant forms of these ligands are capable to potentiate the effect of chemotherapeutic drugs in vitro and in vivo in the animal model. Based on preclinical toxicity and activity profiling, especially TRAIL is considered to be of interest for clinical use. Systemic treatment of non-human primates with TRAIL did not result in acute toxicity. Animal studies demonstrated antitumor activity of TRAIL and potentiation of the chemotherapy efficacy by TRAIL. Phase 1 studies with TRAIL will therefore be initiated. As TRAIL is supposed to be non-toxic, it will be a major challenge to design surrogate end points to find the optimal dose in the clinic. In analogy to the herceptin therapy, it may be helpful to characterize the tumor of the patient. In addition, ex vivo exposure of the tumor may also be useful to select the proper ligand therapy for the individual patient. For optimal effect it is most likely that ligand therapy will be combined with chemotherapy, but even a combination of ligands for patient treatments can be envisioned. It is to be expected that smart, small molecules targeting these death receptors will be designed in order to lower toxicity and increase antitumor activity.