Death Receptor Agonists as a Targeted Therapy for Cancer

Abstract

Apoptosis is integral to normal, physiologic processes that regulate cell number and results in the removal of unnecessary or damaged cells. Apoptosis is frequently dysregulated in human cancers, and recent advancements in our understanding of the regulation of programmed cell death pathways has led to the development of novel agents to reactivate apoptosis in malignant cells. The activation of cell surface death receptors by tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and death receptor agonists represent an attractive therapeutic strategy to promote apoptosis of tumor cells through the activation of the extrinsic pathway. The observation that Apo2L/TRAIL can eliminate tumor cells preferentially over normal cells has resulted in several potential therapeutics that exploit the extrinsic pathway, in particular, the soluble recombinant human (rh)Apo2L/TRAIL protein and agonist monoclonal antibodies that target death receptors 4 or 5. Many of these agents are currently being evaluated in phase 1 or 2 trials, either as a single agent or in combination with cytotoxic chemotherapy or other targeted agents. The opportunities and challenges associated with the development of death receptor agonists as cancer therapeutics, the status of ongoing clinical evaluations, and the progress toward identifying predictive biomarkers for patient selection and pharmacodynamic markers of response are reviewed.

Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

“…However, the overall antitumor activity of these antibodies is modest or limited in unselected patient populations (53,54). In this study, we found that cancer cell lines with ras or B-raf mutation showed a significantly higher response rate than those without these gene mutations (Fig.…”

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

“…Several proapoptotic receptor agonists (PARA), including mAbs, have been developed to target this extrinsic apoptotic pathway (3,4). However, despite promising preclinical data, none of these approaches have thus far demonstrated significant clinical efficacy (5)(6)(7). Although some antibodies appear to be able to autonomously activate DR4 and DR5, many require additional cross-linking to achieve optimal activity in vitro (8)(9)(10)(11).…”

The anti-Fn14 antibody BIIB036 inhibits tumor growth in xenografts and patient derived primary tumor models and enhances efficacy of chemotherapeutic agents in multiple xenograft models

“…Moreover, while clinical trials with TRAIL agonists have demonstrated acceptable safety and tolerability, there has been little evidence to-date of single agent efficacy. 1 However, in numerous ongoing studies, anti-TRAIL receptor agonists and soluble TRAIL are currently being evaluated in combination with standard of care therapies, and the expectation, largely based on a wealth of pre-clinical data, is that the TRAIL therapies may show efficacy in the combination setting. Thus, by analogy, it is significant that BIIB036 has demonstrated enhanced efficacy when administered in combination with a variety of standard of care agents, since BIIB036 may also require combination dosing to reveal its full potential as an anticancer therapeutic in the clinic.…”

“…Among the most promising therapeutics in this category are those targeting the TNFrelated apoptosis inducing ligand (TRAIL/Apo2L) pathway, in the form of agonistic antibodies to the TRAIL receptors [TRAIL-R1 (DR4) and TRAIL-R2 (DR5)] and soluble TRAIL, all of which are currently undergoing clinical evaluation (reviewed in ref. 1).…”