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TRAIL death receptors as tumor suppressors and drug targets
Niklas Finnberg1, Wafik S El-Deiry
1Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine (Hematology/Oncology), The Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Abstract:
Various ways of targeting TRAIL-death receptors for the treatment of a diverse set of malignancies are being explored in ongoing clinical trials. Recent data of ours and others suggest that loss of the only death signaling receptor in mice (TRAIL-R) is associated with susceptibility to various stages of lymphomagenesis and carcinogenesis, perhaps in a complex cell- and model-specific manner. Myc-overexpressing B cell lymphomas with an intact TRAIL-R locus displayed a number of gene expression changes indicating resistance to TRAIL-R signaling. Herein we show some data on the use of recombinant human TRAIL (rhTRAIL) and gamma-radiation (10 Gy) in combination in an autochthonous mouse model for hepatocellular carcinoma. As cell death signaling through the death receptors is evolutionary conserved from zebra fish to man, novel genetically engineered mouse tumor models may prove useful in establishing in vivo models that excel our fundamental understanding of resistance to TRAIL-death receptor signaling, off-target effects from TRAIL-death receptor targeting compounds and help in identifying a clinically cogent rationale for efficient targeting of TRAIL death receptors in patients. Once established, mouse tumor models may prove to be a useful tool in understanding TRAIL-death receptor signaling.
Insights
Targeting tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors shows promise for cancer treatment. Combining recombinant human TRAIL (rhTRAIL) with gamma-radiation may overcome resistance in hepatocellular carcinoma models.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Targeting TRAIL-death receptors is a promising cancer therapy strategy currently in clinical trials.
- Loss of TRAIL-death receptors (TRAIL-R) in mice correlates with increased susceptibility to lymphomagenesis and carcinogenesis.
- Myc-overexpressing B cell lymphomas with intact TRAIL-R exhibit gene expression changes indicating resistance to TRAIL-R signaling.
Purpose of the Study:
- To investigate the combined efficacy of recombinant human TRAIL (rhTRAIL) and gamma-radiation in an autochthonous mouse model of hepatocellular carcinoma.
- To explore the utility of novel genetically engineered mouse tumor models for understanding TRAIL-death receptor signaling resistance.
- To identify potential off-target effects and clinical rationales for TRAIL-death receptor targeting.
Main Methods:
- Utilized an autochthonous mouse model for hepatocellular carcinoma.
- Administered a combination therapy of recombinant human TRAIL (rhTRAIL) and gamma-radiation (10 Gy).
- Leveraged genetically engineered mouse tumor models to study cell death signaling.
Main Results:
- Presented data on the combined use of rhTRAIL and gamma-radiation in a hepatocellular carcinoma mouse model.
- Highlighted the conserved nature of death receptor signaling pathways across species.
- Suggested that mouse models are valuable for understanding TRAIL-death receptor signaling resistance.
Conclusions:
- Novel mouse tumor models can enhance understanding of resistance to TRAIL-death receptor signaling.
- These models may help identify clinically relevant strategies for targeting TRAIL-death receptors in cancer patients.
- Further research using these models can elucidate off-target effects and optimize TRAIL-based therapies.
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