The expanding role of IAP antagonists for the treatment of head and neck cancer

by Selleckchem | Nov 07 2023

Inhibitors of apoptosis proteins (IAPs) inhibit the intrinsic and extrinsic cell death pathways, promoting cell survival. Antagonists of these pathways are under study as anti-cancer therapeutics. A high proportion of head and neck squamous cell carcinomas (HNSCCs) have genomic alterations in IAP pathways, resulting in the dysregulation of cell death pathways and rendering them susceptible to IAP antagonist therapy. Preclinical studies suggest IAP antagonists, also known as second mitochondria-derived activator of caspases mimetics, may be effective treatments for HNSCC, especially when combined with radiation. Mechanistic studies have shown both molecular mechanisms (i.e., enhanced cell death) and immune mechanisms (e.g., immunogenic cell death and T-cell activation), underlying the efficacy of these drugs in preclinical models. Phase I/II clinical trials have shown promising results, portending a future where this class of targeted therapies becomes incorporated into the treatment paradigm for head and neck cancers. IAP antagonists have shown great promise for head and neck cancer, especially in combination with radiation therapy. Here, we review recent preclinical and clinical studies on the use of these novel targeted agents for head and neck cancer.

Comments:

Inhibitors of apoptosis proteins (IAPs) play a crucial role in regulating cell death pathways and promoting cell survival. However, in many cancers, including head and neck squamous cell carcinomas (HNSCCs), there are genomic alterations in IAP pathways that result in the dysregulation of cell death mechanisms. This dysregulation renders HNSCC cells more susceptible to IAP antagonist therapy.

IAP antagonists, also known as second mitochondria-derived activator of caspases (SMAC) mimetics, have emerged as potential anti-cancer therapeutics. These compounds target and inhibit IAPs, which leads to the restoration of cell death pathways and enhances programmed cell death in cancer cells. Preclinical studies, conducted prior to clinical trials, have demonstrated the effectiveness of IAP antagonists as treatments for HNSCC.

In particular, combining IAP antagonists with radiation therapy has shown promise. This combination treatment has been found to increase cell death in HNSCC cells compared to either treatment alone. The molecular mechanisms underlying the efficacy of IAP antagonists include enhanced cell death, while immune mechanisms such as immunogenic cell death and activation of T-cells have also been observed in preclinical models.

Clinical trials, specifically Phase I/II studies, have further supported the potential of IAP antagonists in treating head and neck cancers. These trials have shown promising results, suggesting that IAP antagonists could be incorporated into the standard treatment approach for HNSCC in the future.

In summary, IAP antagonists have demonstrated great promise as targeted therapies for head and neck cancer, particularly when combined with radiation therapy. Both preclinical and clinical studies have provided evidence of their efficacy and potential mechanisms of action. Further research and larger-scale clinical trials are needed to fully establish the safety and long-term effectiveness of IAP antagonists in the treatment of head and neck cancers.