PUBLICATION
Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck
- Authors
- Carter, R.J., Milani, M., Butterworth, M., Alotibi, A., Harper, N., Yedida, G., Greaves, G., Al-Zebeeby, A., Jorgensen, A.L., Schache, A.G., Risk, J.M., Shaw, R.J., Jones, T.M., Sacco, J.J., Hurlstone, A., Cohen, G.M., Varadarajan, S.
- ID
- ZDB-PUB-191206-20
- Date
- 2019
- Source
- Cell Death & Disease 10: 912 (Journal)
- Registered Authors
- Hurlstone, Adam
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis/drug effects
- Cell Line, Tumor
- Cisplatin/pharmacology
- Cisplatin/therapeutic use
- Female
- Humans
- Kaplan-Meier Estimate
- Male
- Middle Aged
- Neoplasm Proteins/metabolism
- Peptide Fragments/chemistry*
- Proto-Oncogene Proteins/chemistry*
- Squamous Cell Carcinoma of Head and Neck/drug therapy*
- Squamous Cell Carcinoma of Head and Neck/pathology
- Treatment Outcome
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 31801952 Full text @ Cell Death Dis.
Citation
Carter, R.J., Milani, M., Butterworth, M., Alotibi, A., Harper, N., Yedida, G., Greaves, G., Al-Zebeeby, A., Jorgensen, A.L., Schache, A.G., Risk, J.M., Shaw, R.J., Jones, T.M., Sacco, J.J., Hurlstone, A., Cohen, G.M., Varadarajan, S. (2019) Exploring the potential of BH3 mimetic therapy in squamous cell carcinoma of the head and neck. Cell Death & Disease. 10:912.
Abstract
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide, with overall survival of less than 50%. Current therapeutic strategies involving a combination of surgery, radiation, and/or chemotherapy are associated with debilitating side effects, highlighting the need for more specific and efficacious therapies. Inhibitors of BCL-2 family proteins (BH3 mimetics) are under investigation or in clinical practice for several hematological malignancies and show promise in solid tumors. In order to explore the therapeutic potential of BH3 mimetics in the treatment of SCCHN, we assessed the expression levels of BCL-2, BCL-XL, and MCL-1 via Western blots and immunohistochemistry, in cell lines, primary cells derived from SCCHN patients and in tissue microarrays containing tumor tissue from a cohort of 191 SCCHN patients. All preclinical models exhibited moderate to high levels of BCL-XL and MCL-1, with little or no BCL-2. Although expression levels of BCL-XL and MCL-1 did not correlate with patient outcome, a combination of BH3 mimetics to target these proteins resulted in decreased clonogenic potential and enhanced apoptosis in all preclinical models, including tumor tissue resected from patients, as well as a reduction of tumor volume in a zebrafish xenograft model of SCCHN. Our results show that SCCHN is dependent on both BCL-XL and MCL-1 for apoptosis evasion and combination therapy targeting both proteins may offer significant therapeutic benefits in this disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping