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
  • Middle Aged
  • Peptide Fragments/chemistry*
  • Male
  • Cell Line, Tumor
  • Cisplatin/pharmacology
  • Cisplatin/therapeutic use
  • Apoptosis/drug effects
  • Neoplasm Proteins/metabolism
  • Squamous Cell Carcinoma of Head and Neck/drug therapy*
  • Squamous Cell Carcinoma of Head and Neck/pathology
  • Treatment Outcome
  • Xenograft Model Antitumor Assays
  • Animals
  • Antineoplastic Agents/pharmacology
  • Antineoplastic Agents/therapeutic use
  • Female
  • Zebrafish
  • Kaplan-Meier Estimate
  • Humans
  • Proto-Oncogene Proteins/chemistry*
(all 20)
PubMed
31801952 Full text @ Cell Death Dis.
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
Figures
Figure Gallery (5 images)
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Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
mitfaw2/w2; mq8Tgcancer xenotransplantationProtruding-mouth
1 - 1 of 1
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
mq8TgTransgenic Insertion
    w2
      		Point Mutation
      1 - 2 of 2
      Show
      Human Disease / Model
      Human Disease Fish Conditions Evidence
      head and neck squamous cell carcinomaTAS
      squamous cell carcinomaTAS
      1 - 2 of 2
      Show
      Sequence Targeting Reagents
      No data available
      Fish
      Fish
      mitfaw2/w2; mq8Tg
      1 - 1 of 1
      Show
      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      mCherryEFGmCherry
      VenusEFGVenus
      1 - 2 of 2
      Show
      Mapping
      No data available
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      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.