DNA Damage; Head and Neck Neoplasms; Salivary Gland Neoplasms; NF-kappa B; Tumor Suppressor Proteins; Human papillomavirus 16; Human Papillomavirus DNA Tests; Diseases
Identification of tumor suppressors in head and neck cancers; Understanding of tumor growth; Association between viruses and the development of cancer, particularly the link between the human papillomavirus and head and neck cancers.
Specialized Terms: Head and neck oncology; Salivary oncology; Mouse modeling of human cancer; Human-in-mouse cancer models; Tumor suppressor activity; Molecular defects in cancer; NF-kappa B; NF-kB; Signaling; DNA damage; Human papilloma virus; HPV
Extensive Research Description
I am a surgeon-scientist active in head & neck cancer research for more than two decades. In 2012, I was appointed Chief of Otolaryngology, Director of the Head & Neck Disease Center and Co-Director of the Molecular Virology Program at Yale. Since my arrival, Dr. Issaeva (Co-PI) and I have worked to established a translational research program at Yale focused on head and neck squamous cell carcinoma (HNSCC) with particular interest in HPV-associated cancers. Priorities have been to better understand defects in HPV-associated HNSCC and to identify molecular characteristics that may be essential for tumor formation or maintenance. While prioritizing projects, we took advantage of hypermethylation of HPV+ cancers to explore demethylating drugs and found that these tumors are very responsive to 5-azacytidine (5-aza). We found that 5-aza decreased expression of HPV genes, restored p53 levels and activity, and caused DNA damage, particularly double strand breaks (DSB). Cytotoxicity of 5-aza toward HPV-positive (HPV+) HNSCC was partially attributable to p53 and partially due to DNA damage. Mechanistic studies found that 5-aza-induced DSB required transcription, replication and APOBEC3B, a cytidine deaminase active in virally infected cells.These studies led to an investigator-initiated window trial at Yale Cancer Center. The desire to translate our discoveries for the benefit of patients drives our research. Although we have only relatively recently focused on HPV(+) HNSCC, our research team has made key discoveries and created the infrastructure that has great potential to advance understanding of mechanisms of tumorigenesis and tumor maintenance in HPV-associated HNSCC.
Characterization of HPV and host genome interactions in primary head and neck cancers.
Characterization of HPV and host genome interactions in primary head and neck cancers. Parfenov M, Pedamallu CS, Gehlenborg N, Freeman SS, Danilova L, Bristow CA, Lee S, Hadjipanayis AG, Ivanova EV, Wilkerson MD, Protopopov A, Yang L, Seth S, Song X, Tang J, Ren X, Zhang J, Pantazi A, Santoso N, Xu AW, Mahadeshwar H, Wheeler DA, Haddad RI, Jung J, Ojesina AI, Issaeva N, Yarbrough WG, Hayes DN, Grandis JR, El-Naggar AK, Meyerson M, Park PJ, Chin L, Seidman JG, Hammerman PS, Kucherlapati R; the Cancer Genome Atlas Network; the Cancer Genome Atlas Network. Proc Natl Acad Sci U S A. 2014 Oct 13. pii: 201416074. [Epub ahead of print]
Conclusions about human papillomavirus-related malignancies.
Conclusions about human papillomavirus-related malignancies. Yarbrough WG, Rosenthal E. Head Neck. 2014 Jun;36(6):826-7. doi: 10.1002/hed.23378. Epub 2013 Sep 2.
Full List of PubMed Publications
- Wamsley JJ, Gary C, Biktasova A, Hajek M, Bellinger G, Virk R, Issaeva N, Yarbrough WG: Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner. Oncogenesis. 2017 Apr 10; 2017 Apr 10. PMID: 28394357
- Fujiwara RJ, Judson BL, Yarbrough WG, Husain Z, Mehra S: Treatment delays in oral cavity squamous cell carcinoma and association with survival. Head Neck. 2017 Apr; 2017 Feb 25. PMID: 28236349
- An Y, Park HS, Kelly JR, Stahl JM, Yarbrough WG, Burtness BA, Contessa JN, Decker RH, Koshy M, Husain ZA: The prognostic value of extranodal extension in human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cancer. 2017 Mar 21; 2017 Mar 21. PMID: 28323338
- Hajek M, Sewell A, Kaech S, Burtness B, Yarbrough WG, Issaeva N: TRAF3/CYLD mutations identify a distinct subset of human papilloma virus-associated head and neck squamous cell carcinoma. Cancer. 2017 Mar 13; 2017 Mar 13. PMID: 28295222
- Tan WJT, Song L, Graham M, Schettino A, Navaratnam D, Yarbrough WG, Santos-Sacchi J, Ivanova AV: Novel Role of the Mitochondrial Protein Fus1 in Protection from Premature Hearing Loss via Regulation of Oxidative Stress and Nutrient and Energy Sensing Pathways in the Inner Ear. Antioxid Redox Signal. 2017 Mar 9; 2017 Mar 9. PMID: 28135838
- Panaccione A, Zhang Y, Mi Y, Mitani Y, Yan G, Prasad ML, McDonald WH, El-Naggar AK, Yarbrough WG, Ivanov SV: Chromosomal abnormalities and molecular landscape of metastasizing mucinous salivary adenocarcinoma. Oral Oncol. 2017 Mar; 2017 Jan 9. PMID: 28249646
- Lee NC, Kelly JR, Park HS, Yarbrough WG, Burtness BA, Husain ZA: The risk of level IB nodal involvement in oropharynx cancer: Guidance for submandibular gland sparing irradiation. Pract Radiat Oncol. 2017 Feb 16; 2017 Feb 16. PMID: 28356201
- Panaccione A, Guo Y, Yarbrough WG, Ivanov SV: Expression Profiling of Clinical Specimens Supports the Existence of Neural Progenitor-Like Stem Cells in Basal Breast Cancers. Clin Breast Cancer. 2017 Jan 27; 2017 Jan 27. PMID: 28216417
- Wamsley JJ, Issaeva N, An H, Lu X, Donehower LA, Yarbrough WG: LZAP is a novel Wip1 binding partner and positive regulator of its phosphatase activity in vitro. Cell Cycle. 2017 Jan 17; 2016 Dec 27. PMID: 28027003
- Kelly JR, Park HS, An Y, Contessa JN, Yarbrough WG, Burtness BA, Decker R, Husain Z: Comparison of Survival Outcomes Among Human Papillomavirus-Negative cT1-2 N1-2b Patients With Oropharyngeal Squamous Cell Cancer Treated With Upfront Surgery vs Definitive Chemoradiation Therapy: An Observational Study. JAMA Oncol. 2017 Jan 5; 2017 Jan 5. PMID: 28056116
- Kuo P, Mehra S, Sosa JA, Roman SA, Husain ZA, Burtness BA, Tate JP, Yarbrough WG, Judson BL: Proposing prognostic thresholds for lymph node yield in clinically lymph node-negative and lymph node-positive cancers of the oral cavity. Cancer. 2016 Dec 1; 2016 Aug 1. PMID: 27479645
- Gary C, Hajek M, Biktasova A, Bellinger G, Yarbrough WG, Issaeva N: Selective antitumor activity of roscovitine in head and neck cancer. Oncotarget. 2016 Jun 21. PMID: 27233076
- Kuo P, Sosa JA, Burtness BA, Husain ZA, Mehra S, Roman SA, Yarbrough WG, Judson BL: Treatment trends and survival effects of chemotherapy for hypopharyngeal cancer: Analysis of the National Cancer Data Base. Cancer. 2016 Jun 15; 2016 Mar 28. PMID: 27019213
- Panaccione A, Chang MT, Carbone BE, Guo Y, Moskaluk CA, Virk RK, Chiriboga L, Prasad ML, Judson B, Mehra S, Yarbrough WG, Ivanov SV: NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma. Clin Cancer Res. 2016 Apr 15. PMID: 27084744
- Schwam ZG, Burtness B, Yarbrough WG, Mehra S, Husain Z, Judson BL: National treatment patterns in patients presenting with Stage IVC head and neck cancer: analysis of the National Cancer Database. Cancer Med. 2015 Dec; 2015 Oct 16. PMID: 26471244
- Uzhachenko R, Shanker A, Yarbrough WG, Ivanova AV: Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation, and autoimmunity. Oncotarget. 2015 Aug 28. PMID: 26246474
- Baldassarri R, Aronberg R, Levi AW, Yarbrough WG, Kowalski D, Chhieng D: Detection and genotype of high-risk human papillomavirus in fine-needle aspirates of patients with metastatic squamous cell carcinoma is helpful in determining tumor origin. Am J Clin Pathol. 2015 May. PMID: 25873503
- Farmer RW, McCall L, Civantos FJ, Myers JN, Yarbrough WG, Murphy B, O'Leary M, Zitsch R, Siegel BA: Lymphatic drainage patterns in oral squamous cell carcinoma: findings of the ACOSOG Z0360 (Alliance) study. Otolaryngol Head Neck Surg. 2015 Apr; 2015 Mar 6. PMID: 25749001
- Yazlovitskaya EM, Voziyan PA, Manavalan T, Yarbrough WG, Ivanova AV: Cellular oxidative stress response mediates radiosensitivity in Fus1-deficient mice. Cell Death Dis. 2015 Feb 19; 2015 Feb 19. PMID: 25695605
- Lu X, Yarbrough WG: Negative regulation of RelA phosphorylation: emerging players and their roles in cancer. Cytokine Growth Factor Rev. 2015 Feb; 2014 Oct 2. PMID: 25438737
- Aronberg RM, Punekar SR, Adam SI, Judson BL, Mehra S, Yarbrough WG: Esophageal perforation caused by edible foreign bodies: a systematic review of the literature. Laryngoscope. 2015 Feb; 2014 Aug 22. PMID: 25155167
- Yarbrough WG, Sewell A, Tickle E, Rhinehardt E, Harkleroad R, Bennett M, Johnson D, Wen L, Pfeiffer M, Benegas M, Morath J: A tool to determine financial impact of adverse events in health care: healthcare quality calculator. J Patient Saf. 2014 Dec. PMID: 24080720
- Parfenov M, Pedamallu CS, Gehlenborg N, Freeman SS, Danilova L, Bristow CA, Lee S, Hadjipanayis AG, Ivanova EV, Wilkerson MD, Protopopov A, Yang L, Seth S, Song X, Tang J, Ren X, Zhang J, Pantazi A, Santoso N, Xu AW, Mahadeshwar H, Wheeler DA, Haddad RI, Jung J, Ojesina AI, Issaeva N, Yarbrough WG, Hayes DN, Grandis JR, El-Naggar AK, Meyerson M, Park PJ, Chin L, Seidman JG, Hammerman PS, Kucherlapati R, Cancer Genome Atlas Network.: Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci U S A. 2014 Oct 28; 2014 Oct 13. PMID: 25313082
- Moser R, Xu C, Kao M, Annis J, Lerma LA, Schaupp CM, Gurley KE, Jang IS, Biktasova A, Yarbrough WG, Margolin AA, Grandori C, Kemp CJ, Méndez E: Functional kinomics identifies candidate therapeutic targets in head and neck cancer. Clin Cancer Res. 2014 Aug 15. PMID: 25125259
- Luryi AL, Yarbrough WG, Niccolai LM, Roser S, Reed SG, Nathan CA, Moore MG, Day T, Judson BL: Public awareness of head and neck cancers: a cross-sectional survey. JAMA Otolaryngol Head Neck Surg. 2014 Jul. PMID: 24902640
- Yarbrough WG, Rosenthal E: Conclusions about human papillomavirus-related malignancies. Head Neck. 2014 Jun; 2013 Sep 2. PMID: 23696473
- Lu X, An H, Jin R, Zou M, Guo Y, Su PF, Liu D, Shyr Y, Yarbrough WG: PPM1A is a RelA phosphatase with tumor suppressor-like activity. Oncogene. 2014 May 29; 2013 Jul 1. PMID: 23812431
- Sewell A, Brown B, Biktasova A, Mills GB, Lu Y, Tyson DR, Issaeva N, Yarbrough WG: Reverse-phase protein array profiling of oropharyngeal cancer and significance of PIK3CA mutations in HPV-associated head and neck cancer. Clin Cancer Res. 2014 May 1; 2014 Mar 5. PMID: 24599934
- Thompson PD, Sakwe A, Koumangoye R, Yarbrough WG, Ochieng J, Marshall DR: Alpha-2 Heremans Schmid Glycoprotein (AHSG) modulates signaling pathways in head and neck squamous cell carcinoma cell line SQ20B. Exp Cell Res. 2014 Feb 15; 2013 Dec 12. PMID: 24332981
- Ivanov SV, Panaccione A, Brown B, Guo Y, Moskaluk CA, Wick MJ, Brown JL, Ivanova AV, Issaeva N, El-Naggar AK, Yarbrough WG: TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior. Oncogene. 2013 Aug 8; 2012 Oct 1. PMID: 23027130
- Ivanov SV, Panaccione A, Nonaka D, Prasad ML, Boyd KL, Brown B, Guo Y, Sewell A, Yarbrough WG: Diagnostic SOX10 gene signatures in salivary adenoid cystic and breast basal-like carcinomas. Br J Cancer. 2013 Jul 23; 2013 Jun 25. PMID: 23799842