Reverse-Phase Protein Array Profiling of Oropharyngeal Cancer and Significance of PIK3CA Mutations in HPV-Associated Head and Neck Cancer

Sewell, Andrew; Brown, Brandee; Biktasova, Asel; Mills, Gordon B.; Lu, Yiling; Tyson, Darren R.; Issaeva, Natalia; Yarbrough, Wendell G.

doi:10.1158/1078-0432.ccr-13-2585

Cited by 85 publications

(74 citation statements)

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“…120,121 In addition, when the protein profiles of HPV-positive and HPV-negative HNSCC were compared, five pathways that regulate cell-cycle, DNA-repair, apoptosis, receptor-kinase signalling and the PI3K/AKT/ mTOR pathway were shown to be differentially involved. 85 Interestingly, the downstream signalling between mutant and wild-type PIK3CA within oropharyngeal cancers differed according to activating mutations in genes encoding mTOR/S6 rather than AKT. 85 This finding indicates that PI3K/mTOR inhibitors might be preferable to AKT inhibitors for the treatments of patients with HPVpositive PIK3CA-mutant cancers.…”

Section: Pik3camentioning

confidence: 99%

Emerging biomarkers in head and neck cancer in the era of genomics

2014

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Head and neck cancer (HNC) broadly includes carcinomas arising from the mucosal epithelia of the head and neck region as well as various cell types of salivary glands and the thyroid. As reflected by the multiple sites and histologies of HNC, the molecular characteristics and clinical outcomes of this disease vary widely. In this Review, we focus on established and emerging biomarkers that are most relevant to nasopharyngeal carcinoma and head and neck squamous-cell carcinoma (HNSCC), which includes primary sites in the oral cavity, oropharynx, hypopharynx and larynx. Applications and limitations of currently established biomarkers are discussed along with examples of successful biomarker development. For emerging biomarkers, preclinical or retrospective data are also described in the context of recently completed comprehensive molecular analyses of HNSCC, which provide a broad genetic landscape and molecular classification beyond histology and clinical characteristics. We will highlight the ongoing effort that will see a shift from prognostic to predictive biomarker development in HNC with the goal of delivering individualized cancer therapy.

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Section: Pik3camentioning

confidence: 99%

Emerging biomarkers in head and neck cancer in the era of genomics

2014

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“…In addition, HPV þ HNSCC responds better to chemotherapy and radiation than HPV À HNSCC, and HPV positivity is associated with improved overall survival (5). At the molecular level, HPV þ and HPV À head and neck cancers have different mutational landscapes and different protein expression profiles (6)(7)(8)(9)(10). HPV À HNSCCs contain mutations and genetic alterations classically associated with tobacco and alcohol exposure, including loss-of-function mutations of TP53 (84%) and loss or inactivating mutations of CDKN2A (54%).…”

Section: Introductionmentioning

confidence: 99%

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

Biktasova

Hajek

Sewell

et al. 2017

Clinical Cancer Research

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Purpose: DNA methylation in human papillomavirus-associated (HPV þ ) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV þ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV þ HNSCC.Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV þ HNSCC.Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV þ HNSCC. classically associated with tobacco and alcohol exposure, including loss-of-function mutations of TP53 (84%) and loss or inactivating mutations of CDKN2A (54%). In contrast, genetic alterations in these genes are extremely rare in the HPV þ subset (TP53, 3%; CDKN2A, 0%; ref. 6), which instead is associated with a mutational signature typical of apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) antiviral proteins (6, 11-13). In addition, The Cancer Genome Atlas (TCGA) head and neck study found that TNF receptor-associated factor 3 (TRAF3) and CYLD genes are commonly mutated and deleted in HPV þ HNSCC (6,8,14). Finally, HPV À HNSCC have relatively low levels of DNA methylation, which is correlated with genomic instability (15), whereas HPV þ HNSCC harbor distinctly hypermethylated genomes (7,8,16,17). Demographic, clinical, molecular, and epigenetic differences between HPV þ and HPV À HNSCC suggest two distinct cancers, yet HPV À status is currently only used for prognosis and not to guide treatment (18). A majority of HNSCC patients are treated with radiation and platin-based chemotherapy, which is associated with deleterious and lifelong side-effects. Despite the relatively good prognosis associated with HPV þ HNSCC, 25%-30% of patients with HPV-positive tumors experience recurrent or metastatic disease, for which treatment options are limited. The molecular and epigenetic differences between HPV þ and HPV À tumors provide an opportunity for therapies that exploit the interaction of the HPV genome and host that result in hypermethylation of cancer cell genomes. 5-Azacytidine (5-aza)

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“…Mutation in PIK3CA gene has also been associated with poorer prognosis in human cancer (94)(95)(96). However, no conclusive data are reported for HNSCC (66,97). Nevertheless, a relevant number of inhibitors targeting PIK3CA or the PI3K pathway are available and on trial (98).…”

Section: Studies Focusing On Immunological and Stem Cell Markers In Tmentioning

confidence: 99%

“…Sewell et al used reverse-phase protein array profiling on a restricted set of 137 total and phosphorylated proteins (66). Differences were found in e.g.…”

Section: Protein Profiling In Oropharyngeal Cancermentioning

confidence: 99%

Human Papillomavirus and Potentially Relevant Biomarkers in Tonsillar and Base of Tongue Squamous Cell Carcinoma

Näsman

Bersani

Lindquist

et al. 2017

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Abstract. Human papillomavirus (HPV)-positive tonsillarand base of tongue cancer is increasing epidemically and has much better outcome than corresponding HPV-negativeIn 2007, human papillomavirus (HPV) was recognized as a risk factor for oropharyngeal squamous cell carcinoma (OPSCC) by the International Agency for Research against Cancer (IARC), besides the traditional risk factors smoking and alcohol (1-4). Concurrently, an increased incidence of OPSCC, more specifically tonsillar and base of tongue cancer (TSCC and BOTSCC, the two main HPV-positive OPSCC sites) was described in many developed countries, and found to be due to a sharp rise of HPV-positive cases (5-18). These HPV-positive tumors had a much better clinical outcome than their HPV-negative counterparts and head and neck squamous cell carcinoma (HNSCC) in general when treated with radiotherapy and surgery (1-3, 15-17, 19, 20). Treatment of HNSCC including OPSCC has, however, gradually become more intensified with induction chemotherapy or concurrent chemo-radiotherapy and sometimes the administration of Erbitux, leading to more severe side effects (16, 20, 21). This is likely unnecessary for most HPV-positive TSCC and BOTSCC patients since they generally respond well to less therapy and furthermore, intensified therapy does not improve survival of [15][16][17] 20, 22, 23). It is, therefore, important to identify patients with HPV-positive TSCC and BOTSCC eligible for less treatment or targeted therapy and efforts focus now on finding predictive and targetable markers for these patients (24-39).Here, a short background of the field and an update on recent attempts to find predictive and targetable markers with different methodologies for individualized therapy is presented. Human Papillomavirus in Tonsillar and Base of Tongue Squamous Cell Carcinoma and an Epidemic Increase of these TumorsIn 2000, an association between HPV and OPSCC and TSCC was reported, and with radiotherapy and surgery, these HPVpositive cases had much better outcome than corresponding HPV-negative cases (80% vs. 40-50% 5-year survival) (1, 2). In 2004, a similar relationship of HPV to BOTSCC, but not to mobile tongue cancer was disclosed (40). Based on 5319

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Reverse-Phase Protein Array Profiling of Oropharyngeal Cancer and Significance of PIK3CA Mutations in HPV-Associated Head and Neck Cancer

Cited by 85 publications

References 50 publications

Emerging biomarkers in head and neck cancer in the era of genomics

Emerging biomarkers in head and neck cancer in the era of genomics

Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer

Human Papillomavirus and Potentially Relevant Biomarkers in Tonsillar and Base of Tongue Squamous Cell Carcinoma

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