HPV-associated Head Research Articles

An Infection-Based Murine Model for Papillomavirus-Associated Head and Neck Cancer.

Human papillomavirus (HPV) is the most common sexually transmitted pathogen, and high-risk HPVs contribute to 5% of human cancers, including 25% of head and neck squamous cell carcinomas (HNSCCs). Despite the significant role played by HPVs in HNSCC, there is currently no available in vivo system to model the process from papillomavirus infection to virus-induced HNSCC. In this paper, we describe an infection-based HNSCC model, utilizing a mouse papillomavirus (MmuPV1), which naturally infects laboratory mice. Infections of the tongue epithelium of two immunodeficient strains with MmuPV1 caused high-grade squamous dysplasia with early signs of invasive carcinoma over the course of 4 months. When combined with the oral carcinogen 4-nitroquinoline-1-oxide (4NQO), MmuPV1 caused invasive squamous cell carcinoma (SCC) on the tongue of both immunodeficient and immunocompetent mice. These tumors expressed markers of papillomavirus infection and HPV-associated carcinogenesis. This novel preclinical model provides a valuable new means to study how natural papillomavirus infections contribute to HNSCC.IMPORTANCE The species specificity of papillomavirus has limited the development of an infection-based animal model to study HPV-associated head and neck carcinogenesis. Our study presents a novel in vivo model using the mouse papillomavirus MmuPV1 to study papillomavirus-associated head and neck cancer. In our model, MmuPV1 infects and causes lesions in both immunodeficient and genetically immunocompetent strains of mice. These virally induced lesions carry features associated with both HPV infections and HPV-associated carcinogenesis. Combined with previously identified cancer cofactors, MmuPV1 causes invasive squamous cell carcinomas in mice. This model provides opportunities for basic and translational studies of papillomavirus infection-based head and neck disease.

Endogenously-Activated Ultrasmall-in-Nano Therapeutics: Assessment on 3D Head and Neck Squamous Cell Carcinomas.

Negative or positive HPV-associated Head and Neck Squamous Cell Carcinomas (HNSCCs) are high recurrence neoplasms usually resulting in a poor prognosis, mainly due to metastasis formation. Despite the low overall patient survival rate and the severe side effects, the treatment of choice is still cisplatin-based chemotherapy. Here, we report a straightforward protocol for the production of high throughput 3D models of negative or positive HPV-associated HNSCCs, together with their employment in the therapeutic evaluation of gold ultrasmall-in-nano architectures comprising an endogenously-activatable cisplatin prodrug. Beyond enhancing the biosafety of cisplatin, our approach paves the way for the establishment of synergistic co-therapies for HNSCCs based on excretable noble metals.

Oropharyngeal HPV Detection Techniques in HPV-associated Head and Neck Cancer Patients.

The incidence of human papilloma virus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has been increasing in the last decades. Analysis of oral brushing or rinsing samples for screening or stratification could potentially improve screening and prevention. Oral brushes and mouthwashes were taken from 20 patients with HPV-associated HNSCC before definite therapy. HPV genotyping was performed for the detection of 14 high-risk HPV subtypes and correlated to DNA isolated from tumor tissue. Ten of 20 patients were tested HPV positive by using either method. There was a significant correlation between macroscopic visibility of tumor and positive HPV detection (p<0.001) and HPV detection and tumor size (p<0.001). HPV was detected in all macroscopically visible tumors. Half of the HPV cases who had macroscopically invisible tumors were missed by both methods. Both techniques are limited in the detection of macroscopically non-visible and small tumors. Therefore, the application of these techniques for screening or diagnosis of HNSCC is not recommended.

STOP HPV study protocol: a nationwide case–control study of the association between oropharyngeal cancer and human papillomavirus (HPV) infection in Brazil

IntroductionHuman papillomavirus (HPV) is the most common sexually transmitted infection and is associated with several types of cancer. The number of cases of HPV-associated head and neck squamous cell carcinomas...

Lessons Learned from Deescalation Trials in Favorable Risk HPV-Associated Squamous Cell Head and Neck Cancer-A Perspective on Future Trial Designs.

In recent years several clinical studies have investigated deintensified treatments in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma. Two large phase III trials, RTOG 1016 and De-ESCALaTE, which attempted to reduce toxicity by replacing radiotherapy in combination with cisplatin with the use of cetuximab in combination with radiotherapy, recently suggested that radiotherapy + cetuximab leads to inferior survival compared with standard therapy (observed HRs of 1.45 and 5 in RTOG 1016 and De-ESCALaTE), as well as increased rates of locoregional failure. These unexpected results should prompt a careful examination of deintensification trials, both in HPV-associated oropharyngeal cancer and in other contexts. Statistical designs for deintensification studies should be consistent with the study aims of reducing toxicities while maintaining survival nearly identical to the standard of care. We suggest criteria to design future deintensification trials and discuss important operating characteristics, including tradeoffs between power and stringent early stopping rules to reduce the number of patients exposed to inferior treatments. Using retrospective analyses of previous clinical studies, we compared designs with different operating characteristics. As an example, using outcomes data from RTOG 1016 and De-ESCALaTE, we conducted analyses to determine advantages of (i) stringent futility early-stopping rules and of (ii) study designs that leverage both toxicity and efficacy endpoints for interim analyses. We show that increasing the frequency of interim-futility analyses has little impact on power, but the average study duration and number of subjects enrolled before the trial is closed for inferiority can decrease substantially (from 57.8 to 18 months, and from 764 to 645 subjects). Moreover, the number of observed deaths during the study can be reduced by up to 68%.

Update on HPV-associated head and neck cancer-highlights from the 2019 ASCO Annual Meeting

At this year's Annual Meeting of the American Society for Clinical Oncology (ASCO), the keyword search "HPV-associated head and neck cancer" resulted in 920 hits-74% of the hits on human papillomavirus (HPV). This underlines the relevance of the topic. The spectrum ranged from validation and separation of the prognostic groups of patients with HPV-associated oropharyngeal carcinoma (OPSCC) according to TNM8, to the characterization of new tumor markers and tumor mutational burden for possible de-escalation strategies to avoid toxicity of standard multimodal treatments. It has been shown that the separation of p16-positive OPSCC into Union for International Cancer Control (UICC) stagesI andII with the current TNM8 classification without further markers is not sufficiently successful to justify de-escalation strategies. Following publication of the results of the De-ESCALaTE- and RTOG-1016 trials in 2018, which confirm the current standard of care for p16-positive OPSCC, no further phaseIII studies on de-escalation were presented. In apresented prospective phaseII study (NCT02281955), the radiotherapy dose was reduced to cumulative 60 Gy, whereby the simultaneous chemotherapy regimen with cisplatin 30 mg/m2 weekly is not standard of care and could be administered as an alternative to cisplatin cetuximab. Some work dealt with the oral and intestinal microbiota as prognostic markers or their treatment-related changes, particularly under immunotherapy. Modification seems to have apositive impact on the success of therapy. However, robust data are still lacking for the various modified treatments for HPV-associated OPSCC, which are needed before their implementation in daily practice.

A Current Update on Human Papillomavirus-Associated Head and Neck Cancers.

Human papillomavirus (HPV) infection is the cause of a growing percentage of head and neck cancers (HNC); primarily, a subset of oral squamous cell carcinoma, oropharyngeal squamous cell carcinoma, and laryngeal squamous cell carcinoma. The majority of HPV-associated head and neck cancers (HPV + HNC) are caused by HPV16; additionally, co-factors such as smoking and immunosuppression contribute to the progression of HPV + HNC by interfering with tumor suppressor miRNA and impairing mediators of the immune system. This review summarizes current studies on HPV + HNC, ranging from potential modes of oral transmission of HPV (sexual, self-inoculation, vertical and horizontal transmissions), discrepancy in the distribution of HPV + HNC between anatomical sites in the head and neck region, and to studies showing that HPV vaccines have the potential to protect against oral HPV infection (especially against the HPV types included in the vaccines). The review concludes with a discussion of major challenges in the field and prospects for the future: challenges in diagnosing HPV + HNC at early stages of the disease, measures to reduce discrepancy in the prevalence of HPV + HNC cases between anatomical sites, and suggestions to assess whether fomites/breast milk can transmit HPV to the oral cavity.

Human papillomavirus 16 promotes microhomology-mediated end-joining

Squamous cell carcinomas (SCCs) arising from aerodigestive or anogenital epithelium that are associated with the human papillomavirus (HPV) are far more readily cured with radiation therapy than HPV-negative SCCs. The mechanism behind this increased radiosensitivity has been proposed to be secondary to defects in DNA repair, although the specific repair pathways that are disrupted have not been elucidated. To gain insight into this important biomarker of radiosensitivity, we first examined genomic patterns reflective of defects in DNA double-strand break repair, comparing HPV-associated and HPV-negative head and neck cancers (HNSCC). Compared to HPV-negative HNSCC genomes, HPV+ cases demonstrated a marked increase in the proportion of deletions with flanking microhomology, a signature associated with a backup, error-prone double-strand break repair pathway known as microhomology-mediated end-joining (MMEJ). Then, using 3 different methodologies to comprehensively profile double-strand break repair pathways in isogenic paired cell lines, we demonstrate that the HPV16 E7 oncoprotein suppresses canonical nonhomologous end-joining (NHEJ) and promotes error-prone MMEJ, providing a mechanistic rationale for the clinical radiosensitivity of these cancers.

Incidence and Demographic Burden of HPV-Associated Oropharyngeal Head and Neck Cancers in the United States.

Human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (OPSCC) is increasing in the United States. Current epidemiologic assessments of the national burden of HPV-positive OPSCC are needed. The Surveillance Epidemiology and End Results HPV Status Database included 12,017 patients with head and neck squamous cell carcinoma of pharyngeal subsites, including OPSCC and non-OPSCC head and neck cancer subsites (hypopharynx, nasopharynx, and "other pharynx"), diagnosed from 2013 to 2014. Age-adjusted incidence rates per 100,000 persons by HPV status were calculated. An exploratory Fine-Gray competing-risks regression determined the associations between HPV status and cancer-specific mortality. From 2013 to 2014, the U.S. incidence of HPV-positive OPSCC was 4.62 [95% confidence interval (CI), 4.51-4.73] versus 1.82 (95% CI, 1.75-1.89) per 100,000 persons for HPV-negative OPSCC. The incidence of HPV-positive versus negative non-OPSCC of the head and neck was 0.62 (95% CI, 0.58-0.66) versus 1.38 (95% CI, 1.32-1.44). White race (5.47) and male sex (8.00) had the highest incidences of HPV-positive OPSCC, with a unimodal age incidence distribution peaking at ages 60 to 64 years (27.23). HPV positivity was associated with lower cancer-specific mortality than HPV-negative disease for OPSCC [adjusted HR (aHR), 0.40; P < 0.001], but not non-OPSCC (aHR, 1.08; P = 0.81), P interaction = 0.002. The U.S. incidence of HPV-positive OPSCC was 4.62 per 100,000 persons. Most cases were found in white male patients younger than 65 years, where it represents the sixth most common incident nonskin cancer. The favorable prognosis associated with HPV appears to be limited to the oropharynx. This large population-based epidemiologic assessment of the U.S. population defines the incidence and demographic burden of HPV-positive OPSCC.

Luciferase-Based Detection of Antibodies for the Diagnosis of HPV-Associated Head and Neck Squamous Cell Carcinoma.

Point-of-care tests are needed for the screening of head and neck squamous cell carcinoma (HNSCC) and other malignancies. Luciferase immunoprecipitation systems (LIPS), employing light-emitting proteins, were used to examine serum antibodies against several cancer-associated targets in blood donor controls and subjects with colon cancer (CC) and HNSCC. The assessment of antibodies against the wild type p53 tumor antigen showed that approximately 25% of the CC and 20% of the HNSCC patients were seropositive. In addition, humoral responses against two p53 mutants, p53-R175H and p53-R273H, generally tracked the antibody responses seen against wild type p53. Analysis of antibodies against highly specific biomarkers of HPV-16-associated malignancy, E2, E6, and E7 oncoproteins, revealed no seropositivity in blood donors and CC patients. However, 45% (9/20) of the HNSCC patients showed E6 seropositivity, which overlapped all the detectable E2 (40%; 8/20) and E7 seropositive subjects (35%; 7/20). Using neodymium magnets, ultrarapid LIPSTICKS testing of HPV-16 E6 antibodies in <60 s per HNSCC sample demonstrated almost the same diagnostic performance (40% sensitivity and 100% specificity) as LIPS testing in 2.5 h. While additional improvements and standardization are needed, these results highlight the possibility of using these approaches for the diagnosis of HPV-16-associated HNSCC.

The Prevalence, Anatomic Distribution and Significance of HPV Genotypes in Head and Neck Squamous Papillomas as Detected by Real-Time PCR and Sanger Sequencing

Squamous papillomas (SPs) of the head and neck are generally regarded as a human papillomavirus (HPV)-driven process, but reported rates of HPV detection vary dramatically. Moreover, they are generally considered a benign condition, but the detection of high risk HPV types is commonly reported. This latter finding is particularly disturbing to clinicians and their patients given the alarming rise of HPV-associated head and neck cancer. The capriciousness of HPV detection reflects in large part differences in methodologies. The purpose of this study was to review an institutional experience using a state of the art detection method to determine the presence, type and anatomic distribution of HPV in head and neck SPs. The surgical pathology files of the Mount Sinai Hospital were reviewed for all SPs that had undergone HPV testing between 2012 and 2018. HPV screening was performed on tissue blocks with real-time PCR using primers designed to target the L1 region of low and high-risk HPV types. Genotyping was performed on HPV positive cases. HPV detection was repeated for cases that were originally reported to be positive for high risk HPV. 134 cases had undergone HPV analysis. Of the 131 with sufficient cellular material, 2 were excluded because the HPV testing yielded inconclusive results. The remaining 129 cases were the basis of this study. Thirty-eight cases (29%) were HPV positive and 91 (71%) were negative. The most common genotype was HPV 6 (n = 27, 71%), followed by HPV 11 (n = 10, 26%). One case (1%) was HPV positive but the genotype could not be determined. Of the HPV negative cases, 3 were originally reported as HPV 16 positive but found to be HPV negative on re-review and repeat testing. SPs arising in the larynx were more likely to harbor HPV than those arising in the oral cavity and oropharynx (64% vs. 10%, p < 0.00001). Similarly, recurrent respiratory papillomatosis (RRP) were much more likely to be HPV positive than solitary SPs (71% vs. 10%, p < 0.00001). Almost a third of head and neck SPs harbor HPV, but incidence is highly dependent on anatomic site. Those arising in the larynx are more prone to be HPV-driven than those arising in the oral cavity and oropharynx, particularly when occurring in the setting of RRP. High risk HPV could not be confirmed in any of the cases. Routine HPV testing as a strategy to unmask potentially malignant lesions harboring high risk HPV is not likely to be useful.

Abstract 4068: Radiation, immune checkpoint inhibition, and modulation of the tumor immune microenvironment promotes immunologic rejection of established HPV-associated tumors

Abstract Immune checkpoint inhibitors (ICI), including those targeting cytotoxic T-lymphocyte-associated-antigen-4 (CTLA-4) and programmed cell death receptor-1 (PD-1), have shown tremendous potential against solid tumor malignancies; however, response to ICI remains unpredictable with 60-90% of patients receiving minimal to no benefit. Lack of efficacy is commonly attributed to inadequate tumor-specific T cell generation and the immunosuppressive effects of the tumor immune microenvironment (TIME). Thus, we hypothesized that a combinatory treatment strategy aiming to enhance antigen presentation and revert the immunosuppressive TIME could improve response rates of ICI in established solid tumors. Using a syngeneic tumor model of HPV-associated head and neck cancer (mEER) established to 60-75 mm2 in size, we found that CTLA-4 and/or PD-1 inhibition only minorly delayed tumor growth and flow cytometry profiling revealed that the TIME maintained a “cold” or immunosuppressed state similar to untreated tumors. When PD-1/CTLA-4 inhibition was combined with a weekly dose of tumor-directed radiation (10 Gy x 2), we observed upregulation of antigen presentation molecules in the draining lymph node but the combination remained incapable of generating long-term survival benefit. This lack of efficacy was attributed to the immunosuppressed and lymphodepleted TIME, a common consequence of radiation. Thus, to improve the TIME, we optimized an immune-stimulating drug combination previously developed in our lab combining cyclophosphamide (CTX) and a small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL). When we combined CTX/L-NIL immunomodulation, PD-1/CTLA-4 checkpoint inhibition, and radiation (collectively called the “CPR” regimen), we observed complete rejection of approximately 70% of established tumors in a CD8 T-cell dependent manner and potent development of immunologic memory against tumor-associated antigens. Tumor immune profiling after treatment revealed a “cold to hot” transition of the TIME, including increased levels of myeloid and lymphoid subsets associated with anti-tumoral immune responses (i.e. CD8 T cells, dendritic cells, M1 macrophages) and downregulation of immunosuppressive cellular subsets (i.e. T regulatory cells, granulocytic myeloid derived suppressor cells). We observed strong lymphoproliferation effects in the tumor-draining lymph node which resulted in significant TIME improvements including a 15-fold increase in the CD8 to regulatory T cell ratio. Thus, we have demonstrated that the rational combination of TIME immunomodulation, localized radiation to enhance antigen presentation, and immune checkpoint inhibitors to prevent T-cell exhaustion can promote the immunologic rejection of established solid tumors. Citation Format: Jared M. Newton, Aurelie Hanoteau, Hsuan-Chen Liu, Angelina Gaspero, Robyn D. Gartrell, Thomas D. Hart, Damya Laoui, Falguni Parikh, Yvonne M. Saenger, Andrew G. Sikora. Radiation, immune checkpoint inhibition, and modulation of the tumor immune microenvironment promotes immunologic rejection of established HPV-associated tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4068.

Practice patterns and knowledge among California pediatricians regarding human papillomavirus and its relation to head and neck cancer.

To identify practice patterns regarding human papillomavirus (HPV) vaccination efforts and vaccination rates in context of head and neck cancer prevention, identify barriers to vaccination, and identify gaps in knowledge regarding the link between HPV and head and neck cancer in the pediatrician population. A 27-question cross-sectional survey was distributed to members of the four California chapters of the American Academy of Pediatrics. Of the completed responses, 89.4% identified as "always" recommending the HPV vaccine to patients, but only 19.5% of pediatricians estimated that >75% of their eligible patients had completed the HPV vaccination series. 71.5% of respondents felt that further education about HPV's link to head and neck cancer them more comfortable discussing vaccination. Physicians who were in practice longer were less likely to respond that additional education about HPV and its link to head and neck cancer would make them more comfortable discussing vaccination with patients (p = 0.043). Physicians who were in practice longer were more likely to correctly respond that HPV type 16 is the most common strain linked to head and neck cancer (p = 0.021). There is need to improve both the knowledge base and comfort level of pediatricians in counseling their patients during vaccine recommendations. Otolaryngologists have a critical role in providing education to physicians, trainees, and the general public in the effort to combat the epidemic of HPV-associated head and neck cancer.

Highlights of This Issue

Despite immense progress in immunotherapy, responses with available anti-PD-1 therapies remain low for patients with HPV-associated head and neck squamous cell cancer (HNSCCa). This clinical trial demonstrates that therapy with MEDI0457, a DNA immunotherapeutic agent targeting HPV 16/18 E6/E7 viral antigens, is safe and feasible. Aggarwal and colleagues demonstrate promising humoral immune activation, and elevated antigen-specific T-cell activity in a majority of the patients with HNSCCa. The findings suggest that HPV viral neoantigens can be targeted therapeutically as a complementary immune strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve patient outcomes.The current standard of care for first-line treatment in patients with RAS wild-type metastatic colorectal cancer (mCRC) is the combination of chemotherapy with either an anti-EGFR or anti-VEGF monoclonal antibody. To identify a potential biomarker that enables a more personalized therapeutic approach for this patient population, Laurent-Puig and colleagues analyzed miR-31-3p expression in tumors from the RAS wild-type population enrolled in the FIRE-3 trial. Their analysis demonstrated the expression level of miR-31-3p is predictive of cetuximab efficacy for patient survival and response-related outcomes as compared with bevacizumab when combined with chemotherapy for first-line treatment of mCRC.Mismatch-repair-deficient (dMMR) tumors generally harbor abundant lymphocytic infiltrates, which are believed to contribute to their prognostic advantage and may underlie their enhanced responsiveness to immunotherapy. Yoon and colleagues examined CD3+ and CD8+ T-cell subtypes in stage III colon cancers from a large adjuvant trial. They found that the density of lymphocytic infiltrates in dMMR colon cancers exhibit greater intertumor heterogeneity than in MMR-proficient tumors. Lymphocyte densities also prognosticated within the dMMR group. This heterogeneity may be relevant for the efficacy of adjuvant immunotherapy, which is currently being studied in stage III colon cancers.T-cell acute lymphoblastic leukemia (T-ALL) is a fulminant blood cancer affecting children and adults. Despite improvements in patient survival on current therapy, frontline treatment will fail in up to 25% of children and 50% of adults, and prognosis for relapsed patients is poor. NOTCH1 is a main oncogene in T-ALL. Jin and colleagues demonstrate that the ubiquitin-specific protease 7 (USP7) interacts with the NOTCH1 complex and controls leukemia growth by stabilizing the levels of the complex and promoting oncogenic transcription. Ultimately, the group suggests a therapeutic modality in leukemia via targeting USP7.

Incidence and Outcomes of HPV-Associated Head and Neck Cancers in the United States: A Large Population-Based Analysis

Human papillomavirus (HPV)-associated oropharyngeal cancers are increasing in the United States (US); yet there are no large epidemiologic studies to define the national burden of HPV-associated head and neck squamous cell carcinomas (HNSCC) of oropharynx and non-oropharynx subsites. A custom Surveillance, Epidemiology, and End Results (SEER) database identified 5,936 patients with HNSCC (oropharynx, nasopharynx, hypopharynx, or other pharynx) and known HPV status, diagnosed from 2013-2014. Age-adjusted HPV-positive HNSCC incidence rates per 100,000 persons were calculated using SEER*Stat. Associations between HPV status and cancer-specific mortality (CSM) were determined using multivariable Fine-Gray competing-risks regression. From 2013-2014, the US incidence of HPV-positive versus negative HNSCC was 2.43 (95% Confidence Interval [CI] 2.35-2.50) versus 1.28 (1.22-1.33) per 100,000 persons, respectively. HPV-positive incidence was 2.26 (2.19-2.34), 0.06 (0.05-0.07), 0.06 (0.05-0.07), and 0.04 (0.01-0.03) for oropharynx, nasopharynx, hypopharynx, and other pharynx HNSCC, respectively. White (2.80, 2.71-2.90), non-Hispanic (2.68, 2.59-2.77) and male patients (4.38, 4.23-4.53) had the highest incidences of HPV-positive disease, with a unimodal age incidence distribution peaking at ages 60-64 (8.04, 7.49-8.62); notably, non-Hispanic white men ages 60-64 had an incidence of 18.56 (17.09-20.13). HPV-positive disease was associated with lower CSM in oropharynx HNSCC (Adjusted Hazard Ratio [AHR] 0.40, P<0.001; 23-month CSM 4.5% versus 11.2%), but not in non-oropharynx HNSCC (AHR 1.08, P=0.81; 23-month CSM 12.2% versus 11.4%), Poropharynx*HPV interaction = 0.002. This large epidemiological study defines the US burden of HPV-associated HNSCC. The highest incidence of US incidence of HPV-positive HNSCC was in non-Hispanic white men, where it represents the sixth most common non-skin solid malignancy in patients 64 and younger. The favorable prognosis associated with HPV appears to be limited to the oropharynx.

The Prevalence of HPV-Associated Head and Neck Cancers and Positive Predictive Value of p16: A Retrospective and Prospective Analysis of 375 Patients

The Prevalence of HPV-Associated Head and Neck Cancers and Positive Predictive Value of p16: A Retrospective and Prospective Analysis of 375 Patients

Abstract LB-333: PARP-1 supports HPV infection and HPV-associated head and neck cancer

Abstract Background: As the incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) continues to rise, mechanistic knowledge of HPV16-driven HNSCC remains incomplete. HPV(+) and HPV(-) HNSCCs are molecularly distinct, with altered signaling pathways that have been characterized by proteomic technologies. We recently reported that poly(ADP-ribose)polymerase-1 (PARP-1) is overexpressed in HPV(+) compared to HPV(-) HNSCC. PARP-1 is a multi-functional protein with the ability to produce polymers of ADP-ribose attached to proteins and with major known roles in maintaining genomic integrity, DNA damage repair, transcription, DNA replication, and cell cycle regulation. However, PARP-1 functions in HPV infection and in head and neck cancer have not been fully uncovered. Here, we examine the role of PARP-1 in HPV infection, the interactions of HPV with cellular proteins, and the therapeutic implications of PARP-1 inhibition in HPV(+) HNSCC. Methods: PARP activity was assessed by immunoblotting for levels of poly(ADP-ribose) and by enzymatic PARP-1 ELISA. Expression of HPV genes was measured by RT-PCR. Murine kidney epithelial cells were established from PARP-1 wild-type and knockout mice, and the absence of PARP-1 expression was confirmed by RT-PCR and immunoblotting. Infection with HPV pseudovirus (PsV) containing a GFP expression plasmid was detected by L1 immunofluorescence staining and GFP detection. Survival studies were done in vitro and in vivo with PARP inhibitors veliparib and olaparib. Results: In addition to being overexpressed, we found that PARP-1 was highly enzymatically active in HPV(+) HNSCC as compared to HPV(-) tumors. HPV16 PsV and major capsid protein L1 activated PARP-1 in vitro and in cells. Depletion of PARP-1 and chemical PARP inhibition repressed HPV16 cellular entry, and infection of cells with HPV PsV increased sensitivity of HPV(-) cells to PARP inhibition. Conclusions: We identified a functional role of PARP-1 in initial HPV infection and in HPV-associated cancer. PARP-1 is activated by HPV major capsid protein L1, and HPV(+) HNSCCs maintain PARP-1 enzymatic activity. On top of its role in initial HPV infection, PARP-1 also appears to be important for survival of HPV-infected cells, as inhibition of PARP-1 sensitized cells to HPV PsV infection. These findings suggest that PARP inhibition may hold significant therapeutic potential in the treatment of HPV-associated HNSCC, with our work resulting in the initiation of a window clinical trial ongoing at the Yale Cancer Center. Citation Format: Cassie Pan, Asel Biktasova, Michael Hajek, Andrew Sewell, Tejas Sathe, Gary Bellinger, Wendell Yarbrough, Natalia Issaeva. PARP-1 supports HPV infection and HPV-associated head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-333.

Genomic Landscapes of EBV-Associated Nasopharyngeal Carcinoma vs. HPV-Associated Head and Neck Cancer.

Epstein-Barr virus-positive nasopharyngeal carcinoma (EBV(+) NPC), and human papillomavirus-positive head and neck squamous cell carcinoma (HPV(+) HNSCC) are two distinct types of aggressive head and neck cancers with early age onsets. Their recently identified genomic landscapes by whole-exome sequencing (WES) clearly reveal critical roles of: (1) inflammation via NF-kB activation, (2) survival via PI3K aberrations, and perhaps (3) immune evasion via MHC loss in these cancers as summarized in this review. Immediate outcomes of these WES studies include the identification of potential prognostic biomarkers, and druggable events for these cancers. The impact of these genomic findings on the development of precision medicine and immunotherapies will be discussed. For both of these cancers, the main lethality comes from metastases and disease recurrences which may represent therapy resistance. Thus, potential curing of these cancers still relies on future identification of key genomic drivers and likely druggable events in recurrent and metastatic forms of these intrinsically aggressive cancers of the head and neck.

Evaluation of Toxicity Profile and Prognosis of Treatment of Hpv Associated Head and Neck Squamous Cell Carcinoma (HNSCC), with Chemoradiotherapy

Evaluation of Toxicity Profile and Prognosis of Treatment of Hpv Associated Head and Neck Squamous Cell Carcinoma (HNSCC), with Chemoradiotherapy

Global human papilloma virus vaccine implementation: An update.

Human papillomavirus (HPV) infections continue to be one of the most common sexually transmitted infections worldwide. The oncogenic potential of this virus was well established in anogenital malignancies and oropharyngeal cancers. Even though a fall in cervical cancer rates has been reported worldwide, the subsequent rise in HPV-associated head and neck cancers among men and women have been reported from developed countries, necessitating the vaccination of adolescent boys as well. The objective of this narrative review is to provide an update on the current status of HPV vaccination worldwide. This will be helpful for clinicians in counseling parents and guardians as this vaccine mainly targets sexually naïve preadolescents. An electronic search of the databases was carried out to retrieve information concerning HPV vaccine implementation between July 2006 and 2017, with special emphasis on the current viewpoints, controversies and ethical issues. Globally, 74 countries have implemented the HPV vaccine in the national immunization schedule, and this vaccine is listed as an essential medicine by WHO. About 60% of the low- and lower-middle-income countries have implemented the vaccine with financial assistance from Gavi and WHO. The HPV vaccine is a safe vaccine with no serious adverse effects as per the data available from developed nations as well as low/lower middle/upper middle-income countries. However, long-term follow-up is essential to substantiate the impact of the vaccination programs in cancer prevention.