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Background: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies.Methods: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin-eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, TTR , is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, TB for Blacks and TW for Whites, for risk stratification.Results: MuNI was statistically significantly different between Black (mean, 3.88e-4; median, 3.67e-04) and White patients (mean, 3.36e-04; median, 2.99e-04), with p = .0078. Using TTR , MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p = .002; 95% confidence interval [CI], 1.21-2.43) and in White patients with HR of 1.72 (p = .005; 95% CI, 1.18-2.51). Population-specific cutoff, TW , yielded improved HR of 1.77 (p = .003; 95% CI, 1.21-2.58) for White patients, whereas TB did not improve risk-stratification in Black patients with HR of 0.6 (p = .3; HR, 0.6; 95% CI, 0.2-1.80).Conclusions: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients. [ABSTRACT FROM AUTHOR]

Background: The incidence of p16+ oropharyngeal squamous cell carcinoma (OPSCC) has been increasing. The notion that p16+ OPSCC has a propensity for atypical and disseminating metastasis has gained traction. We compared treatment failure patterns in p16+ and p16− OPSCC and evaluated survival impact. Methods: Retrospective analysis of patients with recurrent/metastatic OPSCC disease between 1/2009 and 12/2019. Results: Thirty‐eight p16+ and 36 p16− patients were identified. Three distinct failure patterns (distant vs. locoregional, atypical vs. typical, and disseminating vs. non‐disseminating) were studied. No significant differences were found between p16+ and p16− patients. Multivariate analysis showed p16 status was an independent prognostic biomarker; p16+ patients have a favorable overall survival compared to p16− patients (HR 0.34, 95% CI 0.16–0.77; P =.005). Conclusions: We challenge the view that p16+ OPSCC exhibits a distinctive treatment failure pattern and showed that p16 status impacts patient survival independent of disease progression. [ABSTRACT FROM AUTHOR]

PURPOSE Human papilloma virus–positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), diagnosed with p16 immunohistochemistry, is associated with favorable prognosis; however, this connection was established using European American (EA)–skewed populations. The impact of p16/human papillomavirus status on outcomes in African American (AA) OPSCC patients remains to be settled. In this study, we determine the association between cancer disparity and p16 status in an OPSCC cohort controlling for time to treatment initiation (TTI), a surrogate for medical care access. MATERIALS AND METHODS We analyzed data from all patients diagnosed with OPSCC (N = 440) between 2010 and 2017, who received treatment at our academic medical center. Associations between age, disease stage, sex, p16 status, race, TTI, and overall survival (OS) were investigated. RESULTS TTI was similar between AA and EA OPSCC patients in our p161 (P= .291) or p162 (P = .715) cohorts. Among p16+ OPSCC patients, the median OS was . 8.65 years for EA patients compared with 5.038 years (95% CI, 2.019 to 5.30; P = .003, log-rank) for AA patients. For p162 patients, the median OS was >.74 years (95% CI, 3.32 to 6.99) for EA patients and 1.85 years (95% CI, 0.978 to 4.50; P= .03, log-rank) for AA patients. Multivariate Cox regression analysis showed that race was an independent prognostic biomarker and the most impactful co-variate for OS (hazard ratio, 0.40; 95% CI, 0.00 to 0.69; P = .001). CONCLUSION Our work showed that AAs with p16+OPSCC have surprisingly poor clinical outcomes and are thus poor candidates for treatment de-escalation regimens. Caution should be exercised when extending clinical guidelines based on EA-majority studies to non-EA populations. [ABSTRACT FROM AUTHOR]

An increased accumulation of immune-dysfunction-associated CD4+Foxp3+ regulatory T cells (Tregs) is observed in aging oral mucosa during infection. Here we studied the function of Tregs during oral cancer development in aging mucosa. First, we found heightened proportions of Tregs and myeloid-derived suppressor cells (MDSC) accumulating in mouse and human oral squamous cell carcinoma (OSCC) tissues. Using the mouse 4-Nitroquinoline 1-oxide(4-NQO) oral carcinogenesis model, we found that tongues of aged mice displayed increased propensity for epithelial cell dysplasia, hyperplasia, and accelerated OSCC development, which coincided with significantly increased abundance of IL-1β, Tregs, and MDSC in tongues. Partial depletion of Tregs reduced tumor burden. Moreover, fungal abundance and dectin-1 signaling were elevated in aged mice suggesting a potential role for dectin-1 in modulating immune environment and tumor development. Confirming this tenet, dectin-1 deficient mice showed diminished IL-1β, reduced infiltration of Tregs and MDSC in the tongues, as well as slower progression and reduced severity of tumor burden. Taken together, these data identify an important role of dectin-1 signaling in establishing the intra-tumoral immunosuppressive milieu and promoting OSCC tumorigenesis in the context of aging. [ABSTRACT FROM AUTHOR]

Our earlier studies reported a unique potentiated combination (TriCurin) of curcumin (C) with two other polyphenols. The TriCurin-associated C displays an IC50 in the low micromolar range for cultured HPV+ TC-1 cells. In contrast, because of rapid degradation in vivo, the TriCurin-associated C reaches only low nano-molar concentrations in the plasma, which are sub-lethal to tumor cells. Yet, injected TriCurin causes a dramatic suppression of tumors in TC-1 cell-implanted mice (TC-1 mice) and xenografts of Head and Neck Squamous Cell Carcinoma (HNSCC) cells in nude/nude mice. Here, we use the TC-1 mice to test our hypothesis that a major part of the anti-tumor activity of TriCurin is evoked by innate and adaptive immune responses. TriCurin injection repolarized arginase1high (ARG1high), IL10high, inducible nitric oxide synthaselow (iNOSlow), IL12low M2-type tumor-associated macrophages (TAM) into ARG1low, IL10low, iNOShigh, and IL12high M1-type TAM in HPV+ tumors. The M1 TAM displayed sharply suppressed STAT3 and induced STAT1 and NF-kB(p65). STAT1 and NF-kB(p65) function synergistically to induce iNOS and IL12 transcription. Neutralizing IL12 signaling with an IL12 antibody abrogated TriCurin-induced intra-tumor entry of activated natural killer (NK) cells and Cytotoxic T lymphocytes (CTL), thereby confirming that IL12 triggers recruitment of NK cells and CTL. These activated NK cells and CTL join the M1 TAM to elicit apoptosis of the E6+ tumor cells. Corroboratively, neutralizing IL12 signaling partially reversed this TriCurin-mediated apoptosis. Thus, injected TriCurin elicits an M2→M1 switch in TAM, accompanied by IL12-dependent intra-tumor recruitment of NK cells and CTL and elimination of cancer cells. [ABSTRACT FROM AUTHOR]

Complete resection of head and neck tumors relies on palpation and visual inspection. Achieving a negative margin in remote locations in the head and neck region, especially in close proximity to critical structures, is often difficult to achieve. Positive resection margins in head and neck cancer are at high risk to develop recurrent disease and associated with poor prognosis. Near-infrared fluorescence-guided optical imaging is an emerging technology with the potential to move the surgical field forward and facilitate surgeons to visualize tumors in real-time intra-operatively. In this review, our focus is to discuss the recent advances and the potential application of near infrared (NIR) fluorescent-guided surgery in the management of head and neck cancer. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to further define the impact of primary surgery in the management of oropharyngeal squamous cell carcinoma (SCC). Methods Two hundred ninety-six patients with oropharyngeal SCC treated with primary surgery were included. Multivariable analysis and recursive partitioning analysis (RPA) identified predictors of survival and gastrostomy tube presence. Results Multivariable analysis identified that HPV negativity ( p = .0002), presence of extranodal extension ( p = .0025), and advanced T classification ( p = .0081) were independent predictors of survival. For HPV-positive patients, surgical approach ( p = .0111) and margin status ( p = .0287) were significant predictors of survival. For HPV-negative patients, extranodal extension ( p = .0021) and advanced T classification ( p = .0342) were significant predictors of survival. Smoking status and advanced neck disease did not impact survival, and the addition of adjuvant chemotherapy did not confer survival benefit in HPV-positive or HPV-negative subgroups. Conclusion Independent predictors of survival are unique in patients with oropharyngeal SCC treated with primary surgery. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1794-E1802, 2016 [ABSTRACT FROM AUTHOR]

BACKGROUND Human papillomavirus 16 (HPV16) is a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC), particularly the development of oropharyngeal squamous cell carcinoma (OPSCC). Cancer stem cells (CSCs) are resistant to conventional therapies, and it is postulated that they are responsible for disease recurrence and/or progression. Because the prognoses of patients with HPV16-positive and HPV-negative HNSCC are distinct, the authors sought to determine whether differences in the number of CSCs could account for this clinical observation. METHODS CSC populations in HPV16-positive and HPV-negative HNSCC were assessed using a proprietary assay based on expression of the enzyme aldehyde dehydrogenase (ALDH), an in vitro tumorsphere formation assay, and an in vivo limiting cell dilution in nonobese diabetic/severe combined immunodeficiency mice. A high-density tissue microarray was stained with ALDH1, a CSC marker, to determine the association between CSCs and HPV16-positive/HPV-negative OPSCC. RESULTS HPV16-positive HNSCC had a greater intrinsic CSC pool than HPV-negative HNSCC. Inactivation of p53 has been identified as a major mechanism for the elevated CSC population in HPV16-positive HNSCC. In vivo limiting cell dilution experiments using tumors from patients with HPV16-positive and HPV-negative OPSCC indicated that the CSC frequency was 62.5-fold greater in an HPV16-positive OPSCC tumor than in an HPV-negative OPSCC tumor. Primary tumors from patients with HPV16-positive OPSCC were associated with elevated tumor ALDH1 staining, further extending the association between HPV16 and CSCs. CONCLUSIONS The current data and the clinical observation that patients with HPV16-positive HNSCC respond more favorably to current treatment paradigms than patients with HPV-negative HNSCC support the suggestion that CSC phenotype is not homogeneous. Therefore, the reliance on the CSC number may be insufficient to accurately assess the potential of a particular tumor for disease recurrence and/or progression. Cancer 2014;120:992-1001. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Simple Summary: A critical need for optimal management of human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) patients is the development of therapeutic strategies to exploit the inherent vulnerabilities of this unique disease. We identified fenofibrate, an FDA-approved drug, as a potent anti-cancer agent for HPV+ HNSCC. Fenofibrate induced the accumulation of the p53 tumor suppressor and re-programmed the tumor microenvironment to drive immune cell infiltration. We provide compelling evidence to reposition fenofibrate as a single agent or in combination with standard therapies for the HPV+ HNSCC setting. Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV− HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized. [ABSTRACT FROM AUTHOR]

Objective To assess the effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth rate in human squamous cell carcinoma (SCC). Design Three human SCC cell lines were used in this study for both in vitro and in vivo investigations. Conditioned media from untreated and tetrathiomolybdate-treated cell lines were compared with regard to cytokine levels, endothelial cell chemotaxis, endothelial cell tubule formation, and migration and the ability to induce angiogenesis in a rat aortic ring array. In vivo UM-SCC-38 was seeded onto tissue-engineered scaffolds and surgically implanted into the flanks of immunodeficient mice. Tumor growth rates and the level of angiogenesis were compared after 2 weeks of therapy. Setting A tertiary care facility. Results In this study, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by head and neck SCC (HNSCC) cell lines in vitro. Furthermore, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by HNSCC cell lines in vitro. Furthermore, tetrathiomolybdate treatment of HNSCC cell lines results in significantly decreased endothelial cell chemotaxis, tubule formation, and neovascularization in a rat aortic ring assay. This in vitro evidence of decreased angiogenesis by tetrathiomolybdate is confirmed in vivo by using a severe combined immunodeficiency disorder mouse model in which tetrathiomolybdate therapy is shown to prevent human blood vessel formation. Finally, human HNSCC implanted into immunodeficient mice grow to a much larger size in untreated mice compared with those treated with 0.7 mL/kg per day of oral tetrathiomolybdate. Conclusions These findings illustrate the ability of tetrathiomolybdate to down-regulate proinflammatory and proangiogenic cytokines in HNSCC. These observations are potentially exciting from a clinical perspective because a global decrease in these cytokines may decrease tumor aggressiveness and reverse the resistance to chemotherapy and radiation therapy seen in this tumor type. [ABSTRACT FROM AUTHOR]

Simple Summary: Anti-PD-1 immunotherapies are approved for head and neck squamous cell carcinoma in the recurrent/metastatic setting, and utilization of these high-cost biologics is expected to increase as other indications are approved. Due to the high cost and selective response rate of these immunotherapy biologics in HNSCC, it is imperative to better define which patient subsets will realize a clinically meaningful benefit with anti-PD-1 treatment. The impact of anatomical site and p16 status on the efficacy of anti-PD-1 inhibitors remains unresolved. We showed that anatomical site and p16 status are associated with overall survival in anti-PD-1-treated HNSCC patients from a single-institution, real-world cohort. In head and neck squamous cell carcinoma (HNSCC), anti-PD-1 inhibitors are approved for recurrent/metastatic (R/M) disease and anticipated to expand to other indications. The impact of p16 status and anatomical site on overall survival (OS) in immunotherapy-treated HNSCC patients remains unresolved. We performed a retrospective analysis of R/M HNSCC patients receiving anti-PD-1 immunotherapy at our academic medical center with an extensive community satellite network. Fifty-three R/M HNSCC patients were treated with anti-PD-1 immunotherapy and had a median OS of 6 months. Anatomical site was associated with distinct OS; oropharynx and larynx patients have superior OS compared to oral cavity patients. Analysis of the OPSCC subset showed p16+ status as a favorable, independent prognostic biomarker (HR 7.67 (1.23–47.8); p = 0.029). Further studies to assess the link between anatomical site, p16 status, and anti-PD-1 treatment outcomes in large cohorts of R/M HNSCC patients managed in real-world clinical practices and clinical trials should be prioritized. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) survival rates have not improved in a decade, with a 63% 5-year recurrence rate after surgery, making HNSCC a compelling indication for optical surgical navigation (OSN). A promising peptide, HN1, targeted and internalized in human HNSCC cells in multiple laboratories, but was slow (24 h) to accumulate. We modified HN1 and explored structural variables to improve the uptake kinetics and create IRdye800 adducts useful for OSN. Eleven new molecules were synthesized and characterized chemically, in human HNSCC cells (Cal 27), and in HNSCC xenograft mice. Cal 27 flank xenografts in Balb/c nude mice were imaged for 3–48 h after 40 nmol intravenous doses of IR800-labeled molecules. Cell uptake kinetics in the 1–2 h window incubated at 1–10 μM were independent of the dye label (FITC, Cy5, or IR800), but increased markedly with additional N-terminal lipophilic substitution, and after resequencing the peptide to separate polar amino acids and move the lysine-dye more centrally. Microscopy confirmed the strong Cal 27 cell binding and demonstrated primarily cytosolic and membrane localization of the fastest peptide, 4Iphf-HN17. 4Iph-HN17-IR800 showed 26-fold greater rate of uptake in cells than HN1-IR800, and far stronger OSN imaging intensity and tumor to background contrast in mice, suggesting that the new peptide is a promising candidate for OSN of HNSCC. [ABSTRACT FROM AUTHOR]

Summary: Epithelial to mesenchymal transition (EMT) is a dynamic cellular process that is essential for the development of metastatic disease. During EMT, a tumor cell with epithelial characteristics transitions to a tumor cell with mesenchymal characteristics through modulation of cell polarity and adhesion. Two hallmark EMT proteins, E-Cadherin and Vimentin, are tightly controlled during EMT through multiple signal transduction pathways. Epidermal growth factor (EGF) and transforming growth factorβ (TGFβ) promote EMT by regulating a distinct set of transcription factors, including Snail and Twist. Snail, Twist, and Slug are integral to the induction of EMT through direct regulation of genes involved in cellular adhesion, migration, and invasion. This review highlights the current literature on EMT in HNSCC. Understanding the role of EMT will provide insight to the pathogenesis of disease progression and may lead to the development of novel anti-cancer therapeutics for metastatic HNSCC. [ABSTRACT FROM AUTHOR]

High-risk human papillomavirus (HPV) is an etiologic factor in a spectrum of squamous cell carcinomas including anal, cervical, and oropharyngeal. HPV cell free DNA (cfDNA) is shed from the primary tumor into systemic circulation and can be detected using several platforms including quantitative PCR, digital droplet PCR, or next generation sequencing. Levels of HPV cfDNA at time of initial presentation is associated with known poor prognostic clinicopathologic variables, such as advanced stage and, locoregional and distant metastases. Moreover, longitudinal sampling revealed that persistent or increasing HPV cfDNA levels are indicative of treatment relapse and, in some studies, HPV cfDNA detection predicted treatment failures prior to routine post-treatment clinical imaging. A liquid biopsy platform using HPV cfDNA offers unique advantages over traditional approaches and may have clinical utility for detection of minimum residual disease, treatment response, and disease progression in patients with HPV+ cancers. [ABSTRACT FROM AUTHOR]

• Two-dimensional (2D) cell line models fail to capture tumor heterogeneity. • 3D patient derived organoids capture heterogeneity and predict treatment response. • Organotypic cultures model the tumor stromal interface and invasive front. • These techniques may be used to model of critical subpopulations like partial-EMT. Head and neck squamous cell carcinoma (HNSCC) outcomes remain stagnant, in part due to a poor understanding of HNSCC biology. The importance of tumor heterogeneity as an independent predictor of outcomes and treatment failure in HNSCC has recently come to light. With this understanding, 3D culture systems, including patient derived organoids (PDO) and organotypic culture (OTC), that capture this heterogeneity may allow for modeling and manipulation of critical subpopulations, such as p-EMT, as well as interactions between cancer cells and immune and stromal cells in the microenvironment. Here, we review work that has been done using PDO and OTC models of HNSCC, which demonstrates that these 3D culture models capture in vivo tumor heterogeneity and can be used to model tumor biology and treatment response in a way that faithfully recapitulates in vivo characteristics. As such, in vitro 3D culture models represent an important bridge between 2D monolayer culture and in vivo models such as patient derived xenografts. [ABSTRACT FROM AUTHOR]

Background: microRNAs negatively regulate gene expression at the post-transcriptional level. Mounting evidence shows that miR expression is deregulated in human cancers including head and neck squamous cell carcinoma (HNSCC). Epigenetically silenced tumor suppressor miRs may be re-expressed upon treatment with histone deacetylases inhibitors. Suberoylanilide Hydroxamic Acid (SAHA) is a histone deacetylase inhibitor that is currently being investigated in clinical trials for HNSCC. We hypothesized that SAHA will re-express a set of tumor suppressor miRs and enhance the efficacy of cisplatin and radiation in HNSCC.Results: In this study, miR expression profile was utilized to identify the tumor suppressor miRs that are re-expressed following SAHA treatment in HNSCC. Our data demonstrated that two tumor suppressor miRs, miR-107 and miR-138, were significantly up-regulated in CAL27 and SCC25 cell lines, following SAHA treatment. In addition to this, treatment with SAHA in a dose dependent manner significantly inhibited the cell proliferation, cell migration, and anchorage dependent clonogenic survival in CAL27 and SCC25 cell lines, respectively. Further, the expression of several oncogenes, PKCε, HIF1β, CDK6, and RhoC were down regulated in response to SAHA treatment. Additionally, we demonstrated that the combination treatment with SAHA and a chemotherapeutic drug cisplatin caused a significant reduction of cell growth compared to the single agent treatment.Conclusion: Our data indicate that SAHA treatment results in reactivation of the silenced tumor suppressor miRs. Furthermore, this study emphasizes the usefulness of this drug as a novel combination therapy for HNSCC patients. [ABSTRACT FROM AUTHOR]

Objectives: To identify predictors of overall survival (OS) in oropharyngeal squamous cell carcinoma (OPSCC) patients who achieved complete response (CR).Methods: We performed a retrospective study of OPSCC patients who achieved CR from a single academic medical center. Associations between OS, AJCC 8th edition staging system, definitive treatment choice, smoking history, and p16 status were assessed.Results: p16+ status was associated with favorable prognosis for CR (p < 0.001) but not non-CR (p = 0.67) patients. For early stage, p16+ OPSCC patients who achieved CR, surgery + adjuvant radiation (RT) treatment was more durable compared to concurrent chemoradiation (CRT), particularly in smokers.Conclusions: Curative intent treatment choice and smoking history has an impact on the long-term OS of the CR p16+ OPSCC cohort. Prospective studies to define the optimal multi-modality treatment option to manage p16+ OPSCC patients is needed. [ABSTRACT FROM AUTHOR]

Summary: Inactivation of the tumor suppressor p53 is a pathogenetic event in the development of head and neck squamous cell carcinoma (HNSCC). In the absence of functional wildtype p53, HNSCC cells have increased resistance to standard chemotherapeutics and radiation. Numerous approaches to restore p53 function in cancer cells have been developed over the past several decades. This review article focuses on viral approaches to deliver wildtype p53 to HNSCC cells, a designer virus that selectively eliminates mutant p53 HNSCC cells, and chemical approaches to reactivate p53 function in HNSCC cells. These promising studies provide evidence that p53 therapeutics may prove useful alone or in combination with conventional chemotherapy and/or radiation for the management of HNSCC patients. [Copyright &y& Elsevier]

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed in the last year. Our laboratory showed that miR-107 expression is reduced and functions as a tumor suppressor gene in HNSCC suggesting the potential application of miR-107 as a novel anticancer therapeutic. In this study, we determined the efficiency and efficacy of cationic lipid nanoparticles to deliver pre-miR-107 (NP/pre-miR-107) in HNSCC cells in vitro and in vivo. NP/pre-miR-107 increased delivery of miR-107 into HNSCC cells by greater than 80,000-fold compared to free pre-miR-107. Levels of known miR-107 targets, protein kinase Cε (PKCε), cyclin-dependent kinase 6 (CDK6), and hypoxia-inducible factor 1-β (HIF1-β), decreased following NP/pre-miR-107 treatment. Clonogenic survival, cell invasion, and cell migration of HNSCC cells was inhibited with NP/pre-miR-107. Moreover, NP/pre-miR-107 reduced the cancer-initiating cell (CIC) population and dampened the expression of the core embryonic stem cell transcription factors, Nanog, Oct3/4, and Sox2. In a preclinical mouse model of HNSCC, systemic administration of NP/pre-miR-107 significantly retarded tumor growth by 45.2% compared to NP/pre-miR-control (P < 0.005, n = 7). Kaplan-Meier analysis showed a survival advantage for the NP/pre-miR-107 treatment group (P = 0.017). Our results demonstrate that cationic lipid nanoparticles are an effective carrier approach to deliver therapeutic miRs to HNSCC. [ABSTRACT FROM AUTHOR]