Repurposing NFκB and HDAC inhibitors to individually target cancer stem cells and non-cancer stem cells from mucoepidermoid carcinomas.

Drug resistance remains a major obstacle in the treatment of mucoepidermoid carcinomas (MEC) leading to tumor recurrence, disease progression, and metastasis. Emerging evidence suggests that drug resistance is mediated by the presence of a highly adaptative subpopulation of cancer cells known as cancer stem cells (CSC). We have previously reported that solid tumors use NFkB signaling as a chemotherapy-resistant mechanism. We have also shown that interfering with the epigenome of solid tumors is an effective strategy to control the population of CSC. Here, we sought to investigate the effects of the NFkB inhibitor emetine and the HDAC inhibitor SAHA on the biology of MEC CSC and assessed whether this combination therapy would favor the standard of care therapy comprised of the administration of Cisplatin (CDDP). Our findings suggested that the administration of low concentrations of emetine and SAHA is more effective in disrupting CSC in MEC, while the administration of emetine in combination with CDDP constitutes an effective therapy to target non-CSC MEC tumor cells.

Minor Salivary Gland Cancer of the Head and Neck: A Review of Epidemiologic Aspects, Prognostic Factors, and Outcomes.

PURPOSE OF REVIEW: Minor salivary gland carcinomas (MiSGC) of the head and neck are a group of rare cancers with significant heterogeneity in histological types and with variable clinical behavior. This study aims to clarify the incidence, epidemiology, predictive factors, and outcome-based survival in a large cohort of patients treated at the Brazilian National Cancer Institute (BNCI) over a 20-year period by comparing and associating the results of current articles on the world stage. RECENT FINDINGS: The difficulty in developing an algorithm of treatment is due to the low number of cases when evaluated in a single institution and the variety of histological subtypes that have different behaviors and different treatments according to each anatomical location. We reviewed the experience of tertiary centers for the treatment of head and neck cancer and epidemiological studies from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute of the USA. The lack of consensus on the management of MiSGC requires further knowledge about the biological behaviors of these tumors, as the identification of predictive factor of failure and survival to adequate treatment intensity. The growing collaboration of different centers publishing their experience allows us to unify these samples to reach concrete conclusions about these tumors.

Clinicopathological and survival profile of patients with salivary gland myoepithelial carcinoma: A systematic review.

OBJECTIVES: In this systematic review, we aimed to evaluate the clinicopathological and prognosis data of patients with salivary gland myoepithelial carcinoma. MATERIALS AND METHODS: MEDLINE/PubMed, Scopus, and Embase search was performed with the keywords "myoepithelial carcinoma" "malignant myoepithelioma," and "salivary glands." Primary salivary glands myoepithelial carcinoma that fulfilled the World Health Organization diagnostic criteria were included. The Joanna Briggs Institute tool was used to assess the risk of bias. RESULTS: Forty-three studies (71 patients) met the inclusion criteria. The patients showed a mean age of 56.4 ± 19.6 years with no sex predilection. The parotid was the most affected gland (49.3%). The tumor presented as an asymptomatic (65.1%) mass (84%). The most common histological findings were the presence of clear tumor cells (39.7%) and multinodular growth patterns (60.7%). Multivariate analysis showed plasmacytoid cell type (p = 0.010) and solid growth pattern (p = 0.003) were related to decreased disease-free survival. Surgery alone was the most used treatment (53.5%). Patients with a combination of treatments showed a longer disease-free survival (p = 0.049). The 2-year and 5-year overall survival rates were 67.5% and 46.1%, respectively. CONCLUSION: Salivary gland myoepithelial carcinoma showed no sex predilection, with a higher incidence in the parotid gland. Cell type, growth pattern, and treatment type may be related to a lower disease-free survival. Overall, salivary gland myoepithelial carcinoma presented low recurrence and metastasis rates. Registration and protocol: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist and registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022311512).

Perineural Invasion as Worsening Criterion for Salivary Gland Mucoepidermoid Carcinoma.

Mucoepidermoid carcinomas (MECs) are a form of salivary gland malignancy. They are classified according to histological grade and perineural invasion (PNI). In another cancer subtypes, positive-PNI suggests increased poor prognosis; however, the role of isolated positive-PNI salivary gland MEC can still be better investigated as a risk factor. This study investigated whether isolated PNI is independently associated with poor outcomes. Retrospective study, cohort case-series, single-center hospital from 2009 to 2019. Patient demographics, primary tumor, intervention, and survival data are included. Univariate, multivariate, and Kaplan-Meier survival curve analyses were used for comparison.The study group consisted of 32 patients (15 PNI-positive tumors, and 17 PNI-negative tumors), all admitted for surgery. Univariate analysis showed differences in grade (p = 0.038), positive margins (p = 0.034), soft tissue invasion (p < 0.001), pathological stage (p = 0.014), recurrence (p = 0.015), distant metastasis (p = 0.015) and MEC related death (p = 0.015). The risk in PNI-positive patients to develop soft tissue invasion and positive surgical margins was OR = 8.57 and OR = 4.88, respectively. Multivariate analysis found age differences (p = 0.038), with OR = 1.08. The Disease Specific Survival (DSS) was worst in the PNI-positive group (log-rank p-value = 0.0011), where the probability of dying occurred in the 12-24 months period (log-rank p-value = 0.002). PNI-positive salivary gland MEC is an independent prognostic factor, with poor DSS, increased locoregional recurrence, close correlation with a more aggressive pattern of the disease, and should be reviewed as a high grade histological criteria. Our findings may imply changes in the clinical approach with a more aggressive attitude in the overall treatment.

Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells.

AIM: To evaluate the potential use of Cephaeline as a therapeutic strategy to manage mucoepidermoid carcinomas (MEC) of the salivary glands. MATERIAL AND METHODS: UM-HMC-1, UM-HMC-2, and UM-HMC-3A MEC cell lines were used to establish the effects of Cephaeline over tumor viability determined by MTT assay. In vitro wound healing scratch assays were performed to address cellular migration while immunofluorescence staining for histone H3 lysine 9 (H3k9ac) was used to identify the acetylation status of tumor cells upon Cephaeline administration. The presence of cancer stem cells was evaluated by the identification of ALDH enzymatic activity by flow cytometry and through functional assays using in vitro tumorsphere formation. RESULTS: A single administration of Cephaeline resulted in reduced viability of MEC cells along with the halt on tumor growth and cellular migration potential. Administration of Cephaeline resulted in chromatin histone acetylation as judged by the increased levels of H3K9ac and disruption of tumorspheres formation. Interestingly, ALDH levels were increased in UM-HMC-1 and UM-HMC-3A cell lines, while UM-HMC-2 showed a reduced enzymatic activity. CONCLUSION: Cephaeline has shown anti-cancer properties in all MEC cell lines tested by regulating tumor cells' viability, migration, proliferation, and disrupting the ability of cancer cells to generate tumorspheres.

Corrigendum: Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease.

[This corrects the article DOI: 10.3389/fonc.2020.580141.].

The tumor immune contexture of salivary duct carcinoma.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy. Recently, biomarker studies found promising targetable alterations. In this study, we provide a descriptive analysis of tumor and immune biomarkers and survival associations. METHODS: We extracted clinical data and performed immunohistochemistry for AR, AR-V7, HER-2, PD-L1, LAG-3, and tumor-infiltrating immune cells. RESULTS: We included 17 patients. Age ranged from 42 to 85 years old; HER-2 was overexpressed or amplified in 65%. AR was positive in 88% of patients, while AR-V7 was positive in 13% by IHC. We found low scores of immune infiltration and a PD-L1 expression in 53%. We found no clinically significant association between biomarkers and survival outcomes. CONCLUSION: In this small series of SDC, biomarkers do not seem to correlate with disease biology, although they provide additional treatment options. SDC may harbor a different immune profile compared to other subtypes, with an indication of T-cell dysfunction.

Salivary Gland Carcinoma: Novel Targets to Overcome Treatment Resistance in Advanced Disease.

Salivary gland carcinomas (SGCs) account for <5% of head and neck malignant neoplasms, further subcategorized in over 20 histological subtypes. For the most part, treatment for advanced disease is guided by morphology. SGCs in general respond poorly to a wide array of standard chemotherapy, with short durability, and significant toxicity. More recently, next-generation sequencing provided significant input on the molecular characterization of each SGC subtype, not only improving diagnostic differentiation between morphologically similar tumor types but also identifying novel driver pathways that determine tumor biology and may be amenable to targeted therapy. Among the most common histological subtype is adenoid cystic carcinoma, which often harbors a chromosome translocation resulting in an MYB-NFIB oncogene, with various degrees of Myb surface expression. In a smaller subset, NOTCH1 mutations occur, conferring a more aggressive pattern and potential sensitivity to Notch inhibitors. Salivary duct carcinomas may overexpress Her-2 and androgen receptors, with promising clinical outcomes after exposure to targeted therapies approved for other indications. Secretory carcinoma, previously known as mammary analog secretory carcinoma, is distinguished by an ETV6-NTRK3 fusion that can both help differentiate it from its morphologically similar acinar cell carcinoma and make it susceptible to Trk inhibitors. In the present article, we discuss the molecular abnormalities, their impact on tumor biology, and therapeutic opportunities for the most common SGC subtypes and review published and ongoing clinical trials and future perspectives for this rare disease.

Salivary gland tumors: Molecular characterization and therapeutic advances for metastatic disease.

Salivary gland cancers represent a rare group of tumors composed by over 20 histological subtypes. Initially treated as one single disease, its diagnosis, prognosis, and treatment are currently being stratified based on morphology. More recently, insight has been provided on the molecular characterization of each subtype, further improving diagnostic accuracy and paving the way for personalized therapy. In this article, we provide a comprehensive review of recent breakthroughs, preliminary results of novel therapy, and future directions on the treatment of these complex malignancies.

Carcinoma adenoquístico de las glándulas salivales / Adeno cystic carcinoma of salivary glands

Antecedentes: el carcinoma adenoquístico es el tumor maligno más frecuente de las glándulas sub-maxilar y menores. A pesar de su lento crecimiento y diseminación regional, muestra un pronóstico desfavorable debido a su tardía diseminación a distancia. Objetivo: analizar la serie propia a la luz de la bibliografia. Material y métodos: 44 pacientes con una edad media de 52,47 años y predominio del género femenino. De ellos, el 61,3% fueron tumores de glándula salival menor, 20,4% de submaxilar y 18,2% de parótida. En todos se realizó resección completa del tumor, seguida de vaciamiento cervical en el 34%. En el 43,2%, la cirugía fue seguida de Co60 radioterapia. El seguimiento medio de la muestra fue 52,5 (1-120) meses. Resultados: la curva de recurrencia acumulada fue del 36,8% a 5 años. La supervivencia global fue del 60 y 36% a 5 y 10 años, respectivamente, y se vio afectada con significación estadística por los márgenes insuficientes de la resección, el requerimiento de radioterapia adyuvante y el estadio. El análisis multivariado demostró que solo los márgenes insuficientes conservaron su significación estadística para la supervivencia y una tendencia desfavorable para el intervalo libre de enfermedad. Conclusiones: la extensión de la cirugía al cuello y la radioterapia adyuvante dependieron del estadio, los márgenes quirúrgicos, el compromiso nervioso, la presencia de adenopatas positivas y el subtpo histológico.

Background: adenoid cystic carcinoma is the most frequent malignant tumor of submaxillary and mi-nor salivary glands. Despite its slow growth, it shows an unfavorable prognosis because of its distant disseminaton. Objective: to analyse our series of patents in relaton to the literature. Materials and methods: 44 patents with mean age 52.47 years female gender. Of them, 61.3% were of minor salivary glands, 20.4% of submaxillary gland, and 18.2% the parotid gland. All patents underwent complete resecton of the tumor followed by neck dissecton in 34%. Co60 radiotherapy was administered to 43.2%. Mean follow up was 52.5 (range, 1-120) months. Results: 5-year recurrence rate was 36.8%. At 5 and 10 years, overall survival was 60 and 36%,respect-vely. Close surgical margins, requirement of adjuvant radiotherapy and stage significantly afected survival rate. The multivariate analysis showed that close margins was statstically significant for survival and associated with an unfavorable tendency for disease-free interval. Conclusions: extenton of surgery to the neck and adyuvant radiotherapy was dependent of stage, clear surgical margins, neural invasion, positive nodes in the neck and hystological subtype.

Uncovering the role of brain-derived neurotrophic factor/tyrosine kinase receptor B signaling in head and neck malignancies.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that was first known as responsible for sustain the growth, function, and plasticity of neural cells. BDNF exerts its effects by binding to the tyrosine kinase receptor B (TrkB). The BDNF/TrkB axis has been reported to be overexpressed in several neurogenic and non-neurogenic tumors. Its higher expression was associated with a poor prognosis to patients affected by different human malignancies, tumor growth, invasion, and metastasis; epithelial-mesenchymal transition and resistance to chemotherapy. BDNF/TrkB represent promising targets to the development of novel anticancer therapies. Some clinical trials are currently evaluating the efficacy of Trk protein-target drugs in different types of solid tumors. To date, few groups have evaluated the DNF/TrkB pathway in head and neck malignancies. The aims of this study were to review the literature concerning the role of BDNF/TrkB activation in head and neck squamous cell carcinoma and malignant salivary gland tumors and to discuss future perspectives of BDNF/TrkB-target therapy.

BH3-mimetic small molecule inhibits the growth and recurrence of adenoid cystic carcinoma.

OBJECTIVES: To evaluate the anti-tumor effect of BM-1197, a new potent and highly specific small molecule inhibitor of Bcl-2/Bcl-xL, in preclinical models of human adenoid cystic carcinoma (ACC). METHODS: Low passage primary human adenoid cystic carcinoma cells (UM-HACC-2A,-2B,-5,-6) and patient-derived xenograft (PDX) models (UM-PDX-HACC) were developed from surgical specimens obtained from 4 patients. The effect of BM-1197 on cell viability and cell cycle were evaluated in vitro using this panel of low passage ACC cells. The effect of BM-1197 on tumor growth, recurrence and tumor cell apoptosis in vivo was evaluated with the PDX model of ACC (UM-PDX-HACC-5). RESULTS: Exposure of low passage primary human ACC cells to BM-1197 mediated an IC50 of 0.92-2.82 µM. This correlated with an increase in the fraction of apoptotic cells (p<0.0001) and an increase in caspase-3 activity (p<0.0001), but no noticeable differences in cell cycle (p>0.05). In vivo, BM-1197 inhibited tumor growth (p=0.0256) and induced tumor cell apoptosis (p=0.0165) without causing significant systemic toxicities, as determined by mouse weight over time. Surprisingly, weekly BM-1197 decreased the incidence of tumor recurrence (p=0.0297), as determined by Kaplan-Meier analysis. CONCLUSION: These data demonstrated that single agent BM-1197 induces apoptosis and inhibits tumor growth in preclinical models of adenoid cystic carcinoma. Notably, single agent BM-1197 inhibited tumor recurrence, which is considered a major clinical challenge in the clinical management of adenoid cystic carcinoma. Collectively, these results suggest that patients with adenoid cystic carcinoma might benefit from therapy with a BH3-mimetic small molecule.