Kelly R. Magliocca

Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth

How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.

Lymph node ratio influence on risk of head and neck cancer locoregional recurrence after initial surgical resection: Implications for adjuvant therapy

The purpose of this study was to determine if lymph node ratio is associated with locoregional recurrence for patients with oral cavity or laryngeal cancer treated with initial surgical management.

Extent of pathologic extracapsular extension and outcomes in patients with nonoropharyngeal head and neck cancer treated with initial surgical resection

Lymph node extracapsular extension (ECE) is a known adverse prognostic factor in head and neck cancer and is an indication for adjuvant chemoradiation (CRT). However, the extent of ECE may provide additional prognostic information in the setting of adjuvant CRT.

The Prometastatic Ribosomal S6 Kinase 2-cAMP Response Element-binding Protein (RSK2-CREB) Signaling Pathway Up-regulates the Actin-binding Protein Fascin-1 to Promote Tumor Metastasis

Background: RSK2-mediated prometastatic signaling mechanism remains unclear. Results: RSK2-CREB pathway up-regulates Fascin-1 to promote filopodia formation, cancer cell invasion, and tumor metastasis. Conclusion: RSK2-CREB-Fascin-1 pathway could be a promising therapeutic target in metastatic cancers. Significance: These data will advance our understanding of signaling pathways that mediates RSK2-dependent prometastatic signals. Metastasis is the leading cause of death in patients with breast, lung, and head and neck cancers. However, the molecular mechanisms underlying metastases in these cancers remain unclear. We found that the p90 ribosomal S6 kinase 2 (RSK2)-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells, leading to up-regulation of a CREB transcription target Fascin-1. We also observed that the protein expression patterns of RSK2 and Fascin-1 correlate in primary human tumor tissue samples from head and neck squamous cell carcinoma patients. Moreover, knockdown of RSK2 disrupts filopodia formation and bundling in highly invasive cancer cells, leading to attenuated cancer cell invasion in vitro and tumor metastasis in vivo, whereas expression of Fascin-1 significantly rescues these phenotypes. Furthermore, targeting RSK2 with the small molecule RSK inhibitor FMK-MEA effectively attenuated the invasive and metastatic potential of cancer cells in vitro and in vivo, respectively. Taken together, our findings for the first time link RSK2-CREB signaling to filopodia formation and bundling through the up-regulation of Fascin-1, providing a proinvasive and prometastatic advantage to human cancers. Therefore, protein effectors of the RSK2-CREB-Fascin-1 pathway represent promising biomarkers and therapeutic targets in the clinical prognosis and treatment of metastatic human cancers.

Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis

Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.

Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck.

Platinum‐based therapy combined with cetuximab is standard first‐line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN.

Racial disparities in squamous cell carcinoma of the oral tongue among women: A SEER data analysis

OBJECTIVES The incidence of oral tongue cancer (OTC) in the US is increasing in women. To understand this phenomenon, we examined factors influencing OTC incidence and survival. MATERIALS AND METHODS We identified women diagnosed with OTC that were reported to the Surveillance, Epidemiology and End Results (SEER) program from 1973 to 2010. Incidence and survival rates were compared across metropolitan, urban and rural residential settings and several other demographic categories by calculating rate ratios (RRs) with the corresponding 95% confidence intervals (CIs). We examined changes in incidence of OTC across racial groups using joinpoint analyses since 1973, and assessed factors associated with survival. Patients diagnosed prior to 1988 were excluded from the survival analysis due to lack of data on treatment. RESULTS OTC incidence in white females demonstrated a significant upward trend with 0.53 annual percentage change (APC) between 1973 and 2010. The change seems to be limited to white women under the age of 50years and appears to have become pronounced in the 1990s. For African Americans (AA) on the other hand, the incidence has decreased. Incidence estimates did not differ in metropolitan, small urban and rural setting. The 1-, 5- and 10-year relative survival estimates were 86%, 63% and 54% for white women, and 76%, 46% and 33% for AA women. On multivariable analyses factors significantly associated with better survival included lower stage, younger age, married status, and receipt of surgical treatment, but not race. CONCLUSION The racial disparity in OTC survival is evident, but may be attributable to the differences in stage at diagnosis as well as access to and receipt of care. As the incidence of OTC is increasing in young white women, identifying the risk factors in this group may lead to a better understanding of OTC causes.

Craniofacial fibrous dysplasia.

Despite recent advances in the understanding of the natural history and molecular abnormalities, many questions remain surrounding the progression and management of fibrous dysplasia (FD). In the absence of comorbidities, the expected behavior of craniofacial FD (CFD) is to be slow growing and without functional consequence. Understanding of the pathophysiologic mechanisms contributing to the various phenotypes of this condition, as well as the predictors of the different behaviors of FD lesions, must be improved. Long-term follow-up of patients with CFD is vital because spontaneous recovery is unlikely, and the course of disease can be unpredictable.

HPV-related Multiphenotypic Sinonasal Carcinoma

Human papillomavirus (HPV)–related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a peculiar neoplasm that is restricted to the sinonasal tract, exhibits features of both a surface-derived and salivary gland carcinoma (particularly adenoid cystic carcinoma), and is associated with high-risk HPV. Given the limited number of published cases, the full clinicopathologic spectrum of this neoplasm is unclear. Here, we present an updated experience of 49 cases. All cases of HMSC were obtained from the authors’ files. Immunohistochemistry for p16, c-kit, and myoepithelial cell markers (S100, actin, calponin, p63, and/or p40) was performed along with RNA in situ hybridization for HPV (type 33-specific as well as a high-risk cocktail). Fluorescence in situ hybridization studies for fusions of MYB, NFIB, and MYBL1 was performed on a subset of cases. Clinical follow-up was obtained from medical records. A total of 49 cases of HMSC were collected. Twenty-eight (57%) were from women and 18 (43%) from men, ranging in age from 28 to 90 years (mean, 54 y). Of 40 cases with detailed staging information, 43% of HMSCs presented with a high T-stage (T3 or T4). Histologically, most grew predominantly as solid nests of basaloid cells exhibiting high mitotic rates and frequent necrosis, with histologic and immunohistochemical evidence of myoepithelial differentiation. Most cases also demonstrated foci of cribriform and/or tubular growth, along with an inconspicuous population of ducts. Thirty-four (69%) cases demonstrated an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa. Less consistent histologic features included squamous differentiation within the invasive tumor (n=6), sarcomatoid transformation (n=5) including overt chondroid differentiation (n=3), and prominent epithelial-myoepithelial carcinoma-like growth (n=3). All cases were positive for p16 by immunostaining and HPV by RNA in situ hybridization. Thirty-three (67%) were positive for HPV 33. No cases tested for MYB, MYBL1, or NFIB gene fusions were positive. In the 38 cases with follow-up data, (mean follow-up, 42 mo) 14 recurred locally and 2 metastasized (lung, finger). There were no regional lymph node metastases, and no tumor-related deaths. HMSC is a distinct sinonasal neoplasm characterized by myoepithelial differentiation, frequent surface epithelial involvement, and the presence of high-risk HPV (especially type 33). Although it classically exhibits a cribriforming pattern that closely resembles adenoid cystic carcinoma, our expanded series highlights a histologic spectrum that is much broader than previously recognized, warranting a change in terminology. HMSC usually presents as a large and destructive sinonasal mass with high-grade histologic features, but it paradoxically behaves in a relatively indolent manner, underscoring the importance of distinguishing HMSC from true adenoid cystic carcinoma, squamous cell carcinoma, and other histologic mimickers.

The importance of margins in head and neck cancer

An estimated 200,000 deaths each year worldwide are due to cancer of the head and neck, mostly mucosal squamous cell carcinoma and nonmelanoma skin cancer. The status of surgical margins is important for prognosis and need for adjuvant therapy. We will discuss how margin status impacts outcomes and therapy, and the conundrum of determining margin status. J. Surg. Oncol. 2016;113:248–255.