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1
Agee, Robert, Samuel Flashner, Masataka Shimonosono, Andres Klein-Szanto, and Hiroshi Nakagawa. "Abstract 3082: Leveraging 3D organoids to identify molecular changes underlying HNSC initiation and development." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3082. http://dx.doi.org/10.1158/1538-7445.am2022-3082.
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Abstract Head and neck squamous cell carcinoma (HNSC) is a devastating disease accounting for 570,000 newly diagnosed cases and resulting in 344,000 deaths annually. HNSC arises from its histological precursor lesion, squamous dysplasia (HNSD); however, most patients are diagnosed with late-stage HNSC with no prior identification of pre-malignant disease. Earlier diagnosis and intervention could ameliorate the outsized burden of HNSC; therefore, there is an urgent unmet need to characterize the molecular changes underlying progression through HNSD to HNSC. To identify novel therapeutic targets or biomarkers that predict progression to HNSC, we have generated a three dimensional (3D) organoid library derived from dysplastic oral tissue harvested from mice treated with 4-Nitriquinoline N-oxide (4-NQO), a potent mimetic of tobacco smoke. Through RNA sequencing analysis of these organoids, we have identified two distinct gene expression states that accompany either early or late dysplasia. By performing gene set enrichment analysis of these two distinct gene signatures, we have identified c-Jun N-terminal Kinase (JNK) signaling as a potential biomarker that predicts or progression from HNSD to HNSC. Together, we have identified the salient transcriptional changes that accompany progression through the histological precursor lesion of HNSC. This study positions JNK signaling as a potential biomarker or therapeutic target for early intervention during the treatment of a deadly disease. Citation Format: Robert Agee, Samuel Flashner, Masataka Shimonosono, Andres Klein-Szanto, Hiroshi Nakagawa. Leveraging 3D organoids to identify molecular changes underlying HNSC initiation and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3082.
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Burkart, Sebastian, Christopher Weusthof, Karam Khorani, Sonja Steen, Fabian Stögbauer, Kristian Unger, Julia Hess, et al. "A Novel Subgroup of UCHL1-Related Cancers Is Associated with Genomic Instability and Sensitivity to DNA-Damaging Treatment." Cancers 15, no. 6 (March 8, 2023): 1655. http://dx.doi.org/10.3390/cancers15061655.
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Purpose: Identification of molecularly-defined cancer subgroups and targeting tumor-specific vulnerabilities have a strong potential to improve treatment response and patient outcomes but remain an unmet challenge of high clinical relevance, especially in head and neck squamous cell carcinoma (HNSC). Experimental design: We established a UCHL1-related gene set to identify and molecularly characterize a UCHL1-related subgroup within TCGA-HNSC by integrative analysis of multi-omics data. An extreme gradient boosting model was trained on TCGA-HNSC based on GSVA scores for gene sets of the MSigDB to robustly predict UCHL1-related cancers in other solid tumors and cancer cell lines derived thereof. Potential vulnerabilities of UCHL1-related cancer cells were elucidated by an in-silico drug screening approach. Results: We established a 497-gene set, which stratified the TCGA-HNSC cohort into distinct subgroups with a UCHL1-related or other phenotype. UCHL1-related HNSC were characterized by higher frequencies of genomic alterations, which was also evident for UCHL1-related cancers of other solid tumors predicted by the classification model. These data indicated an impaired maintenance of genomic integrity and vulnerability for DNA-damaging treatment, which was supported by a favorable prognosis of UCHL1-related tumors after radiotherapy, and a higher sensitivity of UCHL1-related cancer cells to irradiation or DNA-damaging compounds (e.g., Oxaliplatin). Conclusion: Our study established UCHL1-related cancers as a novel subgroup across most solid tumor entities with a unique molecular phenotype and DNA-damaging treatment as a specific vulnerability, which requires further proof-of-concept in pre-clinical models and future clinical trials.
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Zhao, Yixuan, Xin Huang, Zewei Zhang, Haizhou Li, and Tao Zan. "The Long Noncoding Transcript HNSCAT1 Activates KRT80 and Triggers Therapeutic Efficacy in Head and Neck Squamous Cell Carcinoma." Oxidative Medicine and Cellular Longevity 2022 (August 4, 2022): 1–19. http://dx.doi.org/10.1155/2022/4156966.
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Head and neck squamous carcinoma (HNSC) is the most prevalent malignancy of the head and neck regions. Long noncoding RNAs (lncRNAs) are vital in tumorigenesis regulation. However, the role of lncRNAs in HNSC requires further exploration. Herein, through bioinformatic assays using The Cancer Genome Atlas (TCGA) datasets, rapid amplification of cDNA ends (RACE) assays, and RNA-FISH, we revealed that a novel cytoplasmic transcript, HNSC-associated transcript 1 (HNSCAT1, previously recognized as linc01269), was downregulated in tumor samples and advanced tumor stages and was also associated with favorable outcomes in HNSC. Overexpression of HNSCAT1 triggered treatment efficacy in HNSCs both in vivo and in vitro. More importantly, through high-throughput transcriptome analysis (RNA-seq, in NODE database, OEZ007550), we identified KRT80, a tumor suppressor in HNSC, as the target of HNSCAT1. KRT80 expression was modulated by lncRNA HNSCAT1 and presented a positive correlation in tumor samples ( R = 0.52 , p < 0.001 ). Intriguingly, we identified that miR-1245 simultaneously interacts with KRT80 and HNSCAT1, which bridges the regulatory function between KRT80 and HNSCAT1. Conclusively, our study demonstrated that lncRNA HNSCAT1 functions as a necessary tumor inhibitor in HNSC, which provides a novel mechanism of lncRNA function and provides alternative targets for the diagnosis and treatment of HNSC.
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Tang, Shouyi, Li Zhao, Xing-Bo Wu, Zhen Wang, Lu-Yao Cai, Dan Pan, Ying Li, Yu Zhou, and Yingqiang Shen. "Identification of a Novel Cuproptosis-Related Gene Signature for Prognostic Implication in Head and Neck Squamous Carcinomas." Cancers 14, no. 16 (August 18, 2022): 3986. http://dx.doi.org/10.3390/cancers14163986.
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Head and neck squamous carcinoma (HNSC) is a frequent and deadly malignancy that is challenging to manage. The existing treatment options have considerable efficacy limitations. Hence, the identification of new therapeutic targets and the development of efficacious treatments are urgent needs. Cuproptosis, a non-apoptotic programmed cell death caused by excess copper, has only very recently been discovered. The present study investigated the prognostic importance of genes involved in cuproptosis through the mRNA expression data and related clinical information of HNSC patients downloaded from public databases. Our results revealed that many cuproptosis-related genes were differentially expressed between normal and HNSC tissues in the TCGA cohort. Moreover, 39 differentially expressed genes were associated with the prognosis of HNSC patients. Then, a 24-gene signature was identified in the TCGA cohort utilizing the LASSO Cox regression model. HNSC expression data used for validation were obtained from the GEO database. Consequently, we divided patients into high- and low-risk groups based on the 24-gene signature. Furthermore, we demonstrated that the high-risk group had a worse prognosis when compared to the low-risk group. Additionally, significant differences were found between the two groups in metabolic pathways, immune microenvironment, etc. In conclusion, we found a cuproptosis-related gene signature that can be used effectively to predict OS in HNSC patients. Thus, targeting cuproptosis might be an alternative and promising strategy for HNSC patients.
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Pradhan, Sultan, and Arsheed Hussain Hakeem. "Management of Head and Neck Cancer: Surgical and Nonsurgical." An International Journal of Otorhinolaryngology Clinics 2, no. 1 (2010): 77–85. http://dx.doi.org/10.5005/jp-journals-10003-1020.
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Abstract It is right time to review the management of head and neck squamous cancer (HNSC) because of fundamental changes in both diagnostic and therapeutic modalities. Head and neck cancer affects area highly associated with the individual's. identity and can produce profound alteration in appearance, speech, and swallowing. Due to morbidity, disfigurement and problems of disease control clinicians used to have lot of reservations in treating complex HNSC cases. The field has taken a new vigor by incorporating important basic advances in understanding of cancer, new modalities of treatment and management of functional deficits. Although much progress has been made in understanding the molecular genetics of HNSC for novel diagnostic and therapeutic interventions, they are still far to go before becoming standard of care for head and neck cancer.
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Chen, Yin-Ju, Joseph T. Chang, Guo-Rung You, Chun-Yu Huang, Kang-Hsing Fan, and Ann-Joy Cheng. "Panel biomarkers associated with cancer invasion and prognostic prediction for head–neck cancer." Biomarkers in Medicine 15, no. 11 (August 2021): 861–77. http://dx.doi.org/10.2217/bmm-2021-0213.
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Aim: Cell invasion leading to metastasis is a major cause of treatment failure in head–neck cancers (HNCs). Identifying prognostic molecules associated with invasiveness is imperative for clinical applications. Materials & methods: A systemic approach was used to globally survey invasion-related genes, including transcriptomic profiling, pathway analysis, data mining and prognostic assessment using TCGA-HNSC dataset. Results: Six functional pathways and six hub molecules (LAMA3, LAMC2, THBS1, IGF1R, PDGFB and TGFβ1) were identified that significantly contributed to cell invasion, leading to poor survival in HNC patients. Combinations of multiple biomarkers substantially increased the probability of accurately predicting prognosis. Conclusion: Our six defined invasion-related molecules may be used as a panel signature in precision medicine for prognostic indicators or molecular therapeutic targets for HNC.
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Chuang, Yi-Hsuan, Chun-Yu Lin, Jih-Chin Lee, Chia-Hwa Lee, Chia-Lin Liu, Sing-Han Huang, Jung-Yu Lee, Wen-Sen Lai, and Jinn-Moon Yang. "Identification of the HNSC88 Molecular Signature for Predicting Subtypes of Head and Neck Cancer." International Journal of Molecular Sciences 24, no. 17 (August 22, 2023): 13068. http://dx.doi.org/10.3390/ijms241713068.
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Head and neck squamous cell carcinoma (HNSC) exhibits genetic heterogeneity in etiologies, tumor sites, and biological processes, which significantly impact therapeutic strategies and prognosis. While the influence of human papillomavirus on clinical outcomes is established, the molecular subtypes determining additional treatment options for HNSC remain unclear and inconsistent. This study aims to identify distinct HNSC molecular subtypes to enhance diagnosis and prognosis accuracy. In this study, we collected three HNSC microarrays (n = 306) from the Gene Expression Omnibus (GEO), and HNSC RNA-Seq data (n = 566) from The Cancer Genome Atlas (TCGA) to identify differentially expressed genes (DEGs) and validate our results. Two scoring methods, representative score (RS) and perturbative score (PS), were developed for DEGs to summarize their possible activation functions and influence in tumorigenesis. Based on the RS and PS scoring, we selected candidate genes to cluster TCGA samples for the identification of molecular subtypes in HNSC. We have identified 289 up-regulated DEGs and selected 88 genes (called HNSC88) using the RS and PS scoring methods. Based on HNSC88 and TCGA samples, we determined three HNSC subtypes, including one HPV-associated subtype, and two HPV-negative subtypes. One of the HPV-negative subtypes showed a relationship to smoking behavior, while the other exhibited high expression in tumor immune response. The Kaplan–Meier method was used to compare overall survival among the three subtypes. The HPV-associated subtype showed a better prognosis compared to the other two HPV-negative subtypes (log rank, p = 0.0092 and 0.0001; hazard ratio, 1.36 and 1.39). Additionally, within the HPV-negative group, the smoking-related subgroup exhibited worse prognosis compared to the subgroup with high expression in immune response (log rank, p = 0.039; hazard ratio, 1.53). The HNSC88 not only enables the identification of HPV-associated subtypes, but also proposes two potential HPV-negative subtypes with distinct prognoses and molecular signatures. This study provides valuable strategies for summarizing the roles and influences of genes in tumorigenesis for identifying molecular signatures and subtypes of HNSC.
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Park, Jun-Ook, Young Min Park, Woo-Jin Jeong, Yoo Seob Shin, Yong Tae Hong, Ik Joon Choi, Ji Won Kim, et al. "Survival Benefits From Surgery for Stage IVa Head and Neck Squamous Cell Carcinoma: A Multi-Institutional Analysis of 1,033 Cases." Clinical and Experimental Otorhinolaryngology 14, no. 2 (May 1, 2021): 225–34. http://dx.doi.org/10.21053/ceo.2020.01732.
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Objectives. Head and neck squamous cell carcinomas (HNSCs) are frequently diagnosed at the locoregional advanced stage (stage IVa), but controversy remains regarding whether stage IVa HSNCs should be treated with upfront surgery or definitive chemoradiation therapy (CRT). The purpose of this study was to compare overall survival (OS) and disease-free survival (DFS) in patients with stage IVa HNSC treated primarily by surgery with curative intent with/without (neo)adjuvant treatment (surgery group) versus those treated primarily with CRT (CRT group).Methods. We reviewed data of 1,033 patients with stage IVa HNSC treated with curative intent at 17 cancer centers between 2010 and 2016.Results. Among 1,033 patients, 765 (74.1%) received upfront surgery and 268 (25.9%) received CRT. The 5-year OS and DFS rates were 64.4% and 62.0% in the surgery group and 49.5% and 45.4% in the CRT group, respectively. In multivariate analyses, OS and DFS were better in the surgery group than in the CRT group (odds ratio [OR] for death, 0.762; 95% confidence interval [CI], 0.592–0.981; OR for recurrence, 0.628; 95% CI, 0.492–0.802). In subgroup analyses, the OS and DFS of patients with oropharyngeal cancer were better in the surgery group (OR for death, 0.548; 95% CI, 0.341–0.879; OR for recurrence, 0.598; 95% CI, 0.377–0.948). In the surgery group, patients with laryngeal cancer showed better OS (OR for death, 0.432; 95% CI, 0.211–0.882), while those with hypopharyngeal cancer DFS was improved (OR for recurrence, 0.506; 95% CI, 0.328–0.780).Conclusion. A survival benefit from surgery may be achieved even in patients with stage IVa HNSC, particularly those with oropharyngeal and laryngeal cancer. Surgery led to a reduction in the recurrence rate in patients with hypopharyngeal cancer.
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Xu, Chengbo, Hongfang Xu, and Baimei Liu. "Head and neck squamous cell carcinoma-specific prognostic signature and drug sensitive subtypes based on programmed cell death-related genes." PeerJ 11 (November 21, 2023): e16364. http://dx.doi.org/10.7717/peerj.16364.
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Background As a complex group of malignancies, head and neck squamous cell carcinoma (HNSC) is one of the leading causes of cancer mortality. This study aims to establish a reliable clinical classification and gene signature for HNSC prognostic prediction and precision treatments. Methods A consensus clustering analysis was performed to group HNSC patients in The Cancer Genome Atlas (TCGA) database based on genes linked to programmed cell death (PCD). Differentially expressed genes (DEGs) between subtypes were identified using the “limma” R package. The TCGA prognostic signature and PCD-related prognostic genes were found using a least absolute shrinkage and selection operator (LASSO) regression analysis and univariate Cox regression analysis. The robustness of the LASSO analysis was validated using datasets GSE65858 and GSE41613. A cell counting kit-8 (CCK-8) test, Western blot, and real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) were used to evaluate the expression and viability of prognostic genes. Results Four molecular subtypes were identified in PCD-related genes. Subtype C4 had the best prognosis and the highest immune score, while subtype C1 exhibited the most unfavorable outcomes. Three hundred shared DEGs were identified among the four subtypes, and four prognostic genes (CTLA4, CAMK2N1, PLAU and CALML5) were used to construct a TCGA-HNSC prognostic model. High-risk patients manifested poorer prognosis, more inflammatory pathway enrichment, and lower immune cell infiltration. High-risk patients were more prone to immune escape and were more likely to be resistant to Cisplatin and 5-Fluorouracil. Prognosis prediction was validated in external datasets. The expression of CTLA4, CAMK2N1, PLAU and CALML5 was enhanced in CAL-27 and SCC-25 cell lines, and CALML5 inhibited CAL-27 and SCC-25 cell viability. Conclusion This study shares novel insights into HNSC classification and provides a reliable PCD-related prognostic signature for prognosis prediction and treatment for patients with HNSC.
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Hill, James H., Randall L. Plant, David M. Harris, and Randal C. Paniello. "Photodynamic Therapy for Head and Neck Cancer Xenografts in Athymic Mice." Otolaryngology–Head and Neck Surgery 95, no. 5 (December 1986): 602–6. http://dx.doi.org/10.1177/019459988609500515.
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This study examines efficacy and optimal treatment variables of photodynamic therapy (PDT) for human head and neck squamous cancer (HNSC) xenografts in athymic mice. Two and four days after injection of hematoporphyrin derivative (HPD), tumors were illuminated with red light from an argon-dye laser. Sixty-three tumors were treated. With HPD dose and light intensity constant at 7.5 mg/kg and 100 mW/cm2, respectively, the extent of tumor necrosis was strongly dependent on duration of light exposure. There was no substantial difference in results for 30- and 60-minute treatment durations between animals injected with HPD 2 and 4 days before treatment. After 30 minutes treatment time, responses were seen in 8 of 10 mice (2 days post-HPD) and 11 of 12 mice (4 days post-HPD). After 60 minutes treatment time, toxicity was high. We conclude that, in this model, PDT is effective in selective killing of HNSC. For future comparison studies in this model, if the indicated HPD dose and light intensity are used we recommend a 2-day delay after HPD injection and a light exposure duration of 30 minutes
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Fekete, János Tibor, Ágnes Welker, and Balázs Győrffy. "miRNA Expression Signatures of Therapy Response in Squamous Cell Carcinomas." Cancers 13, no. 1 (December 28, 2020): 63. http://dx.doi.org/10.3390/cancers13010063.
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Introduction: Squamous cell carcinomas (SCC) are a major subgroup of malignant tumors with a platinum-based first-line systematic chemotherapy. miRNAs play a role in various diseases and modulate therapy response as well. The aim of this study was to identify predictive miRNAs in platinum-treated SCCs. Methods: miRNA expression data of platinum-treated head and neck (HNSC), cervical (CESC) and lung (LUSC) cancer were collected from the TCGA repositories. Treatment response was defined based on presence or absence of disease progression at 18 months. Responder and nonresponder cohorts were compared using Mann–Whitney and Receiver Operating Characteristic tests. Logistic regression was developed to establish a predictive miRNA signature. Significance was set at FDR < 5%. Results: The integrated database includes 266 SCC patient samples with platinum-based therapy and available follow-up. We uncovered 16, 103, and 9 miRNAs correlated to chemotherapy response in the CESC, HNSC, and LUSC cohorts, respectively. Eight miRNAs overlapped between the CESC and HNSC subgroups, and three miRNAs overlapped between the LUSC and HNSC subgroups. We established a logistic regression model in HNSC and CESC which included six miRNAs: hsa-miR-5586 (Exp (B): 2.94, p = 0.001), hsa-miR-632 (Exp (B): 10.75, p = 0.002), hsa-miR-2355 (Exp (B): 0.48, p = 0.004), hsa-miR-642a (Exp (B): 2.22, p = 0.01), hsa-miR-101-2 (Exp (B): 0.39, p = 0.013) and hsa-miR-6728 (Exp (B): 0.21, p = 0.016). The model using these miRNAs was able to predict chemotherapy resistance with an AUC of 0.897. Conclusions: We performed an analysis of RNA-seq data of squamous cell carcinomas samples and identified significant miRNAs correlated to the response against platinum-based therapy in cervical, head and neck, and lung tumors.
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Grau, J. J., M. Caballero, E. Verger, and J. L. Blanch. "Actual proportion of patients (pts) receiving chemotherapy or cetuximab for head and neck squamous carcinoma (HNSC)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e17058-e17058. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e17058.
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e17058 Background: With the new indications of chemotherapy or cetuximab in HNSC, the rate of pts receiving these therapies nowadays is unclear. Methods: This retrospective study identified all consecutive pts with HNSC from January 1, 2006, to December 31, 2007, presented in a multidisciplinary team to decide further treatment in a single institution. ASCO guidelines for larynx preservation were followed to select surgery or chemoradiotherapy (ChRt). We classified the intention-to-treat as palliative, adjuvant or induction therapy. In the last case, always with concomitant radiotherapy (Rt) or prior to concomitant ChRt. Cetuximab was indicated with Rt as induction therapy for pts with problems to receive platin-based chemotherapy. Results: : A total of 350 pts were identified, 320 were male (91%), and 30 female (9%), with mean age 60.4 (range 41–90). Primary tumor was located in glottis (41%), supraglottis (19%), hypopharynx (11%), oropharynx (20%), or mouth (9%). Staging was I (27%), II (22%), III (16%), or IV (35%). Surgery alone was performed in 136 pts (39%) and chemotherapy or cetuximab in 214 other pts (61%). The intention-to-treat was palliative in 69 (32%), adjuvant in 51 (24%), or induction 94(44%) of the pts respectively. Rt plus cetuximab was administered to 31/97 (33%) and Rt plus chemotherapy in 63/97 (67%) pts as induction therapy. During this 2-year period, some pts received both induction/adjuvant and palliative chemotherapy. Conclusions: Chemotherapy or cetuximab is indicated as part of treatment in more than a half of pts with HNSC. Induction therapy is the most frequent indication. No significant financial relationships to disclose.
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Baulch, Janet E., Munjal M. Acharya, Barrett D. Allen, Ning Ru, Nicole N. Chmielewski, Vahan Martirosian, Erich Giedzinski, et al. "Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain." Proceedings of the National Academy of Sciences 113, no. 17 (April 4, 2016): 4836–41. http://dx.doi.org/10.1073/pnas.1521668113.
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Cancer survivors face a variety of challenges as they cope with disease recurrence and a myriad of normal tissue complications brought on by radio- and chemotherapeutic treatment regimens. For patients subjected to cranial irradiation for the control of CNS malignancy, progressive and debilitating cognitive dysfunction remains a pressing unmet medical need. Although this problem has been recognized for decades, few if any satisfactory long-term solutions exist to resolve this serious unintended side effect of radiotherapy. Past work from our laboratory has demonstrated the neurocognitive benefits of human neural stem cell (hNSC) grafting in the irradiated brain, where intrahippocampal transplantation of hNSC ameliorated radiation-induced cognitive deficits. Using a similar strategy, we now provide, to our knowledge, the first evidence that cranial grafting of microvesicles secreted from hNSC affords similar neuroprotective phenotypes after head-only irradiation. Cortical- and hippocampal-based deficits found 1 mo after irradiation were completely resolved in animals cranially grafted with microvesicles. Microvesicle treatment was found to attenuate neuroinflammation and preserve host neuronal morphology in distinct regions of the brain. These data suggest that the neuroprotective properties of microvesicles act through a trophic support mechanism that reduces inflammation and preserves the structural integrity of the irradiated microenvironment.
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Zewde, Makda Getachew, Daniel Fulop, Alexander Tsankov, and Kuan-lin Huang. "Abstract A47: Characterization of immune cell composition across cancer types in pan-cancer genomic cohorts." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A47. http://dx.doi.org/10.1158/2326-6074.tumimm22-a47.
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Abstract Introduction: Identifying immune cell signatures in individual tumors can help guide treatment selection for patients. Numerous deconvolution methods have been developed to estimate immune cell fractions from bulk gene expression data, but they have yet to be systematically applied and cross-validated in pan-cancer genomic cohorts. We undertook this study to cross-validate immune cell quantification methods across 25 cancer types spanning 11,011 samples and provide a public immuno-oncology resource. Methods: Using gene expression data from both The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), we employed and compared six methods to estimate immune cell fractions in each cancer type (CIBERSORT, quanTIseq, EPIC, TIMER, MCP-counter, xCell; immunedeconv R package). We mapped these results to a common vocabulary of five broad cell categories for comparison: T cells, B cells, natural killer cells (NK cells), macrophages/monocytes, and myeloid dendritic cells (mDCs). In parallel, we computed immune cell proportions for seven cancer types using single-cell RNA-seq (scRNA-seq) data from a single-cell tumor immune atlas of 217 patients. We correlated the median immune cell fractions estimated from bulk deconvolution with scRNA-seq proportions for each cancer type. To demonstrate the application of this resource, we compared the immune cell fractions (1) in adjacent normal versus tumor tissues, and (2) in head and neck squamous cell carcinoma (HNSC) and colorectal adenocarcinoma (COAD) tumor subtypes using multivariable linear regression adjusted for age and sex. Results: Overall, 9,689 TCGA samples and 1,322 ICGC samples were analyzed, and correlations across six deconvolution tools were performed. Two well-performing cell estimation methods, EPIC and quanTIseq, demonstrated good correlation between median deconvoluted T cell enrichment score and single-cell cytotoxic CD8+ T cell populations (spearman coefficient; EPIC = 0.71, quanTIseq = 0.43). However, cross-cancer type correlations between scRNA-seq and bulk estimated fractions were not statistically significant for most cancer types. In multivariable regression comparing immune cell estimates across cancer subtypes, we found increased T cell (EPIC: OR=1.65, 95% CI = 1.23-2.21, quanTIseq: OR = 1.30, 95% CI = 1.20-1.40) and B cell (EPIC: OR = 2.92, 95% CI = 2.05-4.15, quanTIseq: OR = 1.48, 95% CI = 1.37-1.60) enrichment in HPV-positive compared to HPV-negative HNSC. In COAD, we found increased T cell enrichment in the microsatellite instability (MSI) subtype compared to the genome stable subtype (OR = 1.16, 95% CI = 1.01-1.33). Conclusion: Overall, our study provides a public resource of immune cell annotations for two widely used, pan-cancer genomics cohorts and can facilitate future studies that aim to characterize the tumor immune microenvironment. Furthermore, we validated the use of this resource by demonstrating enrichment of specific immune cell subsets in HNSC and COAD subtypes, consistent with prior reports of these well-characterized cancers. Citation Format: Makda Getachew Zewde, Daniel Fulop, Alexander Tsankov, Kuan-lin Huang. Characterization of immune cell composition across cancer types in pan-cancer genomic cohorts [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A47.
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Yang, Linhui, Zhiwei Chen, Yunliang Liu, Xiaoyan Wang, Jing Li, and Qing Ye. "Immunization Combined with Ferroptosis Related Genes to Construct a New Prognostic Model for Head and Neck Squamous Cell Carcinoma." Cancers 14, no. 17 (August 24, 2022): 4099. http://dx.doi.org/10.3390/cancers14174099.
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Ferroptosis is a new type of programmed cell death that plays a pivotal role in a variety of tumors. Moreover, immunity is closely related to ferroptosis. However, immune-ferroptosis-related mRNAs (IFRMs) are still not fully understood in the regulation of head and neck squamous cell carcinoma (HNSC). The purpose of this paper was to investigate the IFRMs prediction of HNSC and its possible molecular biological role. RNA-Seq and related clinical data were mined from the TCGA database, ImmPort database, GeneCards database, FerrDb database, and previous data. In R software, the “DESeq2” package was used to analyze the differential expression of IFRMs. We used univariate Cox analysis to judge the prognosis of the IFRMs. Using the least absolute shrinkage and selection operator (LASSO) and Cox regression, a prediction model for 12 IFRMs was established. In this study, the Kaplan–Meier survival curve and receiver operating characteristic (ROC) curve analysis were used to evaluate the prediction results. Moreover, factors such as immune landscape, somatic mutations, and drug susceptibility are also discussed. We successfully constructed the signature of 12-IFRMs. The two risk groups were classified according to the risk score obtained by this signature. Compared with conventional clinicopathological features, the characteristic-based risk score was more predictive of survival in patients with HNSC. Furthermore, the expression of CD8+T cells and macrophage M0 differed significantly between the two groups. Moreover, the expression of TNFSF9 and CD44 in high-risk groups was significantly increased compared with the low-risk groups. Then, we found a higher proportion of high-risk mutations than in the low-risk group. Next, the high-risk group was more sensitive to chemotherapy drugs such as bosutinib, docetaxel, erlotinib, gefitinib, imatinib, lapatinib, and sorafenib. Finally, an in-depth analysis of the association and potential value of the 12 genes was performed. In summary, the 12-IFRM signatures established in this paper had good application prospects and could be effectively used to predict the clinical outcome and treatment response of head and neck squamous cell carcinoma.
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Erdim, Ibrahim. "Parotidectomy in head-neck skin cancers: Our clinical experience." Praxis of Otorhinolaryngology 10, no. 3 (October 27, 2022): 101–9. http://dx.doi.org/10.5606/kbbu.2022.88262.
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Objectives: In this study, our experience on diagnosis, treatment, and follow-up processes of patients who underwent parotidectomy for head-neck skin cancer (HNSC) was presented. Patients and Methods: A total of 30 patients (20 male, 10 female; mean age: 76±9.8 year; range, 50 to 90 year) who underwent elective and therapeutic parotidectomy for HNSC between January 2012 and January 2020 were included this retrospective study. Results: Elective parotidectomy was performed on 11 (36.7%) patients, and therapeutic parotidectomy was performed on 19 (63.3%) patients. Primary tumor histopathology was squamous cell carcinoma in 23 patients, basal cell carcinoma in five patients, and malignant melanoma in two patients. The most frequent primary tumor localizations were auricula (n=9), temple region (n=7), and preauricular region (n=6), respectively. Neck dissection was performed on 25 (83.3%) patients. Postoperative radiotheraphy was applied to 12 (40%) patients. Mean follow-up time was 40.3±30.9 (range, 6 to 99) months. While the three-year survival rate was 90% (9/10) and the five-year survival rate was 77.8% (7/9) in patients who underwent elective parotidectomy, the three-year survival rate was 46.2% (6/13) and the five-year survival rate was 22.2% (2/9) in patients who underwent therapeutic parotidectomy. Both the three-year and five-year survival rates of elective parotidectomy patients were higher than those of therapeutic parotidectomy patients (p<0.05). Conclusion: If regional metastasis, particularly in the parotid gland, occurs in patients with HNSC, the survival rate decreases significantly. Therefore, we believe that elective parotidectomy should be performed on patients with high risk. Neck dissection should be performed when therapeutic parotidectomy is needed, and it must be kept in mind that radiotherapy might be required according to the postoperative pathology report.
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Kim, Nari, Mi-Hyun Kim, Junhee Pyo, Soo-Min Lee, Ji-Sung Jang, Do-Wan Lee, and Kyung Won Kim. "CCR8 as a Therapeutic Novel Target: Omics-Integrated Comprehensive Analysis for Systematically Prioritizing Indications." Biomedicines 11, no. 11 (October 27, 2023): 2910. http://dx.doi.org/10.3390/biomedicines11112910.
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Target identification is a crucial process in drug development, aiming to identify key proteins, genes, and signal pathways involved in disease progression and their relevance in potential therapeutic interventions. While C-C chemokine receptor 8 (CCR8) has been investigated as a candidate anti-cancer target, comprehensive multi-omics analyzes across various indications are limited. In this study, we conducted an extensive bioinformatics analysis integrating genomics, proteomics, and transcriptomics data to establish CCR8 as a promising anti-cancer drug target. Our approach encompassed data collection from diverse knowledge resources, gene function analysis, differential gene expression profiling, immune cell infiltration assessment, and strategic prioritization of target indications. Our findings revealed strong correlations between CCR8 and specific cancers, notably Breast Invasive Carcinoma (BRCA), Colon Adenocarcinoma (COAD), Head and Neck Squamous Cell Carcinoma (HNSC), Rectum adenocarcinoma (READ), Stomach adenocarcinoma (STAD), and Thyroid carcinoma (THCA). This research advances our understanding of CCR8 as a potential target for anti-cancer drug development, bridging the gap between molecular insights and creating opportunities for personalized treatment of solid tumors.
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Madan, Sanna, Sanju Sinha, Alejandro A. Schäffer, and Eytan Ruppin. "Abstract LB062: Identifying novel targets for CAR-T therapies from single cell RNA-sequencing data." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB062. http://dx.doi.org/10.1158/1538-7445.am2023-lb062.
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Abstract Chimeric antigen receptor T (CAR-T) cell therapies have revolutionized cancer treatment. While CAR-T has yielded tremendous clinical success for patients with liquid tumors, its potential remains to be unleashed against solid tumors. One key challenge is identifying optimal targets for these therapies: cell surface proteins that are expressed highly and uniformly by a tumor’s constituent malignant cells, and minimally so by healthy tissues. Employing a systematic, data-driven analysis, we first charted the landscape of existing CAR-T targets in the clinic, identifying the leading targets in each indication based on tumor selectivity and safety metrics. Next, from patient tumor single cell transcriptomics data, we performed a genome wide search across many different solid tumor types to identify new and candidate CAR-T targets with better selectivity and safety scores than extant ones. Remarkably, in almost all indications, we could not find such better targets, testifying to the near optimality of the current target space, at least in accordance with our measures. However, one striking exception is HPV-negative head and neck squamous cell carcinoma (HNSC), for which there is currently a dearth of existing CAR-T targets in clinics. Specifically, our investigation has discovered 20 novel CAR-T targets for treating HNSC and one for treating glioblastoma more precisely and safely. Citation Format: Sanna Madan, Sanju Sinha, Alejandro A. Schäffer, Eytan Ruppin. Identifying novel targets for CAR-T therapies from single cell RNA-sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB062.
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Li, Yuan, Jiagen Li, Nan Sun, Mei Luo, Chengcheng Zhou, Xuejiao Shi, Wenhui Yang, Zhiliang Lu, Zhaoli Chen, and Jie He. "Identification and functional characterization of long noncoding RNA NMR as biomarker for metastasis and prognosis in esophageal squamous cell carcinoma." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e15587-e15587. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15587.
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e15587 Background: Long noncoding RNAs (lncRNA) have been implicated in cancer but most of them remain largely unstudied. Methods: In this study, we identified a NSUN2 methylated lncRNA (NMR), which is significantly upregulated in esophageal squamous cell carcinoma (ESCC), functions as a key regulator of ESCC tumor metastasis and drug resistance. Results: In microarray data of 119 paired ESCC and normal tissues, NMR was significantly overexpressed in ESCC (P < 0.001), and overexpression of NMR indicated poor overall survival of ESCC patients (P = 0.003); in RNA sequencing data of 20 cancer types from TCGA, including 426 head and neck squamous cell carcinoma (HNSC) patients, NMR was significantly upregulated in HNSC tissues (P < 0.01), and patients with higher T stage, N stage, and m stage had significantly higher NMR expression (P < 0.05). Dysregulation of NMR was also validated in an independent cohort with 83 ESCC patients. Consistently, NMR was significantly overexpressed in ESCC (P < 0.001), and high NMR expression was significantly associated with lymph node metastasis and poor overall survival (P < 0.05). Functional experiments demonstrated that NMR could promote tumor cell migration and invasion, inhibit cisplatin-induced apoptosis and increase drug resistance in ESCC cells. Mechanistically, transcription of NMR could be upregulated by NF-κB activation after IL-1β and TNF-α treatment. RNA sequencing after interference highlighted alterations in collagen metabolic process and ERK1 and ERK2 cascade. Further validation proved that NMR could promote the expression of MMP3 and MMP10, at least partially by ERK1/2 pathway. Conclusions: Taken together, these findings suggest that NMR functions as an oncogenic gene in ESCC and may serve as novel biomarker and therapeutic target in ESCC.
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Acharya, Munjal M., Lori-Ann Christie, Thomas G. Hazel, Karl K. Johe, and Charles L. Limoli. "Transplantation of Human Fetal-Derived Neural Stem Cells Improves Cognitive Function following Cranial Irradiation." Cell Transplantation 23, no. 10 (October 2014): 1255–66. http://dx.doi.org/10.3727/096368913x670200.
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Treatment of central nervous system (CNS) malignancies typically involves radiotherapy to forestall tumor growth and recurrence following surgical resection. Despite the many benefits of cranial radiotherapy, survivors often suffer from a wide range of debilitating and progressive cognitive deficits. Thus, while patients afflicted with primary and secondary malignancies of the CNS now experience longer local regional control and progression-free survival, there remains no clinical recourse for the unintended neurocognitive sequelae associated with their cancer treatments. Multiple mechanisms contribute to disrupted cognition following irradiation, including the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus. We have explored the potential of using intrahippocampal transplantation of human stem cells to ameliorate radiation-induced cognitive dysfunction. Past studies demonstrated the capability of cranially transplanted human embryonic (hESCs) and neural (hNSCs) stem cells to functionally restore cognition in rats 1 and 4 months after cranial irradiation. The present study employed an FDA-approved fetal-derived hNSC line capable of large scale-up under good manufacturing practice (GMP). Animals receiving cranial transplantation of these cells 1 month following irradiation showed improved hippocampal spatial memory and contextual fear conditioning performance compared to irradiated, sham surgery controls. Significant newly born (doublecortin positive) neurons and a smaller fraction of glial subtypes were observed within and nearby the transplantation core. Engrafted cells migrated and differentiated into neuronal and glial subtypes throughout the CA1 and CA3 subfields of the host hippocampus. These studies expand our prior findings to demonstrate that transplantation of fetal-derived hNSCs improves cognitive deficits in irradiated animals, as assessed by two separate cognitive tasks.
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Lee, Suyeon, Heewon Jung, Jiwoo Park, and Jaegyoon Ahn. "Accurate Prediction of Cancer Prognosis by Exploiting Patient-Specific Cancer Driver Genes." International Journal of Molecular Sciences 24, no. 7 (March 29, 2023): 6445. http://dx.doi.org/10.3390/ijms24076445.
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Accurate prediction of the prognoses of cancer patients and identification of prognostic biomarkers are both important for the improved treatment of cancer patients, in addition to enhanced anticancer drugs. Many previous bioinformatic studies have been carried out to achieve this goal; however, there remains room for improvement in terms of accuracy. In this study, we demonstrated that patient-specific cancer driver genes could be used to predict cancer prognoses more accurately. To identify patient-specific cancer driver genes, we first generated patient-specific gene networks before using modified PageRank to generate feature vectors that represented the impacts genes had on the patient-specific gene network. Subsequently, the feature vectors of the good and poor prognosis groups were used to train the deep feedforward network. For the 11 cancer types in the TCGA data, the proposed method showed a significantly better prediction performance than the existing state-of-the-art methods for three cancer types (BRCA, CESC and PAAD), better performance for five cancer types (COAD, ESCA, HNSC, KIRC and STAD), and a similar or slightly worse performance for the remaining three cancer types (BLCA, LIHC and LUAD). Furthermore, the case study for the identified breast cancer and cervical squamous cell carcinoma prognostic genes and their subnetworks included several pathways associated with the progression of breast cancer and cervical squamous cell carcinoma. These results suggested that heterogeneous cancer driver information may be associated with cancer prognosis.
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Kholod, Olha, William Basket, Danlu Liu, Jonathan Mitchem, Jussuf Kaifi, Laura Dooley, and Chi-Ren Shyu. "Identification of Immuno-Targeted Combination Therapies Using Explanatory Subgroup Discovery for Cancer Patients with EGFR Wild-Type Gene." Cancers 14, no. 19 (September 29, 2022): 4759. http://dx.doi.org/10.3390/cancers14194759.
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(1) Background: Phenotypic and genotypic heterogeneity are characteristic features of cancer patients. To tackle patients’ heterogeneity, immune checkpoint inhibitors (ICIs) represent some the most promising therapeutic approaches. However, approximately 50% of cancer patients that are eligible for treatment with ICIs do not respond well, especially patients with no targetable mutations. Over the years, multiple patient stratification techniques have been developed to identify homogenous patient subgroups, although matching a patient subgroup to a treatment option that can improve patients’ health outcomes remains a challenging task. (2) Methods: We extended our Subgroup Discovery algorithm to identify patient subpopulations that could potentially benefit from immuno-targeted combination therapies in four cancer types: head and neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), and skin cutaneous melanoma (SKCM). We employed the proportional odds model to identify significant drug targets and the corresponding compounds that increased the likelihood of stable disease versus progressive disease in cancer patients with the EGFR wild-type (WT) gene. (3) Results: Our pipeline identified six significant drug targets and thirteen specific compounds for cancer patients with the EGFR WT gene. Three out of six drug targets—FCGR2B, IGF1R, and KIT—substantially increased the odds of having stable disease versus progressive disease. Progression-free survival (PFS) of more than 6 months was a common feature among the investigated subgroups. (4) Conclusions: Our approach could help to better select responders for immuno-targeted combination therapies and improve health outcomes for cancer patients with no targetable mutations.
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Lv, Ran, Fang Lv, Pei Zhihua, Jianing Yu, Xiuyu Zhao, Yiqian Liu, Yaxi Zhang, Geng Chen, Weizhi Chen, and Ji He. "Noninvasive detection of chromosomal instability in plasma circulating cell-free DNA for early pan-cancer diagnosis using low-pass whole-genome sequencing." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e22509-e22509. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e22509.
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e22509 Background: Genomic instability is a typical characteristic of the majority of cancers. Early non-invasive detection of cancer is the most effective way of improving the success of treatment and prognosis at present. Traditional tumor screening methods have limitations in terms of selection methods, sensitivity, specificity, cost, and comfortability. Furthermore, although traditional tumor screening is useful for common cancers, there is no available screening test for rare cancers. Here we developed a novel method for cancer detection with Low-Pass Whole Genome Sequencing (WGS) of cell-free DNA (cfDNA). Methods: The cfDNA samples from 52 healthy donors were first used to establish a blacklist of bins. Then the baseline was established to calculate the chromosomal instability score (CINscore). We optimized the parameters of our model using the following discovery datasets: healthy controls (n = 50), breast invasive carcinoma (BRCA) (n = 44), ovarian serous cystadenocarcinoma (OV) (n = 25), colon adenocarcinoma/rectum adenocarcinoma esophageal carcinoma (COREAD) (n = 52), hepatocellular carcinoma (HCC) (n = 43), Gastric adenocarcinoma (GAC) (n = 31); pancreatic adenocarcinoma (PAC) (n = 38), non-small cell lung cancer (NSCLC) (n = 45). Results: We further evaluated the performance of our method using the confirmation datasets of healthy controls (n = 30), BRCA (n = 20), prostate adenocarcinoma (PRAD) (n = 6), OV (n = 7), head and Neck squamous cell carcinoma (HNSC) (n = 10), Uterine Corpus Endometrial Carcinoma (UCEC) (n = 6), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) (n = 5), COREAD (n = 75), HCC (n = 50), GAC (n = 31), cholangiocarcinoma (CHOL) (n = 8), PAC (n = 10), NSCLC (n = 98), esophageal carcinoma (ESCA) (n = 10), and nasopharyngeal carcinoma (NAC) (n = 4). Overall, the area under the curve (AUC) for pan-cancer is 88.7%, and for BRCA, COREAD, HCC, NSCLC, and GAC are 91.7%, 90.0%, 94.5%, 83.4%, and 88.6%, respectively. Moreover, our approach achieved good performance on the the early stage samples of pan-cancer (AUC = 84.3%) as well as COREAD (AUC = 89.3%) and NSCLC (AUC = 79.0%). Conclusions: Collectively, we show that the CINscore inferred from low-pass WGS could be applied in early non-invasive detection of different cancers with high accuracy. Our approach may aid the improvement of the cancer diagnosis.
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Koenigs, Maria B., Armida Lefranc-Torres, Juliana Bonilla-Velez, Krupal B. Patel, D. Neil Hayes, Krzysztof Glomski, Paul M. Busse, et al. "Association of Estrogen Receptor Alpha Expression With Survival in Oropharyngeal Cancer Following Chemoradiation Therapy." JNCI: Journal of the National Cancer Institute 111, no. 9 (January 31, 2019): 933–42. http://dx.doi.org/10.1093/jnci/djy224.
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Abstract Background Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor α (ERα), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC. Methods To investigate associations among ERα and demographics, HPV status, and survival, we analyzed ERα mRNA expression of head and neck squamous carcinomas (HNSC) from The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) of pretreatment biopsy specimens from an independent group of 215 OPSC patients subsequently treated with primary chemoradiation (OPSC-CR). Associations among variables were evaluated with Fisher exact tests and logistic regression; associations with survival were evaluated with log-rank tests and Cox proportional hazards regression. Results Among 515 patients in TCGA, ERα mRNA expression was highest in HPV-positive OPSC. High ERα mRNA expression was associated with improved survival among those receiving chemoradiation (hazard ratio adjusted for HPV status = 0.44, 95% confidence interval = 0.21 to 0.92). In OPSC-CR, ERα was positive by IHC in 51.6% of tumors and was associated with improved overall, disease-specific, progression-free, and relapse-free survival (log-rank tests: P < .001, P < .001, P = .002, P = .003, respectively); statistically significant associations of ERα positivity with improved survival were maintained after adjusting for clinical risk factors including HPV status. Conclusion In two independent cohorts, ERα is a potential biomarker for improved survival that also may represent a therapeutic target in OPSC.
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Liu, Jinhui, Yuanyuan Wang, Jian Yin, Yan Yang, Rui Geng, Zihang Zhong, Senmiao Ni, et al. "Pan-Cancer Analysis Revealed SRSF9 as a New Biomarker for Prognosis and Immunotherapy." Journal of Oncology 2022 (January 12, 2022): 1–21. http://dx.doi.org/10.1155/2022/3477148.
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Background. Serine/arginine-rich splicing factor 9 (SRSF9) is one of the members of SRSF gene family and related to the tumorigenesis and the progression of tumor. However, whether SRSF9 has a crucial role across pan-cancer is still unknown. Methods. In this study, we used public databases, such as The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx), to analyze SRSF9 expression level among tumor and normal cells. Survival analysis, K-M plotter, and PrognoScan were used to analyze the prognosis value of SRSF9, regarding to overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Moreover, we performed the correlation between SRSF9 and clinical characteristics (including the outcome of prognosis), as well as molecular events of tumor mutation burden (TMB), microsatellite instability (MSI), immune checkpoint gene, tumor microenvironment (TME), immune infiltrating cells, mismatch repair (MMR) genes, m6A genes, DNA methyltransferases, and neoantigen with bioinformatics methods and TISIDB, TIMER, and Sangerbox websites. Results. In general, SRSF9 expression was upregulated in most cancers, such as BLCA, CHOL, and UCEC, which SRSF9 was associated with short survival and severe progression. In COAD, STAD, and UCEC, SRSF9 expression was positively related to both TMB and MSI. In BRCA, BLCA, ESCA, GBM, HNSC, LUSC, LUAD, OV, PRAD, TGCT, THCA, and UCEC, both immune score and stomal score showed a negative relationship with SRSF9 expression. Immune score showed a positive relationship with SRSF9 expression in LGG. SRSF9 expression had a significant and positive correlation with six types of immune infiltration cells in LGG, KIRC, LIHC, PCPG, PRAD, SKCM, THCA, and THYM, except in LUSC. In LIHC, SRSF9 was highly significant correlated with most immune checkpoint genes. For neoantigens, correlation between SRSF9 and the quantity of neoantigens was significantly positive in some cancer types. SRSF9 was also correlated with MMR genes, m6A genes, and DNA methyltransferases. In the 33 cancer types, gene set enrichment analysis (GSEA) demonstrated that SRSF9 was correlated with multiple functions and signaling pathways. Conclusion. These findings demonstrated that SRSF9 may be a new biomarker for the prognosis and immunotherapy in various cancers. As a result, it will be beneficial to provide new therapies for cancer patients, thereby improving the treatment and prognosis of cancer patients.
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Wu, Sheng, Xiangkang Lv, Yilin Li, Xinyi Gao, Zhiqi Ma, Xiao Fu, and Yong Li. "Integrated Machine Learning and Single-Sample Gene Set Enrichment Analysis Identifies a TGF-Beta Signaling Pathway Derived Score in Headneck Squamous Cell Carcinoma." Journal of Oncology 2022 (September 1, 2022): 1–12. http://dx.doi.org/10.1155/2022/3140263.
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Background. The TGF-β signaling pathway is clinically predictive of pan-cancer. Nevertheless, its clinical prognosis and regulation of immune microenvironment (TME) characteristics as well as the prediction of immunotherapy efficacy need to be further elucidated in head and neck squamous cell carcinoma. Method. At first, we summarized TGF-β related genes from previous published articles, used ssGSEA to establish the TGF-β risk score. Considering the complexity of its clinical application, we improved it with the LASSO-COX algorithm to construct the model. In addition, we explored the predictive efficacy of TGF-β risk score in the observation of TME phenotype and immunotherapy effect. Finally, the potency of TGF-β risk score in adjusting precise treatment of HNSC was evaluated. Results. We systematically established TGF-β risk score with multi-level predictive ability. TGF-β risk score was employed to predict the tumor microenvironment status, which was negatively associated with NK cells but positively related to macrophages and fibroblasts. It reveals that patients with high TGF-β risk score predict “cold” TME status. In addition, higher risk scores indicate higher sensitivity to immunotherapy. Conclusion. We first construct and validate TGF-β characteristics that can predict immune microenvironment phenotypes and immunotherapeutic effect in multiple datasets. Noteworthy, TGF-β risk score is helpful for individualized precise treatment of patients with the head and neck squamous cell carcinoma.
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Mahmoud, Yamil Damian, Florencia Veigas, Joaquin Merlo, Monica Balzarini, Dario Rocha, Gabriel Adrian Rabinovich, Elmer Fernandez, and Maria Romina Romina Girotti. "Bioinformatic profiling of tumor immunity from patient biopsies to predict survival and response to immunotherapy." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15198-e15198. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15198.
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e15198 Background: Immunotherapies have revolutionized cancer treatment, but responses are not universal and patients who initially respond to therapy develop resistance. The accurate quantification of tumor-infiltrating immune cells holds the promise to reveal the role of the immune system in human cancers and its involvement in tumor escape mechanisms and response to therapy. We present MIXTURE, a new algorithm for tumor immune cell-type proportions deconvolution from transcriptomic data that overcomes competitive methods and revealed novel associations of immune cell types with patient survival and immunotherapy response. Methods: We applied MIXTURE to transcriptomic data from BRCA (n = 1095), LUAD (n = 506), SKCM (n = 472), HNSC (n = 499) and COAD (n = 521) cohorts from TCGA and five published datasets of melanoma patients treated with anti-PD-1/anti-CLTA-4. Results: The analysis of TCGA breast cancer biopsies showed high proportions of M2-macrophages associated with poor patient survival (p < 0.001). In contrast, we found that proportions of follicular T helper cells were associated with better outcome (p < 0.001). We observed a differential immune composition in biopsies of lung adenocarcinoma patients with mutations in TP53 (WT; n = 247; Mut; n = 259) and EGFR (WT, n = 438; Mut, n = 68) related with their different response to immunotherapy (p < 0.05). We found correlations between immune cells proportions and current biomarkers of response to immunotherapy such as TMB, intratumoral heterogeneity, MSI and PD-L1 expression in the TCGA cohorts (p < 0.05). The meta-analysis of melanoma patients treated with immunotherapy showed a distinct immune infiltrate in patients who responded to anti-PD-1 with an increase of immune effector cells such as CD8, CD4 memory activated and gamma-delta T cells, and a decrease in immunosuppressive M2-macrophages (p < 0.05; R = 81; NR = 107). According with the latest findings, we observed higher presence of B cells in responders to anti-PD-1 on-treatment (p = 0.033; R = 31; NR = 23) and in baseline of responders to anti-CTLA-4 (p = 0.028; R = 14; NR = 26). Interestingly, patients that previously progressed to anti-CTLA-4 showed a differential immune profile that was associated with response to anti-PD-1 (p < 0.05; Ipi-Prog = 59; Ipi-Naïve = 102). Conclusions: We demonstrated the potential of MIXTURE to understand the tumor immune microenvironment and its relationship with patient survival and response to immunotherapies. MIXTURE is available for the wider scientific community as web application and as packages for R and Python.
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Cirillo, Nicola, Carmen Wu, and Stephen S. Prime. "Heterogeneity of Cancer Stem Cells in Tumorigenesis, Metastasis, and Resistance to Antineoplastic Treatment of Head and Neck Tumours." Cells 10, no. 11 (November 8, 2021): 3068. http://dx.doi.org/10.3390/cells10113068.
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The discovery of a small subset of cancer cells with self-renewal properties that can give rise to phenotypically diverse tumour populations has shifted our understanding of cancer biology. Targeting cancer stem cells (CSCs) is becoming a promising therapeutic strategy in various malignancies, including head and neck squamous cell carcinoma (HNSCC). Diverse sub-populations of head and neck cancer stem cells (HNCSCs) have been identified previously using CSC specific markers, the most common being CD44, Aldehyde Dehydrogenase 1 (ALDH1), and CD133, or by side population assays. Interestingly, distinct HNCSC subsets play different roles in the generation and progression of tumours. This article aims to review the evidence for a role of specific CSCs in HNSCC tumorigenesis, invasion, and metastasis, together with resistance to treatment.
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Prince, Mark E. P., and Laurie E. Ailles. "Cancer Stem Cells in Head and Neck Squamous Cell Cancer." Journal of Clinical Oncology 26, no. 17 (June 10, 2008): 2871–75. http://dx.doi.org/10.1200/jco.2007.15.1613.
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Appropriate treatment of head and neck squamous cell cancer (HNSCC) remains one of the most difficult challenges in head and neck oncology. Overall survival of patients with HNSCC remains at approximately 50% at 5 years. Surgical therapy can be mutilating and often has significant effects on swallowing, speech, and physical appearance. The addition of chemotherapy to radiation treatment has shown efficacy in organ preservation in some sites in the head and neck, but has resulted in limited improvement in survival rates. HNSCC resistance to chemotherapy has limited the usefulness of chemotherapy in the treatment of this disease. We have recently demonstrated that human head and neck squamous cell cancers contain a tumorigenic, so-called cancer stem cell, subpopulation of cells that can self-renew and produce differentiated cells that form the bulk of the tumor. These tumorigenic HNSCC cells have a distinct phenotype and can be identified by a surface marker. Current treatment for HNSCC regimens may selectively kill the differentiated cancer cells, producing tumor regression while sparing the cancer stem cells, leading to tumor regrowth and relapse. It is important for us to understand why HNSCC does not respond to chemotherapy and to identify new targeted treatments that can overcome resistance and improve patient outcomes. Further study of HNSCC stem cells will increase our knowledge of this devastating disease and allow us to develop novel treatments.
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Anurag, Meenakshi, Eric Jaehnig, Jonathan Lei, Beom-Jun Kim, Anh Minh Tran Huynh, Yongchao Dou, Tanmayi Vashist, et al. "Abstract 1010: LIG1 deletion predicts chemotherapy resistance, chromosomal instability, and poor prognosis in triple negative breast cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1010. http://dx.doi.org/10.1158/1538-7445.am2022-1010.
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Abstract Introduction: Cytotoxic chemotherapy for sporadic Triple Negative Breast Cancer (TNBC) remains the standard of care and the recent approval for adjuvant PD1 therapy is not biomarker guided. Pathological complete response (pCR) is often not achieved and portends poor survival. Predictive markers for individual drugs have proven elusive. Approach: Microscaled proteogenomics (MPG) was applied to snap-frozen TNBC clinical trial core needle biopsies obtained before treatment with carboplatin and docetaxel (WashU: NCT201404107 and BCM: NCT02544987). Clinical endpoints for discovery analysis were pathological complete response (pCR) and residual cancer burden (RCB). Standard non-parametric statistical tests were employed to identify proteogenomic features associated with these endpoints. Results: Copy number aberrations (CNA) are a recurrent feature of TNBC and a potential driver of chemotherapy sensitivity. We therefore sought CNA with concordant changes at the mRNA and protein levels that also associate with pCR status. Genes located within a recurrent interstitial deletion at chromosomal location 19q13.3 were the most significantly down-regulated at mRNA and protein level in chemotherapy resistant cases. 19q13.3 encodes multiple DNA damage response (DDR) genes; however, only LIG1, a DNA ligase required for lagging strand synthesis and DNA repair, showed concordant changes at both the mRNA and protein level. In multiple independent TNBC data sets, LIG1 deletion was associated lack of pCR and poor metastasis-free survival. Additionally in the BrighTNess TNBC trial lower LIG1 mRNA levels were associated with increased chemotherapy resistance in the carboplatin containing arms (no pCR and residual cancer burden I-III; p=0.0008 and 0.003 respectively). In PDX-derived short-term cultures and PDXs treated with docetaxel or carboplatin, a specific association of carboplatin resistance with LIG1 deletion was observed. LIG1 depleted-tumors did not harbor elevated scores for homologous recombination defect signature, suggesting LIG1 loss is an orthogonal pathway for TNBC pathogenesis The high chromosomal instability index in LIG1 deletion tumors in our TNBC study was robustly reproduced in multiple datasets (including TCGA-BRCA ; Metastatic breast cancer project). LIG1 copy number deletion was also associated with poor progression free survival, and high chromosomal instability in multiple other cancers (including TCGA-UCEC HR=2.23, TCGA-HNSC HR=1.46, TCGA-PRAD HR=2.07, TCGA- COAD HR=1.75 and TCGA-KIRP HR=4.00). Conclusion: Deletion of LIG1 is associated with chromosomal instability in TNBC and occurs in tumors without genomic evidence for defects in homologous recombination. Other clinical features of LIG1 deleted TNBC and how LIG1 loss may cause chromosomal instability and tumorigenesis will be discussed. Citation Format: Meenakshi Anurag, Eric Jaehnig, Jonathan Lei, Beom-Jun Kim, Anh Minh Tran Huynh, Yongchao Dou, Tanmayi Vashist, Erik Bergstrom, Xuxu Gou, Viktoriya Korchina, Donna Marie Muzny, Kristen Otte, Harshavardhan Doddapaneni, Lacey Dobrolecki, Gloria Vittone Echeverria, Bora Lim, Mothaffar Rimawi, Karsten Krug, Ian Hageman, Henry Rodriguez, Ana I. Robles, Tara Hiltke, Kent Osborne, Michael Gillette, George Miles, Steven Carr, Michael T Lewis, Bing Zhang, Foluso Ademuyiwa, Shankha Satpathy, Matthew J. Ellis. LIG1 deletion predicts chemotherapy resistance, chromosomal instability, and poor prognosis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1010.
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Schmidt, Henri, Arutha Kulasinghe, Richard Allcock, Lit Tan, Elisa Mokany, Liz Kenny, and Chamindie Punyadeera. "A Pilot Study to Non-Invasively Track PIK3CA Mutation in Head and Neck Cancer." Diagnostics 8, no. 4 (November 29, 2018): 79. http://dx.doi.org/10.3390/diagnostics8040079.
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Background: PIK3CA pathways are the most frequently mutated oncogenic pathway in head and neck squamous cell carcinoma (HNSCC), including virally driven HNCs. PIK3CA is involved in the PI3K-PTEN-mTOR signalling pathway. PIK3CA has been implicated in HNSCC progression and PIK3CA mutations may serve as predictive biomarkers for therapy selection. Circulating tumour DNA (ctDNA) derived from necrotic and apoptotic tumour cells are thought to harbour tumour-specific genetic alterations. As such, the detection of PIK3CA alterations detected by ctDNA holds promise as a potential biomarker in HNSCC. Methods: Blood samples from treatment naïve HNSCC patients (n = 29) were interrogated for a commonly mutated PIK3CA hotspot mutation using low cost allele-specific Plex-PCRTM technology. Results: In this pilot, cross sectional study, PIK3CA E545K mutation was detected in the plasma samples of 9/29 HNSCC patients using the Plex-PCRTM technology. Conclusion: The results of this pilot study support the notion of using allele-specific technologies for cost-effective testing of ctDNA, and further assert the potential utility of ctDNA in HNSCC.
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Shah, Amit, Shilpa Patel, Jigna Pathak, Niharika Swain, and Shwetha Kumar. "The Evolving Concepts of Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma." Scientific World Journal 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/842491.
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There is increasing evidence that the growth and spread of cancers is driven by a small subpopulation of cancer stem cells (CSCs)—the only cells that are capable of long-term self-renewal and generation of the phenotypically diverse tumor cell population. CSCs have been identified and isolated in a variety of human cancers including head and neck squamous cell carcinoma (HNSCC). The concept of cancer stem cells may have profound implications for our understanding of tumor biology and for the design of novel treatments targeted toward these cells. The present review is an attempt to conceptualize the role of CSCs in HNSCC—its implication in tumorigenesis and the possible additional approach in current treatment strategies.
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Hidy, Samantha, and David Weaver. "230 Single cell PIK3 gene expression patterns support duvelisib (PI3K-delta, gamma inhibitor) treatment of melanoma and other tumors after checkpoint inhibitor therapy." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A248. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0230.
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BackgroundDuvelisib, an FDA-approved oral phosphoinositide 3-kinase (PI3K)-δ,γ inhibitor, targets tumor cells of B/T cell malignancies, but may modulate non-malignant immune cells in the tumor microenvironment (TME) of many cancers. PI3K–δ and PI3K–γ downmodulate immunosuppressive Tregs and myeloid cells in solid tumors.1, 2, 3 We used single-cell RNA analysis of PIK3CD and PIK3CG to explore resistance mechanisms to checkpoint inhibitors (CPI).MethodsSingle-cell melanoma (SKCM) RNAseq datasets: GSE120575;4 CD45+ cells from 48 CPI responders and non-responder tumors, and GSE115978;5 33 treatment-naïve and CPI-progressing (resistant) tumors. Cancer cells and CD45+ TME subpopulations, specified by gene expression signatures and tSNE plots, had PI3K gene expressions profiled. Differential gene expression (DE) was gated in MAST/Seurat. Fishers test Odds Ratio (OR) was calculated for ‘high’ expression.ResultsPIK3CD expression is higher in SKCM than most cancers (10.8 median RSEM log 2).7 By single-cell analysis, PIK3CD (> 0.3 log2 TPM) occurs in 68.2% of cancer cells, with PIK3CB, PIK3CA, and PIK3CG expressed in 32.3%, 12.0%, and 7.2% respectively. PIK3CD-high cancer cells (>4 log2 TPM) have a 711-gene DE gene signature mostly related to immune processes. A higher proportion of cancer cells in CPI resistant tumors express PIK3CD, than untreated tumors (OR 2.02, 95% CI 1.65–2.48, p=3.04 × 10–12), as do PIK3CD+PIK3CG-expressing cancer cells (OR 2.14, 95% CI 1.47–3.13, p=4.2 × 10-5). Additionally, in PI3K–δ or PI3K–γ high melanoma cell lines duvelisib inhibited proliferation, p-AKT and c-myc.7 PIK3CD and PIK3CG are prominently expressed in many SKCM CD45+ TME cells (84.5% and 31.7% CD45+ respectively). PIK3CD (>0.3 log2 TPM) occurs in a high fraction of T (85.7%), CD8+ T (86.3%), CD4+ T (86.9%), B (78.5%), macrophages (88%), and NK (85%). PIK3CG is highest in B, dendritic, cycling lymphocytes and plasma cells. Strikingly, a significantly higher proportion of PIK3CD+ cells occur in resistant tumors compared to untreated for all CD45+ cells, (OR 1.64, 95% CI 1.40–1.94, p=4.79 × 10-10), CD8+ T (OR 2.15, 95% CI 1.61–2.86, p=6.5 × 10-8), and an exhausted C8+ T subpopulation (OR 3.17, 95% CI 1.89–5.37, p=2.95 × 10-6). PIK3CD+PIK3CG-expressing CD45+ cells are significantly increased in CPI-resistant tumors (OR 1.22, 95% CI 1.07–1.39, p=0.002).ConclusionsThese findings support a mechanism where CPI therapies may contribute to modulation of PI3Kδ expression in cancer cells and the immune TME. The PI3K-δ,γ inhibitor duvelisib is being investigated in combination with CPI and evaluated in the context of CPI resistance in clinical trials: pembrolizumab (HNSC, NCT04193293), and nivolumab (Richter’s Syndrome, NCT03892044).ReferencesAli K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, Friedman L, Turner M, Okkenhaug K, Vanhaesebroeck B. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer Nature 2014; 510(7505):407–411.Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, Woo G, Nguyen AV, Figueiredo CC, Foubert P, Schmid MC, Pink M, Winkler DG, Rausch M, Palombella VJ, Kutok J, McGovern K, Frazer KA, Wu X, Karin M, Sasik R, Cohen EE, Varner JA. PI3Kγ is a molecular switch that controls immune suppression. Nature 2016; 539(7629):437–442.De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, Douglas M, Tibbitts T, Sharma S, Proctor J, Kosmider N, White K, Stern H, Soglia J, Adams J, Palombella VJ, McGovern K, Kutok JL, Wolchok JD, Merghoub T. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 2016; 539(7629):443–447.Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, Lieb DJ, Chen JH, Frederick DT, Barzily-Rokni M, Freeman SS, Reuben A, Hoover PJ, Villani AC, Ivanova E, Portell A, Lizotte PH, Aref AR, Eliane JP, Hammond MR, Vitzthum H, Blackmon SM, Li B, Gopalakrishnan V, Reddy SM, Cooper ZA, Paweletz CP, Barbie DA, Stemmer-Rachamimov A, Flaherty KT, Wargo JA, Boland GM, Sullivan RJ, Getz G, Hacohen N. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2018; 175: 998–1013.Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, Melms JC, Leeson R, Kanodia A, Mei S, Lin JR, Wang S, Rabasha B, Liu D, Zhang G, Margolais C, Ashenberg O, Ott PA, Buchbinder EI, Haq R, Hodi FS, Boland GM, Sullivan RJ, Frederick DT, Miao B, Moll T, Flaherty KT, Herlyn M, Jenkins RW, Thummalapalli R, Kowalczyk MS, Cañadas I, Schilling B, Cartwright ANR, Luoma AM, Malu S2, Hwu P, Bernatchez C, Forget MA, Barbie DA, Shalek AK, Tirosh I, Sorger PK, Wucherpfennig K, Van Allen EM, Schadendorf D, Johnson BE, Rotem A, Rozenblatt-Rosen O, Garraway LA, Yoon CH, Izar B, Regev A. A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade. Cell 2018; 175: 984–997.Firebrowse Gene Expression Viewerhttp://firebrowse.org/viewGene.html.Coma S, Weaver DT, Pachter JA. [Poster #663] The dual PI3K-δ/PI3K-γ inhibitor duvelisib inhibits signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ. AACR. 2020.
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Javaid, Sehrish, Antje Schaefer, Craig M. Goodwin, Victoria V. Nguyen, Frances L. Massey, Mariaelena Pierobon, Da'Jhnae Gambrell-Sanders, et al. "Concurrent Inhibition of ERK and Farnesyltransferase Suppresses the Growth of HRAS Mutant Head and Neck Squamous Cell Carcinoma." Molecular Cancer Therapeutics 21, no. 5 (February 28, 2022): 762–74. http://dx.doi.org/10.1158/1535-7163.mct-21-0142.
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Abstract Human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide with an unmet need for more effective, less toxic treatments. Currently, both the disease and the treatment of HNSCC cause significant mortality and morbidity. Targeted therapies hold new promise for patients with HPV-negative status whose tumors harbor oncogenic HRAS mutations. Recent promising clinical results have renewed interest in the development of farnesyltransferase inhibitors (FTIs) as a therapeutic strategy for HRAS-mutant cancers. With the advent of clinical evaluation of the FTI tipifarnib for the treatment of HRAS-mutant HNSCC, we investigated the activity of tipifarnib and inhibitors of HRAS effector signaling in HRAS-mutant HNSCC cell lines. First, we validated that HRAS is a cancer driver in HRAS-mutant HNSCC lines. Second, we showed that treatment with the FTI tipifarnib largely phenocopied HRAS silencing, supporting HRAS as a key target of FTI antitumor activity. Third, we performed reverse-phase protein array analyses to profile FTI treatment-induced changes in global signaling, and conducted CRISPR/Cas9 genetic loss-of-function screens to identify previously unreported genes and pathways that modulate sensitivity to tipifarnib. Fourth, we determined that concurrent inhibition of HRAS effector signaling (ERK, PI3K, mTORC1) increased sensitivity to tipifarnib treatment, in part by overcoming tipifarnib-induced compensatory signaling. We also determined that ERK inhibition could block tipifarnib-induced epithelial-to-mesenchymal transition, providing a potential basis for the effectiveness of this combination. Our results support future investigations of these and other combination treatments for HRAS mutant HNSCC.
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Sarnella, Annachiara, Ylenia Ferrara, Luigi Auletta, Sandra Albanese, Vincenzo Alterio, Jean-Yves Winum, Claudiu T. Supuran, Laura Cerchia, Giuseppina De Simone, and Antonella Zannetti. "Abstract 1040: Blocking hypoxia-induced carbonic anhydrases 9 enhances sensibility to cisplatin of head and neck squamous carcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1040. http://dx.doi.org/10.1158/1538-7445.am2022-1040.
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Abstract The head and neck squamous carcinomas (HNSSCs) are the sixth most common cancer worldwide. Given the heterogeneous nature of HNSCC, this carcinoma results in higher resistance to chemoradiotherapy. Recent evidence highlight the importance of the hypoxic microenvironment in contributing to cisplatin resistance. Therefore, the aim of this study was to investigate the role played by hypoxia-induced protein carbonic anhydrase 9 (CA9) in supporting HNSCC cisplatin resistance. Furthermore, we purpose to investigate the ability of CA9 inhibitor, SLC-0111, a small molecule already used in Phase I clinical trial, to sensitize HNSSC cells to chemotherapy in vitro and in vivo. We analyzed the expression of CA9 in a public data set of 103 HNSCC samples and 22 oral cavity normal tissues and in two HNSSC cell lines (FaDu; SCC-011). HNSCC cells grown in 2D and 3D models under hypoxic conditions (1% O2) showed increased levels of CA9 and greater resistance to cisplatin than cells grown under normoxic conditions. The addition of CA9 inhibitor SLC-0111 to cisplatin sensitized cells to the chemotherapeutic agent and caused a reduction of colony number, spheroid formation, tumor cell, and spheroid migration and invasiveness. Furthermore, the combination therapy hampered activation of STAT3, AKT, ERK, and EMT program whereas it induced apoptosis. Notably, the combined treatment caused inhibition of tumor growth and induction of apoptosis in HNSCC subcutaneous xenografts, as assessed by high-frequency ultrasonography and fluorescent molecular tomography (FMT) with NIR-Annexin V, respectively, at a higher extent than single agents. In addition, FMT with NIR-Prosense revealed a stronger reduction of lymph nodes metastases when mice bearing orthotopic xenografts were treated with cisplatin plus SLC-0111 with respect to a single treatment. Our findings taken together demonstrate the crucial role played by CA9 in promoting cisplatin resistance in HNSCC and the efficacy of SLC-0111 to sensitize tumor cells and xenografts to chemotherapy. Citation Format: Annachiara Sarnella, Ylenia Ferrara, Luigi Auletta, Sandra Albanese, Vincenzo Alterio, Jean-Yves Winum, Claudiu T Supuran, Laura Cerchia, Giuseppina De Simone, Antonella Zannetti. Blocking hypoxia-induced carbonic anhydrases 9 enhances sensibility to cisplatin of head and neck squamous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1040.
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Porcheri, Cristina, and Thimios A. Mitsiadis. "New Scenarios in Pharmacological Treatments of Head and Neck Squamous Cell Carcinomas." Cancers 13, no. 21 (November 3, 2021): 5515. http://dx.doi.org/10.3390/cancers13215515.
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Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent types of cancer with a lethal outcome in half of the diagnosed cases. Mostly, HNSCC develops in the oral cavity, and its development is associated with tobacco and areca nut/betel quid usage, alcohol consumption, and HPV infection. Oral squamous cell carcinoma, as other head and neck cancers, presents a high degree of intratumor heterogeneity, which makes their treatment difficult, and directly correlates with drug resistance. Since the classical treatments for HNSCC oftentimes do not resolve the clinical picture, there is great need for novel therapeutic approaches, models for drug testing, and new drug delivery systems.
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Cruz-Gregorio, Alfredo, Imelda Martínez-Ramírez, José Pedraza-Chaverri, and Marcela Lizano. "Reprogramming of Energy Metabolism in Response to Radiotherapy in Head and Neck Squamous Cell Carcinoma." Cancers 11, no. 2 (February 5, 2019): 182. http://dx.doi.org/10.3390/cancers11020182.
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Head and neck cancer (HNC) is the sixth cause of cancer-related death worldwide. Head and neck squamous cells carcinoma (HNSCC) is the most frequent subtype of HNC. The development of HNSCC is associated to alcohol consumption, smoking or infection by high-risk human Papillomavirus (HR-HPV). Although the incidence of cancers associated with alcohol and tobacco has diminished, HNSCC associated with HR-HPV has significantly increased in recent years. However, HPV-positive HNSCC responds well to treatment, which includes surgery followed by radiation or chemoradiation therapy. Radiation therapy (RT) is based on ionizing radiation (IR) changing cell physiology. IR can directly interact with deoxyribonucleic acid (DNA) or produce reactive oxygen and nitrogen species (RONS), provoking DNA damage. When DNA damage is not repaired, programmed cell death (apoptosis and/or autophagy) is induced. However, cancer cells can acquire resistance to IR avoiding cell death, where reprogramming of energy metabolism has a critical role and is intimately connected with hypoxia, mitochondrial physiology, oxidative stress (OS) and autophagy. This review is focused on the reprogramming of energy metabolism in response to RT in HPV-positive and HPV-negative HNSCC, showing their differences in cellular metabolism management and the probable direction of treatments for each subtype of HNSCC.
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Krishnatry, Rahul, Tejpal Gupta, Vedang Murthy, Sudhir Vasudevan Nair, Deepa Nair, Pankaj Chaturvedi, A. K. Dcruz, et al. "Distant metastasis in head and neck cancer: Baseline factors." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e16021-e16021. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e16021.
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e16021 Background: Loco-regional relapse is predominant pattern of failure in locally advanced head & neck squamous cell cancer (HNSCC). Distant metastasis (DM) is increasingly detected on follow-up. this study attempts to identify baseline patient, tumor & treatment characteristics which determine poor survival in radically treated HNSCC patients developing DM. Methods: Clinical outcome audit of HNSCC receiving radical treatment from 1990-2010 in a single HNCC radiotherapy (RT) clinic who developed DM, using electronic search of a prospectively maintained database. The Disease free survival (DFS) & overall survival (OS) were calculated using Kaplan Meier method. The Log rank test & Cox regression (p< 0.05 significant) were used for univariate & multivariate analysis respectively. Results: 104 HNC patients developed DM, baseline characteristics are shown in table 1. DM was detected at a median of 7(IQR 3-14) months from treatment completion & median survival after diagnosis of DM was 2.6 (0-6) months. The median DFS & OS were 19(13-26), 21.5(16-29) months respectively. On univariate analysis, factors affecting DFS & OS were advanced tumor and nodal stage, perinodal extension & treatment factors (surgery & RT gap >30 days). On multivariate analysis stage and PNE remained significant for DFS while only stage showed significance for OS. Conclusions: Locally advanced stage of presentation (stage IV, T4, N2+) is the most important baseline factor determining poor outcome in HNC patients developing DM. Trials for aggressive primary systemic treatment (chemotherapy, targeted agents) are needed. [Table: see text]
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Miari, Reem, Naiel Azzam, Rinat Bar-Shalom, and Fuad Fares. "5-aza-2’-deoxycytidine induces apoptosis and inhibits tumour growth in vivo of FaDu cells, a specific HPVnegative HNSCC cell line." PLOS ONE 16, no. 9 (September 17, 2021): e0253756. http://dx.doi.org/10.1371/journal.pone.0253756.
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Head and neck cancer squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 600,000 new diagnoses annually. Traditionally, HNCC has been related to tobacco and alcohol exposure; however, over the past decade, a growing number of head and neck cancers are attributed to human papillomavirus (HPV) infection. 5-Aza-2’-deoxycytidine (5-AzaD) was demonstrated as an effective chemotherapeutic agent for acute myelogenous leukaemia. Preclinical data revealed that 5-aza inhibits growth and increases cell death of HPV(+) cancer cells. These effects are associated with reduced expression of HPV genes, stabilization of TP53, and activation of TP53-dependent apoptosis. The aim of the present study is to test the effect of 5-AzaD on growth of human squamous cell carcinoma (FaDu), a HPV(-) and p53 mutated cells, in vitro and in vivo. The effect of 5-AzaD on cell viability, cell cycle progression and induction of apoptosis was tested in vitro. The effect of 5-AzaD on tumour growth in vivo was tested using xenograft mice inoculated with FaDu cells. The results indicated that 5-AzaD reduced cell viability and induced apoptosis in FaDu cells in vitro. In vivo studies revealed that 5-AzaD suppresses the growth of tumours in xenograft mice inoculated with FaDu cells through inhibition of proliferation and induction of apoptosis. These findings may emphasis that 5-AzaD is effective in treatment of HPV(-) HNSCC tumours through TP53 independent pathway. Future studies are needed in order to clarify the molecular mechanism of action of 5-AzaD in HPV(-) cancer cells.
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Pillai, Sangeeth, Jan C. Kwan, Fares Yaziji, Hanwen Yu, and Simon D. Tran. "Mapping the Potential of Microfluidics in Early Diagnosis and Personalized Treatment of Head and Neck Cancers." Cancers 15, no. 15 (July 31, 2023): 3894. http://dx.doi.org/10.3390/cancers15153894.
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Head and neck cancers (HNCs) account for ~4% of all cancers in North America and encompass cancers affecting the oral cavity, pharynx, larynx, sinuses, nasal cavity, and salivary glands. The anatomical complexity of the head and neck region, characterized by highly perfused and innervated structures, presents challenges in the early diagnosis and treatment of these cancers. The utilization of sub-microliter volumes and the unique phenomenon associated with microscale fluid dynamics have facilitated the development of microfluidic platforms for studying complex biological systems. The advent of on-chip microfluidics has significantly impacted the diagnosis and treatment strategies of HNC. Sensor-based microfluidics and point-of-care devices have improved the detection and monitoring of cancer biomarkers using biological specimens like saliva, urine, blood, and serum. Additionally, tumor-on-a-chip platforms have allowed the creation of patient-specific cancer models on a chip, enabling the development of personalized treatments through high-throughput screening of drugs. In this review, we first focus on how microfluidics enable the development of an enhanced, functional drug screening process for targeted treatment in HNCs. We then discuss current advances in microfluidic platforms for biomarker sensing and early detection, followed by on-chip modeling of HNC to evaluate treatment response. Finally, we address the practical challenges that hinder the clinical translation of these microfluidic advances.
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Singh, Khushwant, and Pramod kumar Gautam. "Emulating the Role of Neutrophils in Head and Neck Cancer Microenvironment: Prognostic Role and Therapeutic Strategies." Journal of Cancer Immunology 5, no. 2 (August 28, 2023): 61–73. http://dx.doi.org/10.33696/cancerimmunol.5.076.
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Head and neck squamous cell carcinoma (HNSCC) are a group of cancers that affect various parts of the head and neck, such as the lip, oral cavity, oropharynx, hypopharynx, and nasopharynx. In India, it accounts for approximately 30–40% of all cancers, while in the United States, it represents around 4% of all cancer cases. HNSCC is a significant contributor to cancer-related deaths globally. While smoking is linked to HNSCC, recent research has confirmed the importance of the human papillomavirus (HPV) in its development. Additionally, HNSCC is characterized by immune deficiencies, where the tumor microenvironment alters immune cell activity to facilitate carcinogenesis. However, researchers have identified novel immunotherapeutic targets for HNSCC, mainly by studying the involvement of inflammatory cells such as neutrophils, eosinophils, and macrophages. Unfortunately, patients with recurring malignancy and distant metastases have limited treatment options, with a prognosis of less than one year. Platinum-based chemotherapy, cetuximab, and other conventional therapies are used to treat recurrent and metastatic HNSCC. The pro and anti-tumor roles of neutrophils in cancer and immunotherapy are explored in this study, with a focus on HNSCC. The primary objective is to increase our understanding of HNSCC biology and immunobiology to uncover viable therapeutic options that are both valid and less cytotoxic.
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Xia, Yu, Xiuqin Li, and Wei Sun. "Applications of Recombinant Adenovirus-p53 Gene Therapy for Cancers in the Clinic in China." Current Gene Therapy 20, no. 2 (September 18, 2020): 127–41. http://dx.doi.org/10.2174/1566523220999200731003206.
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Suppression of TP53 function is nearly ubiquitous in human cancers, and a significant fraction of cancers have mutations in the TP53 gene itself. Therefore, the wild-type TP53 gene has become an important target gene for transformation research of cancer gene therapy. In 2003, the first anti-tumor gene therapy drug rAd-p53 (recombinant human p53 adenovirus), trade name Gendicine™, was approved by the China Food and Drug Administration (CFDA) for treatment of head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy. The recombinant human TP53 gene is delivered into cancer cells by an adenovirus vector constructed to express the functional p53 protein. Although the only currently approved used of Gendicine is in combination with radiotherapy for treatment of HNSCC, clinical studies have been carried out for more than 20 other applications of Gendicine in treating cancer, including treatment of advanced lung cancer, advanced liver cancer, malignant gynecological tumors, and soft tissue sarcomas. Currently more than 30,000 patients have been treated with Gendicine. This review provides an overview of the clinical applications of Gendicine in China. We summarize a total of 48 studies with 2,561 patients with solid tumors, including 34 controlled clinical studies and 14 open clinical studies, i.e., clinical studies without a control group. There are 11 studies for head and neck cancer, 10 for liver cancer, 6 for malignant gynecological tumors, 4 for non-small cell lung cancer, 4 for soft tissue sarcoma, 4 for malignant effusion, 2 for gastrointestinal tumors, and 7 for other types of cancer. In all the reported clinical studies, the most common side effect was self-limited fever. Intratumoral injection and intra-arterial infusion were the most common routes of administration. Overall, Gendicine combined with chemotherapy, radiotherapy, or other conventional treatment regimens demonstrated significantly higher response rates compared to standard therapies alone. Some of the published studies also showed that Gendicine combination regimens demonstrated longer progression-free survival times than conventional treatments alone. To date, Gendicine has been clinically used in China for treatment of cancers other than HNSCC for more than ten years, mainly for patients with advanced or unresectable malignant tumors. However, the establishment of standard treatment regimens using TP53 gene therapy is still needed in order to advance its use in clinical practice.
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Shrestha, Gambhir, Bhola Siwakoti, Rashmi Mulmi, and Dejkumar Gautam. "Trend of Head and Neck Cancers in a National Tertiary Cancer Hospital of Nepal from 2012 to 2017." South Asian Journal of Cancer 10, no. 04 (December 2021): 236–40. http://dx.doi.org/10.1055/s-0041-1731131.
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Abstract Introduction Head and neck cancers (HNCs) are increasing in Nepal and have become a major public health issue. This study aims to describe the trend of HNCs in a national tertiary cancer hospital in Nepal. Methods This was a cross-sectional study with secondary data analysis conducted at B.P Koirala Memorial Hospital, Chitwan, Nepal. The data were obtained from the medical record section and included all new HNC cases registered from 2012 to 2017. Analysis was done using Statistical Package for Social Sciences version 17. Subgroup analysis was done according to age, gender, site, and year. Results A total of 4,582 new HNCs were registered, of which 3,097 (67.6%) were males and 1,482 (32.4%) were females. Lip and oral cavity cancers (46.5%) were the most common HNCs followed by tonsil and pharynx (18.0%) and larynx (15.8%). The trend of HNCs shows a steady rise in incidence with difference according to the sites. HNCs were more common among males than females except for thyroid cancer. The most common age group was 60 to 74 years. Conclusions The trend of HNCs is increasing in Nepal especially oral cancers. Awareness of risk factors, effective screening programs, and comprehensive treatment should be focused to decrease the burden of HNCs.
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Kong, Lingyi, and Andrew C. Birkeland. "Liquid Biopsies in Head and Neck Cancer: Current State and Future Challenges." Cancers 13, no. 8 (April 14, 2021): 1874. http://dx.doi.org/10.3390/cancers13081874.
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Head and neck cancers are the seventh most frequent malignancy worldwide, consisting of a heterogeneous group of cancers that develop in the oral cavity, pharynx, and larynx, with head and neck squamous cell carcinoma (HNSCC) being the most common pathology. Due to limitations with screening and physical examination, HNSCC often presents in advanced disease states and is thus associated with poor survival. In this setting, liquid biopsies, or obtaining patient bodily fluid samples for cancer diagnosis and prognosis, may play a dramatic role in optimizing care for HNSCC patients. In recent years, there have been dramatic advancements in investigations focused on optimizing and implementing liquid biopsies in general, and specifically for HNSCC patients. Moving forward, there remain significant challenges in liquid biopsy technological development, as well as opportunities for the development of HNSCC liquid biopsy clinical trials and treatment paradigms. In this review, we discuss the current state of liquid biopsy technologies via circulating tumor cells, circulating tumor DNA and exosomes, approaches in head and neck cancer, challenges to optimization and application of liquid biopsies for clinical study, and future prospects for this field of research as it applies to head and neck cancer.
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Liu, Xiqiang, Zugen Chen, Jinsheng Yu, James Xia, and Xiaofeng Zhou. "MicroRNA Profiling and Head and Neck Cancer." Comparative and Functional Genomics 2009 (2009): 1–11. http://dx.doi.org/10.1155/2009/837514.
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Head and neck/oral cancer (HNOC) is a devastating disease. Despite advances in diagnosis and treatment, mortality rates have not improved significantly over the past three decades. Improvement in patient survival requires a better understanding of the disease progression so that HNOC can be detected early in the disease process and targeted therapeutic interventions can be deployed. Accumulating evidence suggests that microRNAs play important roles in many human cancers. They are pivotal regulators of diverse cellular processes including proliferation, differentiation, apoptosis, survival, motility, and morphogenesis. MicroRNA expression patterns may become powerful biomarkers for diagnosis and prognosis of HNOC. In addition, microRNA therapy could be a novel strategy for HNOC prevention and therapeutics. Recent advances in microRNA expression profiling have led to a better understanding of the cancer pathogenesis. In this review, we will survey recent technological advances in microRNA profiling and their applications in defining microRNA markers/targets for cancer prediction, diagnostics, treatment, and prognostics. MicroRNA alterations that consistently identified in HNOC will be discussed, such as upregulation of miR-21, miR-31, miR-155, and downregulation of miR-26b, miR-107, miR-133b, miR-138, and miR-139.
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Bejenaru, Paula Luiza, Bogdan Popescu, Alina Lavinia Antoaneta Oancea, Catrinel Beatrice Simion-Antonie, Gloria Simona Berteșteanu, Mihnea Condeescu-Cojocarița, Anca Ionela Cîrstea, et al. "Quality-of-Life Assessment after Head and Neck Oncological Surgery for Advanced-Stage Tumours." Journal of Clinical Medicine 11, no. 16 (August 19, 2022): 4875. http://dx.doi.org/10.3390/jcm11164875.
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Squamous cell carcinoma of the head and neck (HNSCC) is a common malignancy often diagnosed in the advanced stage with a complex negative influence on the patient’s quality of life (QoL). Given its multi-modal treatment, the first step is to adequately balance the needs of the patient, and the second step includes the consultations, interventions, and care provided by the medical team, with the purpose of improving the overall management of the HNSCC. Current attempts to develop and validate quality-of-life instruments specific to cancers of the head and neck have been reported, and certain questionnaires are now available. We performed a retrospective study in a tertiary centre, involving 89 patients who survived 3 years after HNSCC surgery. A patient-related outcome measurement was made using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-H&N35 instruments to assess QoL at admission and 3 years after treatment. The 3-year survivors reported an overall improvement in QoL compared with those in the pre-treatment period. The unique details of head and neck cancer treatments outline the importance of considering the characteristics of the patient population in quality-of-life research and also identify how quality-of-life data can contribute to the care provided by the multi-disciplinary team involved in a patient’s follow-up.
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Meliante, Piero Giuseppe, Carla Petrella, Marco Fiore, Antonio Minni, and Christian Barbato. "Antioxidant Use after Diagnosis of Head and Neck Squamous Cell Carcinoma (HNSCC): A Systematic Review of Application during Radiotherapy and in Second Primary Cancer Prevention." Antioxidants 12, no. 9 (September 12, 2023): 1753. http://dx.doi.org/10.3390/antiox12091753.
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Approximately 5–20% of HNSCC patients experience second primary cancers within the first 5 years of treatment, contributing to high mortality rates. Epidemiological evidence has linked a low dietary intake of antioxidants to an increased risk of cancer, especially squamous cell carcinoma, prompting research into their potential in neoplasm chemoprevention. Cigarette smoking is the primary risk factor for HNSCC, and a diet rich in antioxidants offers protective effects against head and neck cancer. Paradoxically, smokers, who are at the highest risk, tend to consume fewer antioxidant-rich fruits and vegetables. This has led to the hypothesis that integrating antioxidants into the diet could play a role in both primary and secondary prevention for at-risk individuals. Furthermore, some HNSCC patients use antioxidant supplements during chemotherapy or radiotherapy to manage side effects, but their impact on cancer outcomes remains uncertain. This systematic review explores the evidence for the potential use of antioxidants in preventing second primary cancers in HNSCC patients. In conclusion, none of the antioxidants tested so far (α-tocopherol, β-carotene, JP, Isotretinoin, interferon α-2a, vitamin E, retinyl palmitate, N-acetylcysteine) was effective in preventing second primary tumors in HNSCC patients, and they could only be used in reducing the side effects of radiotherapy. Further research is needed to better understand the interplay between antioxidants and cancer outcomes in this context.
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Rühle, Alexander, Anca-Ligia Grosu, and Nils H. Nicolay. "De-Escalation Strategies of (Chemo)Radiation for Head-and-Neck Squamous Cell Cancers—HPV and Beyond." Cancers 13, no. 9 (May 4, 2021): 2204. http://dx.doi.org/10.3390/cancers13092204.
Full textAbstract:
Oncological outcomes for head-and-neck squamous cell carcinoma (HNSCC) patients are still unsatisfactory, especially for advanced tumor stages. Besides the moderate survival rates, the prevalence of severe treatment-induced normal tissue toxicities is high after multimodal cancer treatments, both causing significant morbidity and decreasing quality of life of surviving patients. Therefore, risk-adapted and individualized treatment approaches are urgently needed for HNSCC patients to optimize the therapeutic gain. It has been a well-known fact that especially HPV-positive oropharyngeal squamous cell carcinoma (OSCC) patients exhibit an excellent prognosis and may therefore be subject to overtreatment, resulting in long-term treatment-related toxicities. Regarding the superior prognosis of HPV-positive OSCC patients, treatment de-escalation strategies are currently investigated in several clinical trials, and HPV-positive OSCC may potentially serve as a model for treatment de-escalation also for other types of HNSCC. We performed a literature search for both published and ongoing clinical trials and critically discussed the presented concepts and results. Radiotherapy dose or volume reduction, omission or modification of concomitant chemotherapy, and usage of induction chemotherapy are common treatment de-escalation strategies that are pursued in clinical trials for biologically selected subgroups of HNSCC patients. While promising data have been reported from various Phase II trials, evidence from Phase III de-escalation trials is either lacking or has failed to demonstrate comparable outcomes for de-escalated treatments. Therefore, further data and a refinement of biological HNSCC stratification are required before deescalated radiation treatments can be recommended outside of clinical trials.
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Kuo, Selena Z., Christine O. Honda, Wei Tse Li, Thomas K. Honda, Elizabeth Kim, Xabier Altuna, Eric Abhold, Jessica Wang-Rodriguez, and Weg M. Ongkeko. "Metformin Results in Diametrically Opposed Effects by Targeting Non-Stem Cancer Cells but Protecting Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma." International Journal of Molecular Sciences 20, no. 1 (January 7, 2019): 193. http://dx.doi.org/10.3390/ijms20010193.
Full textAbstract:
Cancer stem cells (CSCs) have been shown as a distinct population of cancer cells strongly implicated with resistance to conventional chemotherapy. Metformin, the most widely prescribed drug for diabetes, was reported to target cancer stem cells in various cancers. In this study, we sought to determine the effects of metformin on head and neck squamous cell carcinoma (HNSCC). CSCs and non-stem HNSCC cells were treated with metformin and cisplatin alone, and in combination, and cell proliferation levels were measured through MTS assays. Next, potential targets of metformin were explored through computational small molecule binding analysis. In contrast to the reported effects of metformin on CSCs in other cancers, our data suggests that metformin protects HNSCC CSCs against cisplatin in vitro. Treatment with metformin resulted in a dose-dependent induction of the stem cell genes CD44, BMI-1, OCT-4, and NANOG. On the other hand, we observed that metformin successfully decreased the proliferation of non-stem HNSCC cells. Computational drug–protein interaction analysis revealed mitochondrial complex III to be a likely target of metformin. Based on our results, we present the novel hypothesis that metformin targets complex III to reduce reactive oxygen species (ROS) levels, leading to the differential effects observed on non-stem cancer cells and CSCs.
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Allevato, Michael, Yumi Yokoyama, Robert Wild, and J. Silvio Gutkind. "Abstract 3027: Elucidating the role of glutamine metabolism in head & neck squamous cell carcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3027. http://dx.doi.org/10.1158/1538-7445.am2022-3027.
Full textAbstract:
Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 14,600 deaths each year in the United States alone. HNSCC is associated with human papillomavirus (HPV) infection, tobacco use, and abusive alcohol intake. Without truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. Unfortunately, these treatments are associated with significant morbidity and a reduction in quality of life. Immunotherapies have recently revolutionized HNSCC treatment, but <20% of patients exhibit clinical responses, albeit often not durable (Saddawi-Konefka et al. Frontiers in Oncology 2021). This highlights the unmet need to identify novel therapeutic options and biomarkers predicting a more favorable response to maximize the efficacy of targeted cancer strategies for HNSCC treatment. Glutamine is a conditionally essential amino acid for rapidly proliferating cancer cells making glutamine pathway inhibition an attractive approach for anti-cancer therapy. We found that treatment with the broad glutamine antagonist sirpiglenastat (DRP-104), which irreversibly inhibits all known enzymes involved in glutamine metabolism, results in metabolically halted cell growth in a large panel (n=8) of HPV- and HPV+ HNSCC cell lines (IC50 of 0.2-25uM). Interestingly, HNSCC cells bearing genetic alterations in PIK3CA and PTEN were significantly more sensitive to glutamine antagonism than unaltered HNSCC cells. The dependence of glutamine in HNSCC growth and the increased sensitivity of PIK3CA/PTEN aberrant cells was also observed in orosphere assays and HNSCC tumor xenografts in mice in vivo. We next explored the mechanism of glutamine suppression in HNSCC by integrating the results from genome-wide CRISPR-Cas9 knockout library screens and broad-spectrum metabolomics analysis. Both approaches converged on the identification of a dysregulated metabolic pathway that represents a synthetic lethal vulnerability that can be exploited via targeted therapies. Our data suggest that broad glutamine antagonism using sirpiglenastat (DRP-104) has therapeutic potential in HNSCC by dismantling cancer metabolism and sensitizing cells to additional perturbations leading to specific cell death. A clinical trial of sirpiglenastat (DRP-104) is currently ongoing (NCT04471415). Citation Format: Michael Allevato, Yumi Yokoyama, Robert Wild, J. Silvio Gutkind. Elucidating the role of glutamine metabolism in head & neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3027.