Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

Hedberg, ML; Goh, Gyuhyeong; Chiosea, Simion I.; Bauman, JE; Freilino, ML; Zeng, Yanwu; Wang, L; Diergaarde, Brenda; Gooding, WE; Lui, Vwy; Herbst, R.; Rp, Lifton; Grandis,

doi:10.1172/jci86862

Cited by 99 publications

(108 citation statements)

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“…For example, SRC has recently shown a possibility for promoting recurrence and metastasis in HNSCC. 39 In conclusion, our present study is the first one to show that SFKs inhibition is effective as an adjuvant to conventional therapy by modulating the micro and macroenvironments of HNSCC by reducing MDSCs.…”

Section: Discussionmentioning

confidence: 60%

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Inhibition of SRC family kinases reduces myeloid‐derived suppressor cells in head and neck cancer

Mao

Deng

et al. 2016

Intl Journal of Cancer

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SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was overexpressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid-derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI 1 SRT 1 )was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy.

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Section: Discussionmentioning

confidence: 60%

“…[39][40][41] However, the exact role of SFKs expression with immune suppressive function remains unclear. In the present study, we confirmed for the first time that SFKs inhibition by dasatinib indeed decreased tumor size and reduced MDSCs in peripheral immune organs and the tumor microenvironment of the immunocompetent HNSCC mouse model.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of SRC family kinases reduces myeloid‐derived suppressor cells in head and neck cancer

Mao

Deng

et al. 2016

Intl Journal of Cancer

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“…Despite previous exposure to ionizing radiation and DNA-damaging cytotoxic chemotherapy, the global load of genomic alterations was high but similar between treatmentnaive tumors and recurrences, in line with the mutational burden described in whole-exome analysis of ASCC 17 and in other types of carcinoma. 18,19 Surprisingly, several individual genomic alterations were observed more frequently in the group of treatment-naive tumors.…”

Section: Discussionmentioning

confidence: 99%

Array comparative genomic hybridization identifies high level of PI3K/Akt/mTOR pathway alterations in anal cancer recurrences

et al. 2018

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Genomic alterations of anal squamous cell carcinoma (ASCC) remain poorly understood due to the rarity of this tumor. Array comparative genomic hybridization and targeted gene sequencing were performed in 49 cases of ASCC. The most frequently altered regions (with a frequency greater than 25%) were 10 deleted regions (2q35, 2q36.3, 3p21.2, 4p16.3, 4p31.21, 7q36.1, 8p23.3, 10q23.2, 11q22.3, and 13q14.11) and 8 gained regions (1p36.33, 1q21.1, 3q26.32, 5p15.33, 8q24.3, 9q34.3, 16p13.3, and 19p13.3). The most frequent minimal regions of deletion (55%) encompassed the 11q22.3 region containing ATM, while the most frequent minimal regions of gain (57%) encompassed the 3q26.32 region containing PIK3CA. Recurrent homozygous deletions were observed for 5 loci (ie, TGFR2 in 4 cases), and recurrent focal amplifications were observed for 8 loci (ie, DDR2 and CCND1 in 3 cases, respectively). Several of the focal amplified genes are targets for specific therapies. Integrated analysis showed that the PI3K/Akt/mTOR signaling pathway was the pathway most extensively affected, particularly in recurrences compared to treatment‐naive tumors (64% vs 30%; P = .017). In patients with ASCC recurrences, poor overall survival (OS) was significantly correlated with a large number of altered regions (P = .024). These findings provide insight into the somatic genomic alterations in ASCC and highlight the key role of the druggable PI3K/Akt/mTOR signaling pathway.

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“…Next-generation sequencing has yielded insights into the genetic heterogeneity of HNSCC tumor cells in the malignant field, 26,27 tumor cells evolve over time, location (tumor microenvironment), random genetic drifting, and genetic drifting in response to chemotherapy. This constant transformation of the genetic landscape enables those cells harboring unique mutational events to drive carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma

Will¹,

Purcz²,

Chalaris³

et al. 2016

IJN

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Despite aggressive treatment with radiation and combination chemotherapy following tumor resection, the 5-year survival rate for patients with head and neck cancer is at best only 50%. In this study, we examined the therapeutic potential of localized release of diclofenac from electrospun nanofibers generated from poly(D,L-lactide-co-glycolide) polymer. Diclofenac was chosen since anti-inflammatory agents that inhibit cyclooxygenase have shown great potential in their ability to directly inhibit tumor growth as well as suppress inflammation-mediated tumor growth. A mouse resection model of oral carcinoma was developed by establishing tumor growth in the oral cavity by ultrasound-guided injection of 1 million SCC-9 cells in the floor of the mouth. Following resection, mice were allocated into four groups with the following treatment: 1) no treatment, 2) implanted scaffolds without diclofenac, 3) implanted scaffolds loaded with diclofenac, and 4) diclofenac given orally. Small animal ultrasound and magnetic resonance imaging were utilized for longitudinal determination of tumor recurrence. At the end of 7 weeks following tumor resection, 33% of mice with diclofenac-loaded scaffolds had a recurrent tumor, in comparison to 90%–100% of the mice in the other three groups. At this time point, mice with diclofenac-releasing scaffolds showed 89% survival rate, while the other groups showed survival rates of 10%–25%. Immunohistochemical staining of recurrent tumors revealed a near 10-fold decrease in the proliferation marker Ki-67 in the tumors derived from mice with diclofenac-releasing scaffolds. In summary, the local application of diclofenac in an orthotopic mouse tumor resection model of oral cancer reduced tumor recurrence with significant improvement in survival over a 7-week study period following tumor resection. Local drug release of anti-inflammatory agents should be investigated as a therapeutic option in the prevention of tumor recurrence in oral squamous carcinoma.

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Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

Cited by 99 publications

References 0 publications

Inhibition of SRC family kinases reduces myeloid‐derived suppressor cells in head and neck cancer

Inhibition of SRC family kinases reduces myeloid‐derived suppressor cells in head and neck cancer

Array comparative genomic hybridization identifies high level of PI3K/Akt/mTOR pathway alterations in anal cancer recurrences

Increased survival rate by local release of diclofenac in a murine model of recurrent oral carcinoma

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