Clinical Trial Development in <i>TP53-</i>Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

Rodriguez, Cristina P.; Kang, Hyunseok; Geiger, J.L.; Burtness, Barbara; Chung, Christine H.; Pickering, Curtis R.; Fakhry, Carole; Le, Quynh Thu; Yom, Sue S.; Galloway, Thomas J.; Golemis, Erica A.; Li, Alice; Wong, Stuart J.; Mehra, Ranee; Skinner, Heath D.; Saba, Nabil F.; Flores, Elsa R.; Myers, Jeffrey N.; Ford, James M.; Karchin, Rachel; Ferris, Robert L.; Kunos, Charles; Lynn, Jean; Malik, Shakun

doi:10.1093/jnci/djac163

Cited by 2 publications

(1 citation statement)

References 46 publications

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“…Head and neck squamous cell carcinoma (HNSC) is a common malignant solid tumor that lacks effective treatment options, especially targeted therapies (Mody et al, 2021; Noronha et al, 2022). Although cumulative studies have revealed that human papillomavirus (HPV) infection, mammalian target of rapamycin signaling dysregulation, epidermal growth factor receptor amplification, and TP53 mutation are risk factors for HNSC and participate in tumor development, clinical trials based on these pan‐cancer oncogenic factors have not been very satisfactory (Nathan et al, 2022; Rodriguez et al, 2022; Schinke et al, 2022). Developing efficient therapeutic strategies for HNSC patients based on the concept of precision medicine remains a great challenge (Gu et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Homeobox‐D 1 and FTO form a transcriptional–epigenetic feedback loop to promote head and neck cancer proliferation

Zhang,

Xie,

Lin

2023

Cell Biology International

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Transcription factors (TFs) and N6‐methyladenosine (m6A) modifiers are involved in tumor progression through transcriptional regulation and posttranscriptional regulation of genes, respectively. However, the crosstalk and role of these two types of gene expression regulators in head and neck squamous cell carcinoma (HNSC) remains poorly understood. In this study, we demonstrate that the TF homeobox‐D1 (HOXD1) and the m6A demethylase fat mass and obesity‐associated protein (FTO) form a positive feedback loop to promote cell proliferation and survival in HNSC. Clinically, HOXD1 expression is dysregulated in multiple cancer types and is associated with worse prognosis in patients with HNSC, stomach adenocarcinoma, uterine corpus endometrial carcinoma, and pheochromocytoma and paraganglioma. Mechanistically, FTO is overexpressed in HNSC tumor samples and positively regulates HOXD1 expression in an m6A‐dependent manner. Functionally, deficiency of HOXD1 relieved the resistance of HNSC cells to apoptosis and arrested tumor cells at the G0/G1 phase, thereby inhibiting cell growth, whereas overexpression of HOXD1 caused the opposite effect. Furthermore, HOXD1 activates the transcription of the oncogenic factor FTO by directly targeting its promoter. Downregulation of FTO mimicked the biological effect of HOXD1 knockdown on HNSC. Importantly, overexpression of HOXD1 significantly rescued the proliferation inhibition and apoptosis promotion of HNSC cells induced by deficiency of FTO. Together, our findings reveal HOXD1 as a novel prognostic predictor and a potential target for HNSC, providing mechanistic insights into the role of the HOXD1–FTO circuit in this cancer.

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Section: Introductionmentioning

confidence: 99%

Homeobox‐D 1 and FTO form a transcriptional–epigenetic feedback loop to promote head and neck cancer proliferation

Zhang,

Xie,

Lin

2023

Cell Biology International

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Immune related gene signature derived from integrate machine learning algorithm predicts outcomes of HNSC patients

Xiao

Liu

Shen

et al. 2023

Preprint

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Background: Due to the highly heterogeneous of tumor, head and neck squamous cancer (HNSC) patients are in variable immunotherapeutic response and have different clinical outcomes. We since develop the immune related gene signature (IRGS) using a machine learning based integrative procedure for distinguishing the immune microenvironment subtype of diverse HNSC patients and then help improve the outcomes of HNSC. Methods: This study integrate 10 machine learning algorithms to 111 combination for screening out the best immune related gene signature (IRGS) based on 4 multicenter cohorts. Survival analysis, multivariate Cox regression analysis, and decision curve analysis (DCA) were employed to assess the performance of IRGS. Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomesenrichment (KEGG) analyses were conducted to evaluate the potential biological functions and mechanisms of IRGS. Results: Through the integrated machine learning algorithms, we constructed a 17-IRG signature, which demonstrated to be an excellent prognostic model in all cohorts and displayed better efficiency when compared with other 68 published prognostic signatures. IRGS exhibits a strong negative correlation with immune characteristics. The IRGS low group demonstrates increased immune infiltration and heightened sensitivity to immunotherapy, whereas the IRGS high group exhibits a higher frequency of deletion mutations in tumor suppressor genes. Besides, considering IRGS high patients insensitive to immunotherapy and their poor prognosis, we scheduled an agents screening strategy and selected dasatinib as the most potential target drug for IRGS high patients. Conclusions: IRGS was demonstrated excellent prognostic efficiency and offer a more precise selection for assessing pre-immune efficacy, which will help improve clinical outcomes for individual HNSC patients.

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Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

Cited by 2 publications

References 46 publications

Homeobox‐D 1 and FTO form a transcriptional–epigenetic feedback loop to promote head and neck cancer proliferation

Homeobox‐D 1 and FTO form a transcriptional–epigenetic feedback loop to promote head and neck cancer proliferation

Immune related gene signature derived from integrate machine learning algorithm predicts outcomes of HNSC patients

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