The Effects of ML385 on Head and Neck Squamous Cell Carcinoma: Implications for NRF2 Inhibition as a Therapeutic Strategy
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ABSTRACT:
SUBMITTER: Jeong E
PROVIDER: S-EPMC11241175 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:The literature contains numerous references describing heterogeneity for tumor phenotypes including cell proliferation, invasiveness, metastatic potential, and response to therapies. However, data regarding angiogenic heterogeneity are limited. In this study, we investigated the degree of intertumoral angiogenic heterogeneity present in head and neck squamous cell carcinomas (HNSCC). In addition, we investigated the biological relevance that this heterogeneity may have in the context of cytokine directed antiangiogenic therapy. Keratinocytes were harvested from HNSCC specimens using laser capture microdissection (LCM). Gene expression profiling of the RNA extracted from these specimens demonstrated variability in the expression of angiogenesis-related genes. Hierarchical clustering and principal component analyses (PCA) demonstrated the presence of unique patient clusters, suggesting that there may be two potentially distinct pathways by which HNSCC induce angiogenesis. Immunohistochemistry for VEGF, IL-8/CXCL8, HGF, and FGF-2, cytokines that play functional roles in HNSCC angiogenesis was performed on the original patient samples as well as a larger panel of normal, dysplastic and HNSCC specimens to validate the heterogeneous expression observed in the gene expression profiling studies. Finally, the therapeutic response of HNSCC tumor xenografts to anti-VEGF therapy was found to be dependent on the amount of VEGF produced by the tumor cells. These findings support the hypothesis of intertumoral angiogenic heterogeneity. They imply that there are differences with regard to the specific molecular mechanisms by which individual tumors within the same histological type induce angiogenesis. Moreover, they demonstrate the need for a more in-depth understanding of the variability of the angiogenic phenotype within a given type of neoplasm when designing cytokine targeted antiangiogenic therapies. Finally, they suggest that studies in conjunction with the ongoing clinical trials that explore the correlation between target expression and clinical outcome are warranted.
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Project description:Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentially increase autophagy in HNSCC and indirectly support cancer cell survival. Here, we sought to understand the relationship between the PI3K signaling pathway and autophagy during their dual inhibition in a panel of HNSCC cell lines. We used acridine orange staining, immunoblotting, and tandem sensor Red Fluorescent Protein- Green Fluorescent Protein-, microtubule-associated protein 1 light chain 3 beta (RFP-GFP-LC3B) expression analysis to show that PI3K inhibitors increase autophagosomes in HNSCC cells, but that chloroquine treatment effectively inhibits the autophagy that is induced by PI3K inhibitors. Using the Bliss independence model, we determined that the combination of chloroquine with PI3K inhibitors works in synergy to decrease cancer cell proliferation, independent of the PIK3CA status of the cell line. Our results indicate that a strategy focusing on autophagy inhibition enhances the efficacy of therapeutics already in clinical trials. Our results suggest a broader application for this combination therapy that can be promptly translated to in vivo studies.
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Project description:Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.
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Project description:Cells experience both endogenous and exogenous DNA damage daily. To maintain genome integrity and suppress tumorigenesis, individuals have evolutionarily acquired a series of repair functions, termed DNA damage response (DDR), to repair DNA damage and ensure the accurate transmission of genetic information. Defects in DNA damage repair pathways may lead to various diseases, including tumors. Accumulating evidence suggests that alterations in DDR-related genes, such as somatic or germline mutations, single nucleotide polymorphisms (SNPs), and promoter methylation, are closely related to the occurrence, development, and treatment of head and neck squamous cell carcinoma (HNSCC). Despite recent advances in surgery combined with radiotherapy, chemotherapy, or immunotherapy, there has been no substantial improvement in the survival rate of patients with HNSCC. Therefore, targeting DNA repair pathways may be a promising treatment for HNSCC. In this review, we summarized the sources of DNA damage and DNA damage repair pathways. Further, the role of DNA damage repair pathways in the development of HNSCC and the application of small molecule inhibitors targeting these pathways in the treatment of HNSCC were focused.
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Project description:Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignancies which have shown exponential incidence in the last two decades especially due to human papillomavirus (HPV) infection. The HPV family comprises more than 100 types of viruses with HPV16 and HPV18 being the most prevalent strains in HNSCC. Literature data reveal that the mutation profile as well as the response to chemotherapy and radiotherapy are distinct among HPV+ versus HPV-negative tumors. Furthermore, the presence of the virus induces activation of an immune response, in particular the recruitment of specific antiviral T lymphocytes to tumor sites. These T cells when activated produce soluble factors including cytokines and chemokines capable of modifying the local immune tumor microenvironment and impact on tumor response to the treatment. In this comprehensive review we investigated current knowledge on how the presence of an HPV can modify the inflammatory response systemically and within the tumor microenvironment's immunological responses, thereby impacting on disease prognosis and survival. We highlighted the research gaps and emerging approaches necessary to discover novel immunotherapeutic targets for HPV-associated HNSCC.
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Project description:The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Results: Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regulated genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Conclusions: Our findings reveal that BRD4 serves as a novel and critical mediator underlying tumorigenesis and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.
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Project description:The histone methyltransferase EZH2 silences gene expression via H3 lysine 27 trimethylation and has been recognized as an important antitumour therapeutic target. However, the clinical application of existing EZH2 inhibitors is not satisfactory for the treatment of solid tumours. To discover novel strategies against head and neck squamous cell carcinoma (HNSCC), we performed genomics, metabolomics and RNA omics studies in HNSCC cells treated with EZH2 inhibitors. It was found that EZH2 inhibitors strongly induced the expression of genes in cholesterol synthesis. Through extensive drug screening we found that inhibition of squalene epoxidase (a key enzyme of endogenous cholesterol synthesis) synergistically increased the squalene content and enhanced the sensitivity of HNSCC cells to EZH2 inhibitors. Our findings provide an experimental and theoretical basis for the development of new combinations of EZH2 inhibitors to treat HNSCC.
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Project description:Quantitative (iTRAQ 4-plex) proteomic analysis of progressive head and neck cancers
2022-03-01 | PXD001438 | Pride
Project description:Therapeutic vaccination is one of the most effective immunotherapeutic approaches, second only to immune checkpoint inhibitors (ICIs), which have already been approved for clinical use. Head and neck squamous cell carcinomas (HNSCCs) are heterogenous epithelial tumors of the upper aerodigestive tract, and a significant proportion of these tumors tend to exhibit unfavorable therapeutic responses to the existing treatment options. Comprehending the immunopathology of these tumors and choosing an appropriate immunotherapeutic maneuver seems to be a promising avenue for solving this problem. The current review provides a detailed overview of the strategies, targets, and candidates for therapeutic vaccination in HNSCC. The classical principle of inducing a potent, antigen-specific, cell-mediated cytotoxicity targeting a specific tumor antigen seems to be the most effective mechanism of therapeutic vaccination, particularly against the human papilloma virus positive subset of HNSCC. However, approaches such as countering the immunosuppressive tumor microenvironment of HNSCC and immune co-stimulatory mechanisms have also been explored recently, with encouraging results.
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Project description:PurposeHead and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including NOTCH1, but lacks a biomarker-driven targeted therapy. Although the PI3K/mTOR pathway is frequently altered in HNSCC, the disease has modest clinical response rates to PI3K/mTOR inhibitors and lacks validated biomarkers of response. We tested the hypothesis that an unbiased pharmacogenomics approach to PI3K/mTOR pathway inhibitors would identify novel, clinically relevant molecular vulnerabilities in HNSCC with loss of tumor suppressor function.Experimental Design: We assessed the degree to which responses to PI3K/mTOR inhibitors are associated with gene mutations in 59 HNSCC cell lines. Apoptosis in drug-sensitive cell lines was confirmed in vitro and in vivo. NOTCH1 pathway components and PDK1 were manipulated with drugs, gene editing, knockdown, and overexpression.ResultsPI3K/mTOR inhibition caused apoptosis and decreased colony numbers in HNSCC cell lines harboring NOTCH1 loss-of-function mutations (NOTCH1 MUT) and reduced tumor size in subcutaneous and orthotopic xenograft models. In all cell lines, NOTCH1 MUT was strongly associated with sensitivity to six PI3K/mTOR inhibitors. NOTCH1 inhibition or knockout increased NOTCH1 WT HNSCC sensitivity to PI3K/mTOR inhibition. PDK1 levels dropped following PI3K/mTOR inhibition in NOTCH1 MUT but not NOTCH1 WT HNSCC, and PDK1 overexpression rescued apoptosis in NOTCH1 MUT cells. PDK1 and AKT inhibitors together caused apoptosis in NOTCH1 WT HNSCC but had little effect as single agents.ConclusionsOur findings suggest that NOTCH1 MUT predicts response to PI3K/mTOR inhibitors, which may lead to the first biomarker-driven targeted therapy for HNSCC, and that targeting PDK1 sensitizes NOTCH1 WT HNSCC to PI3K/mTOR pathway inhibitors.
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