RESUMO
Aim: Acquired resistance to the targeted agent cetuximab poses a significant challenge in finding effective anti-cancer treatments for head and neck squamous cell carcinoma (HNSCC). To accurately study novel combination treatments, suitable preclinical mouse models for cetuximab resistance are key yet currently limited. This study aimed to optimize an acquired cetuximab-resistant mouse model, with preservation of the innate immunity, ensuring intact antibody-dependent cellular cytotoxicity (ADCC) functionality. Methods: Cetuximab-sensitive and acquired-resistant HNSCC cell lines, generated in vitro, were subcutaneously engrafted in Rag2 knock-out (KO), BALB/c Nude and CB17 Scid mice with/without Matrigel or Geltrex. Once tumor growth was established, mice were intraperitoneally injected twice a week with cetuximab for a maximum of 3 weeks. In addition, immunohistochemistry was used to evaluate the tumor and its microenvironment. Results: Despite several adjustments in cell number, cell lines and the addition of Matrigel, Rag2 KO and BALB/C Nude mice proved to be unsuitable for xenografting our HNSCC cell lines. Durable tumor growth of resistant SC263-R cells could be induced in CB17 Scid mice. However, these cells had lost their resistance phenotype in vivo. Immunohistochemistry revealed a high infiltration of macrophages in cetuximab-treated SC263-R tumors. FaDu-S and FaDu-R cells successfully engrafted into CB17 Scid mice and maintained their sensitivity/resistance to cetuximab. Conclusion: We have established in vivo HNSCC mouse models with intact ADCC functionality for cetuximab resistance and sensitivity using the FaDu-R and FaDu-S cell lines, respectively. These models serve as valuable tools for investigating cetuximab resistance mechanisms and exploring novel drug combination strategies.
RESUMO
Resistance to EGFR-targeted therapy is a major obstacle on the road to effective treatment options for head and neck cancers. During the search for underlying mechanisms and regulators of this resistance, there were several indications that EGFR-targeted therapy resistance is (partially) mediated by aberrant signaling of the PI3K/Akt pathway. Genomic alterations in and/or overexpression of major components of the PI3K/Akt pathway are common in HNSCC tumors. Therefore, downstream effectors of the PI3K/Akt pathway serve as promising targets in the search for novel therapeutic strategies overcoming resistance to EGFR inhibitors. As both the EGFR/Ras/Raf/MAPK and the PI3K/Akt pathway are involved in autophagy, combinations of EGFR and PI3K/Akt pathway inhibitors can induce an autophagic response in tumor cells. This activation of autophagy can be seen as a "double-edge sword", depending on the cellular context. Autophagy is largely known as a cytoprotective mechanism, but it can also be a mechanism of programmed (autophagic) cell death. The activation of autophagy during anti-cancer treatment is, therefore, not necessarily a bad sign. However, in HNSCC, the role of therapy-induced autophagy as an anti-tumor mechanism is still largely unclear. Further research is warranted to understand the potential of combination treatments targeting both the EGFR and PI3K/Akt pathway.
RESUMO
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that retain their poor prognosis despite recent advances in their standard of care. As the involvement of the immune system against HNSCC development is well-recognized, characterization of the immune signature and the complex interplay between HNSCC and the immune system could lead to the identification of novel therapeutic targets that are required now more than ever. In this study, we investigated RNA sequencing data of 530 HNSCC patients from The Cancer Genome Atlas (TCGA) for which the immune composition (CIBERSORT) was defined by the relative fractions of 10 immune-cell types and expression data of 45 immune checkpoint ligands were quantified. This initial investigation was followed by immunohistochemical (IHC) staining for a curated selection of immune cell types and checkpoint ligands markers in tissue samples of 50 advanced stage HNSCC patients. The outcome of both analyses was correlated with clinicopathological parameters and patient overall survival. Our results indicated that HNSCC tumors are in close contact with both cytotoxic and immunosuppressive immune cells. TCGA data showed prognostic relevance of dendritic cells, M2 macrophages and neutrophils, while IHC analysis associated T cells and natural killer cells with better/worse prognostic outcome. HNSCC tumors in our TCGA cohort showed differential RNA over- and underexpression of 28 immune inhibitory and activating checkpoint ligands compared to healthy tissue. Of these, CD73, CD276 and CD155 gene expression were negative prognostic factors, while CD40L, CEACAM1 and Gal-9 expression were associated with significantly better outcomes. Our IHC analyses confirmed the relevance of CD155 and CD276 protein expression, and in addition PD-L1 expression, as independent negative prognostic factors, while HLA-E overexpression was associated with better outcomes. Lastly, the co-presence of both (i) CD155 positive cells with intratumoral NK cells; and (ii) PD-L1 expression with regulatory T cell infiltration may hold prognostic value for these cohorts. Based on our data, we propose that CD155 and CD276 are promising novel targets for HNSCC, possibly in combination with the current standard of care or novel immunotherapies to come.
Assuntos
Antígeno B7-H1 , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Antígeno B7-H1/metabolismo , Prognóstico , Neoplasias de Cabeça e Pescoço/genética , Ligante de CD40 , Ligantes , RNA , Antígenos B7RESUMO
Resistance to therapies targeting the epidermal growth factor receptor (EGFR), such as cetuximab, remains a major roadblock in the search for effective therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). Due to its close interaction with the EGFR pathway, redundant or compensatory activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been proposed as a major driver of resistance to EGFR inhibitors. Understanding the role of each of the main proteins involved in this pathway is utterly important to develop rational combination strategies able to circumvent resistance. Therefore, the current work reviewed the role of PI3K/Akt pathway proteins, including Ras, PI3K, tumor suppressor phosphatase and tensing homolog, Akt and mammalian target of rapamycin in resistance to anti-EGFR treatment in HNSCC. In addition, we summarize PI3K/Akt pathway inhibitors that are currently under (pre)clinical investigation with focus on overcoming resistance to EGFR inhibitors. In conclusion, genomic alterations in and/or overexpression of one or more of these proteins are common in both human papillomavirus (HPV)-positive and HPV-negative HNSCC tumors. Therefore, downstream effectors of the PI3K/Akt pathway serve as promising drug targets in the search for novel therapeutic strategies that are able to overcome resistance to anti-EGFR treatment. Co-targeting EGFR and the PI3K/Akt pathway can lead to synergistic drug interactions, possibly restoring sensitivity to EGFR inhibitors and hereby improving clinical efficacy. Better understanding of the predictive value of PI3K/Akt pathway alterations is needed to allow the identification of patient populations that might benefit most from these combination strategies.
Assuntos
Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço , Fosfatidilinositol 3-Quinase , Proteínas Proto-Oncogênicas c-akt , Carcinoma de Células Escamosas de Cabeça e Pescoço , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológicoRESUMO
Cetuximab has an established role in the treatment of patients with recurrent/metastatic colorectal cancer and head and neck squamous cell cancer (HNSCC). However, the long-term effectiveness of cetuximab has been limited by the development of acquired resistance, leading to tumor relapse. By contrast, immunotherapies can elicit long-term tumor regression, but the overall response rates are much more limited. In addition to epidermal growth factor (EGFR) inhibition, cetuximab can activate natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC). In view of the above, there is an unmet need for the majority of patients that are treated with both monotherapy cetuximab and immunotherapy. Accumulated evidence from (pre-)clinical studies suggests that targeted therapies can have synergistic antitumor effects through combination with immunotherapy. However, further optimizations, aimed towards illuminating the multifaceted interplay, are required to avoid toxicity and to achieve better therapeutic effectiveness. The current review summarizes existing (pre-)clinical evidence to provide a rationale supporting the use of combined cetuximab and immunotherapy approaches in patients with different types of cancer.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/terapia , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia Adotiva , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Animais , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/efeitos adversos , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Citocinas/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacosRESUMO
The epidermal growth factor receptor (EGFR) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). Resistance to EGFR-targeted therapies, such as cetuximab, poses a challenging problem. This study aims to characterize acquired cetuximab resistance mechanisms in HNSCC cell lines by protein phosphorylation profiling. Through this, promising combination treatments can be identified to possibly overcome acquired cetuximab resistance in HNSCC. Protein phosphorylation profiling showed increased phosphorylation of Akt1/2/3 after cetuximab treatment in acquired cetuximab resistant cells compared to cetuximab sensitive cells, which was confirmed by western blotting. Based on this protein phosphorylation profile, a novel combination treatment with cetuximab and the Akt1/2/3 inhibitor MK2206 was designed. Synergy between cetuximab and MK2206 was observed in two cetuximab sensitive HNSCC cell lines and one acquired cetuximab resistant variant in simultaneous treatment schedules. In conclusion, this study demonstrates that increased Akt1/2/3 phosphorylation seems to be characteristic for acquired cetuximab resistance in HNSCC cell lines. Our results also show an additive to synergistic interaction between cetuximab and MK2206 in simultaneous treatment schedules. These data support the hypothesis that the combination of cetuximab with PI3K/Akt pathway inhibition might be a promising novel therapeutic strategy to overcome acquired cetuximab resistance in HNSCC patients.
RESUMO
BACKGROUND: The epidermal growth factor receptor (EGFR) is overexpressed by 80-90% of squamous cell carcinoma of head and neck (HNSCC). In addition to inhibiting EGFR signal transduction, cetuximab, a monoclonal antibody targeting EGFR can also bind to fragment crystallisable domain of immunoglobulins G1 present on natural killer (NK), causing antibody-dependent cellular cytotoxicity (ADCC). However, presence of cetuximab resistance limits effective clinical management of HNSCC. METHODS: In this study, differences in induction of ADCC were investigated in a panel of ten HNSCC cell lines. Tumour cells were co-cultured with NK cells and monitored using the xCELLigence RTCA. RESULTS: While ADCC was not influenced by HPV status, hypoxia and cetuximab resistance did affect ADCC differentially. Intrinsic cetuximab-resistant cell lines showed an increased ADCC induction, whereas exposure to hypoxia reduced ADCC. Baseline EGFR expression was not correlated with ADCC. In contrast, EGFR internalisation following cetuximab treatment was positively correlated with ADCC. CONCLUSION: These findings support the possibility that resistance against cetuximab can be overcome by NK cell-based immune reactions. As such, it provides an incentive to combine cetuximab with immunotherapeutic approaches, thereby possibly enhancing the anti-tumoural immune responses and achieving greater clinical effectiveness of EGFR-targeting agents.
Assuntos
Cetuximab/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Infecções por Papillomavirus/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologiaRESUMO
Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in non-small cell lung cancer (NSCLC) making it an interesting drug target. We examined the in vitro therapeutic effects of volasertib, a Plk1 inhibitor, in combination with irradiation in a panel of NSCLC cell lines with different p53 backgrounds. Pretreatment with volasertib efficiently sensitized p53 wild type cells to irradiation. Flow cytometric analysis revealed that significantly more cells were arrested in the G2/M phase of the cell cycle after the combination therapy compared to either treatment alone (p < 0.005). No significant synergistic induction of apoptotic cell death was observed, but, importantly, significantly more senescent cells were detected when cells were pretreated with volasertib before irradiation compared to both monotherapies alone (p < 0.001), especially in cells with functional p53. Consequently, while most cells with functional p53 showed permanent growth arrest, more p53 knockdown/mutant cells could re-enter the cell cycle, resulting in colony formation and cell survival. Our findings assign functional p53 as a determining factor for the observed radiosensitizing effect of volasertib in combination with radiotherapy for the treatment of NSCLC.
RESUMO
PURPOSE: Patients with recurrent and/or metastatic head and neck squamous cell cancer are offered platinum-based chemotherapy plus cetuximab; however, this strategy is not cost-effective. We evaluated the cost-effectiveness of a hypothetical predictive molecular test to identify and treat only patients potentially responsive to cetuximab (C) added to platinum-fluorouracil (PF) (PF + C POS) versus the administration of PF + C to all patients (PF + C ALL). METHODS: A Markov model has been developed to estimate health outcomes (quality-adjusted life years [QALYs]; life years [LYs]) and costs of the 2 strategies on a time horizon of 3 years from the Italian health care perspective. For the response to treatment, a definition, including partial or complete response, has been applied. In the base-case scenario, molecular test sensitivity, specificity, and cost have been assumed equal to 85%, 70%, and 4000, respectively. FINDINGS: The model estimated 0.5285 QALYs (0.9245 LYs) and 0.5666 QALYs (0.9949 LYs) for PF + C POS and PF + C ALL, respectively. The incremental cost-utility ratio of PF + C ALL versus PF + C POS was 112,462/QALY, suggesting the administration of PF + C only to patients who would be responsive to it. IMPLICATIONS: The use of cetuximab with chemotherapy could be a cost-effective choice in first-line recurrent and/or metastatic head and neck squamous cell cancer if based on a molecular selection able to identify which patients will achieve partial or complete response to the treatment. The developed model may be usefully applied to new emerging treatments, such as immunotherapeutic agents in the same setting.
Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Técnicas de Diagnóstico Molecular , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Cetuximab/economia , Cetuximab/uso terapêutico , Análise Custo-Benefício , Fluoruracila/economia , Fluoruracila/uso terapêutico , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/economia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Seleção de PacientesRESUMO
Polo-like kinase 1 (Plk1), a master regulator of mitosis and the DNA damage response, is considered to be an intriguing target in the research field of mitotic intervention. The observation that Plk1 is overexpressed in multiple human malignancies, including non-small-cell lung cancer (NSCLC), gave rise to the development of several small-molecule inhibitors. Volasertib, presently the most extensively studied Plk1 inhibitor, has been validated to efficiently reduce tumor growth in preclinical settings. Unfortunately, only modest antitumor activity against solid tumors was reported in clinical trials. This discrepancy prompted research into the identification of predictive biomarkers. In this study, we investigated the therapeutic effect of volasertib monotherapy (i.e., cytotoxicity, cell cycle distribution, apoptotic cell death, cellular senescence, and migration) in a panel of NSCLC cell lines differing in p53 status under both normal and reduced oxygen tension (<0.1% O2 ). A strong growth inhibitory effect was observed in p53 wild-type cells (A549 and A549-NTC), with IC50 values significantly lower than those in p53 knockdown/mutant cells (A549-920 and NCI-H1975) (P < 0.001). While mitotic arrest was significantly greater in cells with nonfunctional p53 (P < 0.005), apoptotic cell death (P < 0.026) and cellular senescence (P < 0.021) were predominantly induced in p53 wild-type cells. Overall, the therapeutic effect of volasertib was reduced under hypoxia (P < 0.050). Remarkably, volasertib inhibited cell migration in all cell lines tested (P < 0.040), with the exception of for the NCI-H1975 p53 mutant cell line. In conclusion, our results show an important difference in the therapeutic effect of Plk1 inhibition in NSCLC cells with versus without functional p53. Overall, the p53 wild-type cell lines were more sensitive to volasertib treatment, suggesting that p53 might be a predictive biomarker for Plk1 inhibition in NSCLC. Moreover, our results pave the way for new combination strategies with Plk1 inhibitors to enhance antitumor activity.
Assuntos
Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pteridinas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Apoptose/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/genética , Quinase 1 Polo-LikeRESUMO
BACKGROUND: Radiation-associated-dysphagia is a serious side effect of radiotherapy (RT) for head and neck cancer (HNC). METHODS: Seventy-six patients had a weekly prospective follow-up from baseline until one week post-RT. Combined mixed model analysis (n = 43) determined the evolution of self-perceived swallowing function, isometric tongue strength (MIP), tongue strength (TS) during swallowing (Pswal), and quality of life (QoL) in these patients during RT. RESULTS: Swallowing deteriorated from the third week on, resulting in an increase of tube dependency from 10% at baseline toward 31% post-RT. Both MIP and Pswal are reduced, with anterior MIP decreasing in 29% of patients and posterior MIP in 17%. Pswal decreases for saliva and a bolus swallow. All QoL subscales except "sleep" were affected during RT. CONCLUSIONS: Self-perceived swallowing function, TS and QoL decrease during RT for HNC. Current findings highlight the need for early monitoring of these parameters.
Assuntos
Transtornos de Deglutição/etiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Qualidade de Vida , Radioterapia/efeitos adversos , Língua/efeitos da radiação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Força da Mão , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escala Visual AnalógicaRESUMO
The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the clinic. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. The objective of this study was to investigate the expression of human epidermal growth factor (HER) receptors and the efficacy of afatinib, a second-generation irreversible EGFR-tyrosine kinase inhibitor, in RAS wild-type CRC cell lines with different cetuximab sensitivities. CRC cell lines with different sensitivities to cetuximab showed rather low EGFR expression but high HER2 and HER3 expression. These results were in line with the The Cancer Genome Atlas (TCGA) data from CRC patients, where higher mRNA levels of HER2 and HER3 were also detected compared to EGFR. Therefore, the targets of afatinib were indeed expressed on the CRC cell lines used in this study and in CRC patients. Furthermore, cetuximab resistance had no significant influence on the expression levels of HER receptors in CRC cell lines (p ≥ 0.652). This study also demonstrated that afatinib was able to induce a concentration-dependent cytotoxic effect in RAS wild-type CRC cell lines with different cetuximab sensitivities. Neither cetuximab resistance (p = 0.233) nor hypoxia (p = 0.157) significantly influenced afatinib's cytotoxic effect. In conclusion, our preclinical data support the hypothesis that treatment with afatinib might be a promising novel therapeutic strategy for CRC patients experiencing intrinsic and acquired cetuximab resistance.
RESUMO
The epidermal growth factor receptor (EGFR, HER1) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). After initial promising results with EGFR-targeted therapies such as cetuximab, therapeutic resistance has become a major clinical problem, and new treatment options are therefore necessary. Moreover, the relationship between HER receptors, anti-EGFR therapies, and the human papillomavirus (HPV) status in HNSCC is not fully understood. In contrast to first-generation EGFR inhibitors, afatinib irreversibly inhibits multiple HER receptors simultaneously. Therefore, treatment with afatinib might result in a more pronounced therapeutic benefit, even in patients experiencing cetuximab resistance. In this study, the cytotoxic effect of afatinib as single agent and in combination with cisplatin was investigated in cetuximab-sensitive, intrinsically cetuximab-resistant, and acquired cetuximab-resistant HNSCC cell lines with different HPV status under normoxia and hypoxia. Furthermore, the influence of cetuximab resistance, HPV, and hypoxia on the expression of HER receptors was investigated. Our results demonstrated that afatinib was able to establish cytotoxicity in cetuximab-sensitive, intrinsically cetuximab-resistant, and acquired cetuximab-resistant HNSCC cell lines, independent of the HPV status. However, cross-resistance between cetuximab and afatinib might be possible. Treatment with afatinib caused a G0 /G1 cell cycle arrest as well as induction of apoptotic cell death. Additive to antagonistic interactions between afatinib and cisplatin could be observed. Neither cetuximab resistance nor HPV status significantly influenced the expression of HER receptors in HNSCC cell lines. In contrast, the expression of EGFR, HER2, and HER3 was significantly altered under hypoxia. Oxygen deficiency is a common characteristic of HNSCC tumors, and these hypoxic tumor regions often contain cells that are more resistant to treatment. However, we observed that afatinib maintained its cytotoxic effect under hypoxia. In conclusion, our preclinical data support the hypothesis that afatinib might be a promising therapeutic strategy to treat patients with HNSCC experiencing intrinsic or acquired cetuximab resistance.
Assuntos
Afatinib/farmacologia , Cetuximab/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-4/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Concentração Inibidora 50 , Oxigênio/farmacologia , Receptor ErbB-2/metabolismo , Receptor ErbB-4/metabolismoRESUMO
PURPOSE: The aim of this study was to investigate the feasibility of tongue strength measures (TSMs) and the influence of bulb location, sex, and self-perceived pain and mucositis in head and neck cancer (HNC) patients during chemoradiotherapy (CRT). METHODS: Twenty-six newly diagnosed HNC patients treated with CRT performed anterior and posterior maximal isometric tongue pressures by means of the Iowa Oral Performance Instrument (IOPI). The Oral Mucositis Weekly Questionnaire (OMWQ) and a Visual Analogue Scale (VAS) for pain during swallowing were completed weekly from baseline to 1 week post CRT. RESULTS: Feasibility of TSMs during CRT declines significantly from 96 to 100% at baseline to 46% after 6 weeks of CRT. But post-hoc analyses reveal only significant differences in feasibility between baseline and measurements after 4 weeks of treatment. No effect of gender or bulb location was established, but feasibility is influenced by pain and mucositis. CONCLUSIONS: Feasibility of TSMs declines during CRT and is influenced by mucositis and pain. For the majority of subjects, TSMs were feasible within the first 4 weeks, which provides a window of scientific and clinical opportunities in this patient population.
Assuntos
Quimiorradioterapia/efeitos adversos , Transtornos de Deglutição/etiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Língua/patologia , Idoso , Transtornos de Deglutição/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Background: Currently, prognosis of non-small cell lung cancer (NSCLC) patients is based on clinicopathological factors, including TNM stage. However, there are considerable differences in patient outcome within a similar staging group, even when patients received identical treatments. In order to improve prognostic predictions and to guide treatment options, additional parameters influencing outcome are required. Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division and the DNA damage response, is considered as a new potential biomarker in this research area. While several studies reported Plk1 overexpression in a broad range of human malignancies, inconsistent results were published regarding the clinical significance hereof. A prognostic panel, consisting of Plk1 and additional biomarkers that are related to the Plk1 pathway, might further improve prediction of patient prognosis. Methods: In this study, we evaluated for the first time the prognostic value of Plk1 mRNA and protein expression in combination with the TP53 mutation status (next generation sequencing), induction of apoptotic cell death (immunohistochemistry for cleaved caspase 3) and hypoxia (immunohistochemistry for carbonic anhydrase IX (CA IX)) in 98 NSCLC adenocarcinoma patients. Results: Both Plk1 mRNA and protein expression and CA IX protein levels were upregulated in the majority of tumor samples. Plk1 mRNA and protein expression levels were higher in TP53 mutant samples, suggesting that Plk1 overexpression is, at least partially, the result of loss of functional p53 (<0.05). Interestingly, the outcome of patients with both Plk1 mRNA and CA IX protein overexpression, who also harbored a TP53 mutation, was much worse than that of patients with aberrant expression of only one of the three markers (p=0.001). Conclusion: The combined evaluation of Plk1 mRNA expression, CA IX protein expression and TP53 mutations shows promise as a prognostic panel in NSCLC patients. Moreover, these results pave the way for new combination strategies with Plk1 inhibitors.
RESUMO
PURPOSE OF REVIEW: High-risk human papillomaviruses (HPVs) are implicated in the development of a subset of head and neck squamous cell cancers (HNSCCs), especially those arising from the lingual or palatine tonsils. HPV-associated HNSCCs represent a different disease entity from those associated with the traditional risk factors of tobacco and alcohol use. The demonstration that HPV is causally associated with a subset of HNSCC has tremendous clinical and research implications. RECENT FINDINGS: In recent years, there has been an increase in the annual incidence of HPV-related HNSCC in the United States and Europe. It has now become clear that a subset of HNSCC is a sexually transmitted disease with distinct pathogenesis and clinical/pathological features. HPV-associated HNSCCs have a better prognosis compared with stage-matched non-HPV-related HNSCC in the majority of studies. Research efforts are now focusing on deintensification of treatment to reduce treatment-associated morbidity. HPV-targeted therapies are under investigation. SUMMARY: The increasing incidence of HPV-related HNSCC has led to the development of novel research strategies in HNSCC. This review summarizes the epidemiology, clinical presentation, molecular pathogenesis, diagnosis, and therapy of HPV-associated HNSCC; it also summarizes how a better understanding of the molecular pathogenesis of HPV-associated HNSCC is expected to change treatment.
Assuntos
Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/terapia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/terapia , Infecções por Papillomavirus/virologia , PrognósticoRESUMO
OBJECTIVE: The introduction of human papillomavirus (HPV) detection in cervical screening will make it necessary to provide appropriate information to the general public. Only 3% of Flemish women could name HPV as the viral agent involved in cervical cancer development. The aim of this study was to investigate whether general practitioners (GPs) have appropriate knowledge of the relationship between HPV and cervical cancer to be able to inform women. METHODS: A questionnaire was developed to measure perception of 20 risk factors for cervical cancer development, on a scale of 1 (unimportant) to 5 (very important). Respondents were also asked to give an estimate of the chances of survival for women, diagnosed with cervical cancer detected by screening. RESULTS: Sixty GPs and 28 trainees filled in the questionnaire. The five most important risk factors in the perception of the respondents were, in order of decreasing importance, viral infection, number of sex partners, sexual behaviour of the partner, unsafe sex, and early start of sexual activity. Fifty-six percent of the GPs expected the chance of survival to be between 80 and 100%, compared to only 31% of the trainees. CONCLUSION: Most GPs are well aware of sexual habits as risk factors for cervical cancer development, including the role of HPV as the viral agent in the etiology. However, they seem to underestimate the role of smoking and are unable to identify the correct chance of survival for women in whom cervical cancer is detected within the frame of the cervical smear program. PRACTICE IMPLICATIONS: Attention should be given to education of medical students and practitioners, in order to allow them to supply patients with sufficient background information to make an informed choice on participating in cervical cancer screening.