scholarly journals Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: Why clinical trials have failed and how they could succeed

2020 ◽  
Author(s):  
Madusha Meemanage ◽  
Lindsay C Spender ◽  
Diane Collinson ◽  
Joanna Iannetta ◽  
Pranavi Challapalli ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Clinical Trials ◽  
Cell Carcinoma ◽  
Cancer Patients ◽  
Drug Combination ◽  
Cytotoxic Chemotherapy ◽  
Randomised Clinical Trials ◽  
Oesophageal Squamous Cell Carcinoma ◽  
Gastroesophageal Cancer ◽  
Combination Studies

Abstract BACKGROUND Oesophageal squamous cell carcinoma (ESCC) has high mortality and poor prognosis. Advanced tumours are treated with fluoropyrimidine/platinum chemotherapy (PBC) followed by second-line irinotecan or taxane monotherapy, but resistance is common and new therapeutic approaches are needed. Approximately 20% of ESCC tumours carry copy number gain (CNG) of the epidermal growth factor receptor (EGFR) gene. Previous analysis of randomised clinical trials shows that anti-EGFR monotherapy benefits biomarker-selected patients with EGFR CNG and/or high expression by Immunohistochemistry (IHC). However, responses are often of short duration indicating that combining anti-EGFR therapy with other agents is required to optimise the benefit from anti-EGFR therapies even in biomarker selected patients. Randomised clinical trials have not shown benefit from the addition of anti-EGFR therapies to platinum fluoropyrimidine chemotherapy and uncertainty remains regarding the optimal cytotoxic chemotherapy partner for anti-EGFR therapies in ESCC. METHODS The effects of EGFR CNG on sensitivity to PBC in a cohort of gastroesophageal cancer patients (n = 302) was evaluated. Drug combination studies using the EGFR inhibitor gefitinib with cytotoxic chemotherapies, docetaxel, cisplatin, oxaliplatin and irinotecan, on cell proliferation and cell death of EGFR CNG ESCC cell lines were assessed. RESULTS EGFR CNG in gastroesophageal cancer patients was associated with better overall survival following platinum-based chemotherapy. Drug combination studies showed that co-administration of gefitinib and platinum-based cytotoxics was frequently antagonistic in cell-based assays in EGFR CNG ESCC, whereas the combination of gefitinib with docetaxel or irinotecan was more efficacious. Co-administration of gefitinib/docetaxel and sequential administration of docetaxel before gefitinib showed synergy, but docetaxel given after gefitinib was antagonistic. CONCLUSIONS Gefitinib/docetaxel co-administration demonstrated synergy and taxanes are likely to provide the most effective cytotoxic chemotherapy partner for anti-EGFR therapies in EGFR CNG-positive advanced ESCC. Combination of gefitinib and platinum-based cytotoxics was antagonistic suggesting anti-EGFR therapies might reduce anti-cancer effects of chemotherapy which could provide a key explanation for the lack of benefit for the addition of anti-EGFR therapies to PBC in randomised clinical trials. Our data suggest that the combination of docetaxel with anti-EGFR therapies, with careful consideration of dosing schedules, should be evaluated in advanced EGFR CNG-positive and/or IHC high EGFR expressing ESCC.

scholarly journals Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: why clinical trials might have failed and how they could succeed

2020 ◽  
Author(s):  
Madusha Meemanage ◽  
Lindsay C. Spender ◽  
Diane Collinson ◽  
Joanna Iannetta ◽  
Pranavi Challapalli ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cancer Patients ◽  
Squamous Cell ◽  
Cytotoxic Chemotherapy ◽  
Oesophageal Squamous Cell Carcinoma ◽  
Gastroesophageal Cancer ◽  
Egfr Expression ◽  
Sequential Administration ◽  
Platinum Chemotherapy

Abstract Purpose Oesophageal squamous cell carcinoma (ESCC) has a poor prognosis. Advanced tumours are treated with fluoropyrimidine/platinum chemotherapy followed by irinotecan or taxane monotherapy, but resistance is common and new treatments are needed. Approximately 20% of ESCCs carry copy number gain (CNG) of the epidermal growth factor receptor (EGFR) gene. Previous trials show that while anti-EGFR monotherapy benefits biomarker-selected patients with EGFR CNG and/or high EGFR expression, combining anti-EGFR therapies with platinum fluoropyrimidine chemotherapies is not effective, and uncertainty remains regarding the optimal cytotoxic chemotherapy partner for anti-EGFR therapies in ESCC. Methods The effects of EGFR CNG on fluoropyrimidine/platinum chemotherapy sensitivity in a cohort of gastroesophageal cancer patients (n = 302) was evaluated. Drug combination studies using the EGFR inhibitor gefitinib with cytotoxic chemotherapies, docetaxel, cisplatin, oxaliplatin and irinotecan, on cell proliferation and cell death of EGFR CNG ESCC cell lines were assessed. Results EGFR CNG in gastroesophageal cancer patients was associated with improved overall survival following fluoropyrimidine/platinum chemotherapy. However, co-administration of gefitinib and oxaliplatin or cisplatin was frequently antagonistic in cell-based assays in EGFR CNG ESCC, whereas the combination of gefitinib with docetaxel or irinotecan was more efficacious. Co-administration of gefitinib/docetaxel and sequential administration of docetaxel before gefitinib showed synergy, but docetaxel given after gefitinib was antagonistic. Conclusion Gefitinib/platinum co-administration demonstrated antagonism suggesting a possible explanation for the lack of benefit from addition of anti-EGFR therapies to fluoropyrimidine/platinum chemotherapy in trials. Gefitinib/docetaxel co-administration demonstrated synergy suggesting taxanes could be the most effective cytotoxic partner for anti-EGFR therapies in EGFR CNG-positive ESCC, but careful consideration of drug scheduling is required.

Resveratrol and prostate cancer: the power of phytochemicals

2020 ◽  
Vol 28 ◽  
Author(s):  
Nadia Zaffaroni ◽  
Giovanni L. Beretta
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Antitumor Activity ◽  
Cancer Patients ◽  
Drug Combination ◽  
Natural Compound ◽  
Latency Period ◽  
Chemopreventive Agent ◽  
Long Latency ◽  
Combination Studies

: Prostate cancer is the fifth cause of tumor-related deaths in man worldwide. Due to its long latency period, this pathology represents an ideal type of disease for chemopreventive studies. Among the drugs considered thus far for the treatment of prostate cancer, the natural compound resveratrol emerged as very promising. Resveratrol is a widely recognized as chemopreventive agent and was shown to potentiate the antitumor activity of conventional chemotherapeutics in several tumors, including prostate cancer. Here we overview the literature of the last five years and summarize the recent achievements of resveratrol and its derivatives as antimetastatic agents in prostate cancer. Moreover, drug combination studies as well as nanomedicine approaches proposed to improve resveratrol activity and to overcome delivery drawbacks are addressed. The last part of the review discusses the clinical trials containing resveratrol ongoing on cancer patients.

scholarly journals Progress of molecular targeted therapy for head and neck cancer in clinical aspects

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Kenji Nakano
Keyword(s):  
Squamous Cell Carcinoma ◽  
Clinical Trials ◽  
Head And Neck Cancer ◽  
Targeted Therapy ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Cancer Patients ◽  
Neck Cancer ◽  
Squamous Cell ◽  
Molecular Targeted Therapy

AbstractSince the body’s head and neck area affects many functions such as breathing, swallowing, and speaking, systemic treatments to head and neck cancer patients are important not only for survival but also for preserving functions and quality of life. With the progress that has been made in molecular targeted therapy, anti-EGFR antibody (cetuximab) and immune checkpoint inhibitors (nivolumab, pembrolizumab) have provided survival benefits to head and neck cancer patients and are approved for clinical practice. Clinical trials incorporating these new drugs for patients with locally advanced head/neck cancers are underway. However, the existing clinical evidence regarding molecular targeted drugs for head and neck cancers is based mostly on clinical trials allocated to squamous cell carcinoma patients. New targeted therapies for non-squamous cell carcinoma patients were recently reported, e.g., tyrosine kinase inhibitors for the treatment of thyroid cancers and HER2-targeted therapy for salivary gland cancers. With the goal of improving local control, molecular targeted treatment strategies as salvage local therapy are being investigated, including boron neutron capture therapy (BNCT) and near-infrared photoimmunotherapy (NIR-PIT). Herein the history and landscape of molecular targeted therapy for head and neck cancers are summarized and reviewed.

scholarly journals Aspirin enhances the therapeutic efficacy of cisplatin in oesophageal squamous cell carcinoma by inhibition of putative cancer stem cells

2021 ◽  
Author(s):  
Zhigeng Zou ◽  
Wei Zheng ◽  
Hongjun Fan ◽  
Guodong Deng ◽  
Shih-Hsin Lu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Squamous Cell Carcinoma ◽  
Cancer Stem Cells ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Squamous Cell ◽  
High Throughput Sequencing ◽  
Combined Treatment ◽  
Oesophageal Squamous Cell Carcinoma

Abstract Background Cancer stem cells (CSCs) are related to the patient’s prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood. Methods We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells. Results ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model. Conclusions ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.

scholarly journals Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323276
Author(s):  
Jin Zhou ◽  
Zhong Wu ◽  
Zhouwei Zhang ◽  
Louisa Goss ◽  
James McFarland ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Large Scale ◽  
Cell Cancer ◽  
Oesophageal Squamous Cell Carcinoma ◽  
Squamous Cancer ◽  
Striking Success

ObjectiveOesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.DesignWe combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.ResultsWe identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.ConclusionThese results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.

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