The influence of PI3K inhibition on the radiotherapy response of head and neck cancer cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Glorieux M
PROVIDER: S-EPMC7529775 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
The influence of PI3K inhibition on the radiotherapy response of head and neck cancer cells.
Glorieux Mary M Dok Rüveyda R Nuyts Sandra S
Scientific reports 20201001 1
Radiotherapy has a central role in the treatment of head and neck squamous cell carcinoma (HNSCC). Activation of the PI3K/AKT/mTOR pathway can decrease the efficiency of radiotherapy via the promotion of cell survival and DNA repair. Here, the influence of PI3K pathway inhibition on radiotherapy response was investigated. Two PI3K inhibitors were investigated and both BKM120 and GDC0980 effectively inhibited cellular and clonogenic growth in 6 HNSCC cells, both HPV-positive as well as HPV-negati ...[more]
Similar Datasets
Project description:Head and neck squamous cancers are a heterogeneous group of cancers that arise from the upper aerodigestive tract. Etiologically, these tumors are linked to alcohol/tobacco abuse and infections with high-risk human papillomavirus (HPV). HPV-positive HNSCCs are characterized by a different biology and also demonstrate better therapy response and survival compared to alcohol/tobacco-related HNSCCs. Despite this advantageous therapy response and the clear biological differences, all locally advanced HNSCCs are treated with the same chemo-radiotherapy schedules. Although we have a better understanding of the biology of both groups of HNSCC, the biological factors associated with the increased radiotherapy response are still unclear. Hypoxia, i.e., low oxygen levels because of an imbalance between oxygen demand and supply, is an important biological factor associated with radiotherapy response and has been linked with HPV infections. In this review, we discuss the effects of hypoxia on radiotherapy response, on the tumor biology, and the tumor microenvironment of HPV-positive and HPV-negative HNSCCs by pointing out the differences between these two tumor types. In addition, we provide an overview of the current strategies to detect and target hypoxia.
| S-EPMC8656584 | biostudies-literature
Project description:The application of radiotherapy to the treatment of cancer has existed for over 100 years. Although its use has cured many, much work remains to be done to minimize side effects, and in-field tumor recurrences. Resistance of the tumor to a radiation-mediated death remains a complex issue that results in local recurrence and significantly decreases patient survival. Here, we review mechanisms of radioresistance and selective treatment combinations that improve the efficacy of the radiation that is delivered. Further investigation into the underlying mechanisms of radiation resistance is warranted to develop not just novel treatments, but treatments with improved safety profiles relative to current radiosensitizers. This review is written in memory and honor of Dr. Peter Stambrook, an avid scientist and thought leader in the field of DNA damage and carcinogenesis, and a mentor and advocate for countless students and faculty.
| S-EPMC10228519 | biostudies-literature
Project description:Phosphoinositide 3-kinase (PI3K) is aberrantly activated in head and neck squamous cell carcinomas (HNSCC) and plays a pivotal role in tumorigenesis by driving Akt signaling, leading to cell survival and proliferation. Phosphorylation of Akt Thr308 by PI3K-PDK1 and Akt Ser473 by mammalian target of rapamycin complex 2 (mTORC2) activates Akt. Targeted inhibition of PI3K is a major area of preclinical and clinical investigation as it reduces Akt Thr308 phosphorylation, suppressing downstream mTORC1 activity. However, inhibition of mTORC1 releases feedback inhibition of mTORC2, resulting in a resurgence of Akt activation mediated by mTORC2. While the role of PI3K-activated Akt signaling is well established in HNSCC, the significance of mTORC2-driven Akt signaling has not been thoroughly examined. Here we explore the expression and function of mTORC2 and its obligate subunit RICTOR in HNSCC primary tumors and cell lines. We find RICTOR to be overexpressed in a subset of HNSCC tumors, including those with PIK3CA or EGFR gene amplifications. Whereas overexpression of RICTOR reduced susceptibility of HNSCC tumor cells to PI3K inhibition, genetic ablation of RICTOR using CRISPR/Cas9 sensitized cells to PI3K inhibition, as well as to EGFR inhibition and cisplatin treatment. Further, mTORC2 disruption led to reduced viability and colony forming abilities of HNSCC cells relative to their parental lines and induced loss of both activating Akt phosphorylation modifications (Thr308 and Ser473). Taken together, our findings establish RICTOR/mTORC2 as a critical oncogenic complex in HNSCC and rationalize the development of an mTORC2-specific inhibitor for use in HNSCC, either combined with agents already under investigation, or as an independent therapy.
| S-EPMC6763779 | biostudies-literature
Project description:Head and neck cancer is the seventh most common cancer in Australia and globally. Despite the current improved treatment modalities, there is still up to 50?60% local regional recurrence and or distant metastasis. High-resolution medical imaging technologies such as PET/CT and MRI do not currently detect the early spread of tumour cells, thus limiting the potential for effective minimal residual detection and early diagnosis. Circulating tumour cells (CTCs) are a rare subset of cells that escape from the primary tumour and enter into the bloodstream to form metastatic deposits or even re-establish themselves in the primary site of the cancer. These cells are more aggressive and accumulate gene alterations by somatic mutations that are the same or even greater than the primary tumour because of additional features acquired in the circulation. The potential application of CTC in clinical use is to acquire a liquid biopsy, by taking a reliable minimally invasive venous blood sample, for cell genotyping during radiotherapy treatment to monitor the decline in CTC detectability, and mutational changes in response to radiation resistance and radiation sensitivity. Currently, very little has been published on radiation therapy, CTC, and circulating cancer stem cells (CCSCs). The prognostic value of CTC in cancer management and personalised medicine for head and neck cancer radiotherapy patients requires a deeper understanding at the cellular level, along with other advanced technologies. With this goal, this review summarises the current research of head and neck cancer CTC, CCSC and the molecular targets for personalised radiotherapy response.
| S-EPMC6468366 | biostudies-literature
Project description:We have an incomplete understanding of the differences between cancer stem cells (CSCs) in human papillomavirus-positive (HPV-positive) and -negative (HPV-negative) head and neck squamous cell cancer (HNSCC). The PI3K pathway has the most frequent activating genetic events in HNSCC (especially HPV-positive driven), but the differential signaling between CSCs and non-CSCs is also unknown. We addressed these unresolved questions using CSCs identified from 10 HNSCC patient-derived xenografts (PDXs). Sored populations were serially passaged in nude mice to evaluate tumorigenicity and tumor recapitulation. The transcription profile of HNSCC CSCs was characterized by mRNA sequencing, and the susceptibility of CSCs to therapy was investigated using an in vivo model. SOX2 transcriptional activity was used to follow the asymmetric division of PDX-derived CSCs. All statistical tests were two-sided. CSCs were enriched by high aldehyde dehydrogenase (ALDH) activity and CD44 expression and were similar between HPV-positive and HPV-negative cases (percent tumor formation injecting ≤ 1x10(3) cells: ALDH(+)CD44(high) = 65.8%, ALDH(-)CD44(high) = 33.1%, ALDH(+)CD44(high) = 20.0%; and injecting 1x10(5) cells: ALDH(-)CD44(low) = 4.4%). CSCs were resistant to conventional therapy and had PI3K/mTOR pathway overexpression (GSEA pathway enrichment, P < .001), and PI3K inhibition in vivo decreased their tumorigenicity (40.0%-100.0% across cases). PI3K/mTOR directly regulated SOX2 protein levels, and SOX2 in turn activated ALDH1A1 (P < .001 013C and 067C) expression and ALDH activity (ALDH(+) [%] empty-control vs SOX2, 0.4% ± 0.4% vs 14.5% ± 9.8%, P = .03 for 013C and 1.7% ± 1.3% vs 3.6% ± 3.4%, P = .04 for 067C) in 013C and 067 cells. SOX2 enhanced sphere and tumor growth (spheres/well, 013C P < .001 and 067C P = .04) and therapy resistance. SOX2 expression prompted mesenchymal-to-epithelial transition (MET) by inducing CDH1 (013C P = .002, 067C P = .01), followed by asymmetric division and proliferation, which contributed to tumor formation. The molecular link between PI3K activation and CSC properties found in this study provides insights into therapeutic strategies for HNSCC. Constitutive expression of SOX2 in HNSCC cells generates a CSC-like population that enables CSC studies.
| S-EPMC5025278 | biostudies-literature
Project description:Concurrent chemoradiotherapy represents one of the most used strategies in the curative treatment of patients with head and neck (HNC) cancer. Locoregional failure is the predominant recurrence pattern. Tumor hypoxia belongs to the main cause of treatment failure. Positron emission tomography (PET) using hypoxia radiotracers has been studied extensively and has proven its feasibility and reproducibility to detect tumor hypoxia. A number of studies confirmed that the uptake of FMISO in the recurrent region is significantly higher than that in the non-recurrent region. The escalation of dose to hypoxic tumors may improve outcomes. The technical feasibility of optimizing radiotherapeutic plans has been well documented. To define the hypoxic tumour volume, there are two main approaches: dose painting by contour (DPBC) or by number (DPBN) based on PET images. Despite amazing technological advances, precision in target coverage, and surrounding tissue sparring, radiation oncology is still not considered a targeted treatment if the "one dose fits all" approach is used. Using FMISO and other hypoxia tracers may be an important step for individualizing radiation treatment and together with future radiomic principles and a possible genome-based adjusting dose, will move radiation oncology into the precise and personalized era.
| S-EPMC9410424 | biostudies-literature
Project description:Radiotherapy has long been the mainstay of treatment for patients with head and neck cancer and has traditionally involved a stage-dependent strategy whereby all patients with the same TNM stage receive the same therapy. We believe there is a substantial opportunity to improve radiotherapy delivery beyond just technological and anatomical precision. In this Series paper, we explore several new ideas that could improve understanding of the phenotypic and genotypic differences that exist between patients and their tumours. We discuss how exploiting these differences and taking advantage of precision medicine tools-such as genomics, radiomics, and mathematical modelling-could open new doors to personalised radiotherapy adaptation and treatment. We propose a new treatment shift that moves away from an era of empirical dosing and fractionation to an era focused on the development of evidence to guide personalisation and biological adaptation of radiotherapy. We believe these approaches offer the potential to improve outcomes and reduce toxicity.
| S-EPMC7771279 | biostudies-literature
Project description:Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common cancer globally and commonly presents with locally advanced disease, which has a recurrence rate of around 50% despite aggressive multi-modality treatment involving surgery, radiotherapy and chemotherapy or EGFR inhibition where appropriate. As understanding of the underlying cancer biology and the complex interactions within the tumor microenvironment improves, there is gathering interest in and evidence for the role of immunomodulating agents in the management of HNSCC. Immune checkpoint inhibitors, which aim to hinder the inhibitory interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1, have demonstrated durable improvements in patient outcomes in advanced / metastatic HNSCC, with both pembrolizumab and nivolumab being granted FDA approval in 2016. There are numerous ongoing clinical trials exploring the role of checkpoint inhibitors both as single agents and in combination, administered with established treatment modalities such as chemotherapy and radiotherapy, as well as alongside other novel immune modulators. These trials are not limited to advanced / metastatic HNSCC, but also to the neo-adjuvant or adjuvant settings. As studies complete and more results become available, the role immunotherapy agents will have within the treatment strategies for HNSCC may change, with increasing biomarker selection resulting in personalized therapy aiming to further improve patient outcomes.
| S-EPMC6123367 | biostudies-literature
Project description:In India, a considerable proportion of patients with head and neck cancer present with locoregionally advanced disease. Symptom palliation becomes a major objective in these cases when they could not be considered for a curative approach.The aim of this study is to assess the role of palliative radiotherapy for symptom control in patients with locally advanced head and neck cancer.This was a retrospective study.Between July 2015 and June 2016, 98 patients with stage IV head and neck cancer were treated with palliative radiotherapy 25 Gray (Gy)/4 fractions (fr)/1 fraction (6.25 Gy)/week. Presenting symptoms were noted. The primary end point was relief of symptoms in the 4th week after radiotherapy. Percentage symptom relief was quantified by the patient using a rupee scale. Treatment response was noted using the WHO criteria. Acute toxicity was graded as per the Radiation Therapy Oncology Group (RTOG) criteria.The most common presenting symptom was pain. At 4 weeks after radiotherapy completion, all patients had >50% pain relief. Dysphagia was improved in 82% of patients. Respiratory distress was improved in all the symptomatic patients. Tumor complete response (CR) was seen in 2 patients, partial response in 89, stable disease in 3, and progressive disease in 4. RTOG Grade 2 and 3 acute skin and mucosal toxicities were seen in 29% and 27% cases, respectively. No patient had Grade 4 adverse effect.Hypofractionated radiation could provide effective symptom palliation in advanced head and neck cancers. The weekly schedule was well tolerated and found convenient by the patients.
| S-EPMC5545959 | biostudies-other
Project description:Purpose: Tumor markers that are related to hypoxia, proliferation, DNA damage repair and stem cell-ness, have a prognostic value in advanced stage HNSCC patients when assessed individually. Here we aimed to evaluate and validate this in a multifactorial context and assess interrelation and the combined role of these biological factors in determining chemo-radiotherapy response in HPV-negative advanced HNSCC. Methods: RNA sequencing data of pre-treatment biopsy material from 197 HPV-negative advanced stage HNSCC patients treated with definitive chemoradiotherapy was analyzed. Biological parameter scores were assigned to patient samples using previously generated and described gene expression signatures. Locoregional control rates were used to assess the role of these biological parameters in radiation response and compared to distant metastasis data. Biological factors were ranked according to their clinical impact using bootstrapping methods and multivariate Cox regression analyses that included clinical variables. Multivariate Cox regression analyses comprising all biological variables were used to define their relative role among all factors when combined. Results: Only few biomarker scores correlate with each other, underscoring their independence. The different biological factors do not correlate or cluster, except for the two stem cell markers CD44 and SLC3A2 (r = 0.4, p < 0.001) and acute hypoxia prediction scores which correlated with T-cell infiltration score, CD8+ T cell abundance and proliferation scores (r = 0.52, 0.56, and 0.6, respectively with p < 0.001). Locoregional control association analyses revealed that chronic (Hazard Ratio (HR) = 3.9) and acute hypoxia (HR = 1.9), followed by stem cell-ness (CD44/SLC3A2; HR = 2.2/2.3), were the strongest and most robust determinants of radiation response. Furthermore, multivariable analysis, considering other biological and clinical factors, reveal a significant role for EGFR expression (HR = 2.9, p < 0.05) and T-cell infiltration (CD8+T-cells: HR = 2.2, p < 0.05; CD8+T-cells/Treg: HR = 2.6, p < 0.01) signatures in locoregional control of chemoradiotherapy-treated HNSCC. Conclusion: Tumor acute and chronic hypoxia, stem cell-ness, and CD8+ T-cell parameters are relevant and largely independent biological factors that together contribute to locoregional control. The combined analyses illustrate the additive value of multifactorial analyses and support a role for EGFR expression analysis and immune cell markers in addition to previously validated biomarkers. This external validation underscores the relevance of biological factors in determining chemoradiotherapy outcome in HNSCC.
| S-EPMC6966332 | biostudies-literature