scholarly journals A Comprehensive Evaluation of Biomarkers Predictive of Response to PI3K Inhibitors and of Resistance Mechanisms in Head and Neck Squamous Cell Carcinoma

2014 ◽  
Vol 13 (11) ◽  
pp. 2738-2750 ◽  
Author(s):  
Tuhina Mazumdar ◽  
Lauren A. Byers ◽  
Patrick Kwok Shing Ng ◽  
Gordon B. Mills ◽  
Shaohua Peng ◽  
...  
2020 ◽  
Vol 26 (12) ◽  
pp. 2956-2971 ◽  
Author(s):  
Federica Ganci ◽  
Claudio Pulito ◽  
Sara Valsoni ◽  
Andrea Sacconi ◽  
Chiara Turco ◽  
...  

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A22-A22
Author(s):  
Charles Abbott ◽  
Nikita Bedi ◽  
Jing Wang ◽  
Josette Northcott ◽  
Rachel Pyke ◽  
...  

BackgroundTypical liquid biopsy panels offer a limited understanding of tumor biology, potentially under-representing the heterogeneity of resistance in late-stage cancers. Here, diminished scope can result in undetected, therapeutically-relevant biomarkers which respond dynamically to treatment, as well as potentially missed resistance mechanisms and pathway-level events. To address the challenges associated with identifying multiple concurrent heterogeneous resistance mechanisms in individual patients, we evaluated longitudinal exome-scale tumor-informed cell-free DNA (cfDNA) data from head and neck squamous cell carcinoma (HNSCC) patients receiving anti-PD1 therapy.MethodsPre- and post-intervention matched tumor, normal and plasma samples were retrospectively obtained from 15 stage II-IV HNSCC patients. Following baseline sample collection, all patients received a single dose of nivolumab or pembrolizumab. The primary tumor was then resected approximately one month later when possible, or a second biopsy collected where resection was impractical. Paired tumor and normal samples were then profiled using ImmunoID NeXT Platform®, an augmented exome/transcriptome platform and analysis pipeline. Exome-scale cfDNA profiling of matched plasma samples was performed using the NeXT Liquid BiopsyTM platform to detect somatic variants.ResultsPatient neoantigen presentation score (NEOPSTM) rapidly and significantly contracted following therapy (p=.00098). Novel neoantigens arising post-treatment which were predicted to be presented on lost HLA alleles were significantly higher in patients with longer overall survival (p=.019). Variant detection across same-patient serial cfDNA samples revealed significantly correlated VAFs (R=.62, p<.0001) despite significant contraction of mutational burden in solid tumor (p=.0039), suggesting complex clonal/subclonal dynamics. Investigation of the evolving tumor and cfDNA subclonal architecture revealed significant association between decreasing cellular prevalence and NOTCH signaling (q=.001) and the innate immune system (q=.002), while increasing cellular prevalence was associated with p53 signalling (q=.02) and hypoxia (q=.02). These findings were complimented by transcriptomic data which showed significant enrichment of multiple immune pathways across treatment.ConclusionsWe found that immune checkpoint blockade precipitates rapid evolution of the HNSCC tumor microenvironment. By leveraging comprehensive, tumor-informed liquid biopsy data we were able to identify contracting cellular populations enriched for NOTCH pathway mutations. Longer OS following either intervention was associated with an expansion of novel neoantigens predicted to be presented by lost HLA alleles. Our results suggest that tumor-informed liquid biopsy provides a more robust understanding of therapeutic response and resistance mechanisms than that attainable with typical liquid biopsy panels alone.Ethics ApprovalThis study obtained ethics approval from Human Subjects Research at Stanford University. ID number is 40425. All participants gave informed consent prior to enrollment.


PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245715
Author(s):  
Fu-Cheng Chuang ◽  
Chih-Chun Wang ◽  
Jian-Han Chen ◽  
Tzer-Zen Hwang ◽  
Shyh-An Yeh ◽  
...  

Approximately 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are reported annually. Radiation therapy is an important treatment for oral squamous cell carcinoma (OSCC). The survival rate of patients with HNSCC remained low (50%) in decades because of radiation therapy failure caused by the radioresistance of HNSCC cells. This study aimed to identify PI3K inhibitors that can enhance radiosensitivity. Results showed that pan-Phosphoinositide 3-kinases (PI3K) inhibitor BKM120 and class I α-specific PI3K inhibitor BYL719 dose-dependently reduced the growth of OSCC cells but not that of radioresistant OML1-R cells. The combination treatment of BKM120 or BYL719 with radiation showed an enhanced inhibitory effect on OSCC cells and radioresistant OML1-R cells. Furthermore, the enhanced inhibitory effect of the combination treatment was confirmed in patient-derived OSCC cells. The triple combination treatment of mTOR inhibitor AZD2014 and BKM120 or AZD2014 and BYL719 with radiation showed a significantly enhanced inhibitory effect on radioresistant OML1-R cells. These results suggest that the PI3K inhibitors are potential therapeutic agents with radiosensitivity for patients with OSCC.


2018 ◽  
Vol 97 (6) ◽  
pp. 622-626 ◽  
Author(s):  
J.M. Moskovitz ◽  
R.L. Ferris

The immune system plays an important role in the evolution of malignancy and has become an important target for novel antineoplastic agents. This review article focuses on key features of tumor immunology, including the role of immunotherapy in general and as it pertains to head and neck squamous cell carcinoma. Side effects, resistance mechanisms, and therapeutic monitoring strategies pertaining to immunotherapy are discussed.


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