Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors

Fasano, Morena; Perri, Francesco; Corte, Carminia Maria Della; Liello, Raimondo Di; Scarpati, Giuseppina Della Vittoria; Cascella, Marco; Ottaiano, Alessandro; Ciardiello, Fortunato; Solla, Raffaele

doi:10.3390/biomedicines9081045

Cited by 5 publications

(1 citation statement)

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“…Advanced HPV-negative head and neck squamous cell carcinoma (HPV(-) HNSCC) continues to carry a poor prognosis compared to its HPV-positive counterpart 1 . The emergence of modern targeted therapies such as anti-EGFR and anti-PD(L)1 agents has had limited overall impact on oncologic outcomes for these patients 2 . Other recently proposed strategies, including PI3K and CDK 4/6 inhibition, have yet to show utility in clinical trials for monotherapy or combination therapy, as they may be hampered by prognostic associations with genomic subgroups of HPV(-) HNSCC.…”

Section: Introductionmentioning

confidence: 99%

Cancer type-specific prioritization strategy for targetable dependencies developed from the DepMap profile of head and neck cancer

Cao

Sannigrahi

Rajagopalan

et al. 2022

Preprint

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Objectives: The DepMap genome-wide loss of function CRISPR screens offer new insight into gene dependencies in HPV(-) head and neck squamous cell carcinoma (HNSCC) cell lines. We aimed to leverage this data to guide preclinical studies by cataloging novel targetable dependencies that are predicted to offer a useful therapeutic window. We also aimed to identify targets potentially representing synthetic lethalities by testing for associations between genetic alterations and gene dependency profile. Methods: DepMap was queried for gene probability and effect scores in cell lines from 87 tumors, including 63 HPV(-) HNSCCs plus 24 esophageal squamous cell carcinomas (ESCCs), which have comparable etiology, tissue or origin, and genetic profile to HNSCC. A probability score of ≥ 0.5 was used as the threshold for essentiality. Essential genes were selected for analysis by 4 criteria: (1) presence in ≥10% cell lines, (2) lack of common essential designation by DepMap, (3) lack of predicted dependency in normal cell lineages, and (4) designation as druggable by the Drug-Gene Interaction Database. Results: The 143 genes meeting selection criteria had a median gene effect score of 0.56. Selection criteria captured targets of standard therapeutic agents of HNSCC including TYMS (5-FU), tubulin genes (taxanes), EGFR (cetuximab), plus additional known oncogenes like PIK3CA and ERBB3. Functional classification analysis showed enrichment of tyrosine kinases, serine/threonine kinases, RNA-binding proteins, and mitochondrial carriers. 90% of the 143 dependencies were not known oncogenes in the OncoKB Database. 10% of targets had inhibitors previously used in a non-HNSCC phase II trial, including 8 that have not yet been tested in cancer. The 13 genes with median gene effect scores greater than of PIK3CA and not well-studied in HNSCC were assigned highest priority, including DHRSX, MBTPS1, TDP2, FARS2, TMX2, RAB35, CFLAR, GPX4, SLC2A1, TP63, PKN2, MAP3K11, and TIPARP. A novel association was found between NOTCH1 mutation and increased TAP1 dependency. Conclusions: The DepMap CRISPR screens capture well-studied targets in HNSCC as well as numerous genes without known roles in HNSCC or malignancy in general. Several of these targets have well-developed inhibitors that provide resources to guide preclinical studies. Association of some of the dependencies with known molecular subgroups in HNSCC may enhance use of cell line models to guide personalization of therapy.

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Section: Introductionmentioning

confidence: 99%

Cancer type-specific prioritization strategy for targetable dependencies developed from the DepMap profile of head and neck cancer

Cao

Sannigrahi

Rajagopalan

et al. 2022

Preprint

View full text Add to dashboard Cite

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Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Hypopharynx, Larynx, Trachea and Parapharyngeal Space

Zidar

Gale

2022

Head and Neck Pathol

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In this article, we review the chapter on tumors of the larynx, hypopharynx, trachea and parapharyngeal space in the new edition of the WHO book, focusing on the new developments in comparison to the previous edition. Squamous cell carcinoma (SCC) and its variants are by far the most common malignancies at these locations, with very limited new insights. The most important is the introduction of new targeted treatment—checkpoint inhibitors, with a new task for pathologists, who may help to predict the response to treatment by analyzing the expression of targeted proteins in biopsy samples. Precancerous lesions remain a controversial topic and, similarly to other organs, it is acceptable to use the terms “dysplasia” or “squamous intraepithelial lesion” (SIL), but there is a slight difference between low-grade dysplasia and low-grade SIL: in the former, mild atypia must be present, while the latter also includes hyperplastic epithelium without atypia. Two approaches have been proposed: a two-tiered system with low- and high-grade dysplasia/SIL and a three-tiered system with an additional category, carcinoma in situ. We are still searching for reliable diagnostic markers to surpass the subjectivity in biopsy diagnosis, with a few potential candidate markers on the horizon, e.g., stem cell markers. Other tumors are rare at these locations, e.g., hematolymphoid, neuroendocrine and salivary gland neoplasms, and are no longer included in Chapter 3. They must be diagnosed according to criteria described in specific chapters. The same holds true for soft tissue tumors, with the exception of cartilaginous neoplasms, which are still included in Chapter 3.

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