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A Contemporary Review of Molecular Therapeutic Targets for Adenoid Cystic Carcinoma.

ABSTRACT: ACC is a rare malignant tumor of the salivary glands. In this contemporary review, we explore advances in identification of targetable alterations and clinical trials testing these druggable targets. A search of relevant articles and abstracts from national meetings and three databases, including PubMed, Medline, and Web of Science, was performed. Following keyword search analysis and double peer review of abstracts to ensure appropriate fit, a total of 55 manuscripts were included in this review detailing advances in molecular targets for ACC. The most researched pathway associated with ACC is the MYB-NFIB translocation, found to lead to dysregulation of critical cellular pathways and thought to be a fundamental driver in a subset of ACC disease pathogenesis. Other notable molecular targets that have been studied include the cKIT receptor, the EGFR pathway, and NOTCH1, all with limited efficacy in clinical trials. The ongoing investigation of molecular abnormalities underpinning ACC that may be responsible for carcinogenesis is critical to identifying and developing novel targeted therapies.

SUBMITTER: Miller LE

PROVIDER: S-EPMC8869877 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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A Contemporary Review of Molecular Therapeutic Targets for Adenoid Cystic Carcinoma.

Miller Lauren E LE Au Vivienne V Mokhtari Tara E TE Goss Deborah D Faden Daniel L DL Varvares Mark A MA

Cancers 20220216 4

ACC is a rare malignant tumor of the salivary glands. In this contemporary review, we explore advances in identification of targetable alterations and clinical trials testing these druggable targets. A search of relevant articles and abstracts from national meetings and three databases, including PubMed, Medline, and Web of Science, was performed. Following keyword search analysis and double peer review of abstracts to ensure appropriate fit, a total of 55 manuscripts were included in this revie ...[more]

PMID: 35205740

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Project description:BACKGROUND:Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy without effective systemic therapies. Delineation of molecular profiles in ACC has led to an increased number of biomarker-stratified clinical trials; however, the clinical utility and U.S.-centric financial sustainability of integrated next-generation sequencing (NGS) in routine practice has, to our knowledge, not been assessed. MATERIALS AND METHODS:In our practice, NGS genotyping was implemented at the discretion of the primary clinician. We combined NGS-based mutation and fusion detection, with MYB break-apart fluorescent in situ hybridization (FISH) and MYB immunohistochemistry. Utility was defined as the fraction of patients with tumors harboring alterations that are potentially amenable to targeted therapies. Financial sustainability was assessed using the fraction of global reimbursement. RESULTS:Among 181 consecutive ACC cases (2011-2018), prospective genotyping was performed in 11% (n = 20/181; n = 8 nonresectable). Testing identified 5/20 (25%) NOTCH1 aberrations, 6/20 (30%) MYB-NFIB fusions (all confirmed by FISH), and 2/20 (10%) MYBL1-NFIB fusions. Overall, these three alterations (MYB/MYBL1/NOTCH1) made up 65% of patients, and this subset had a more aggressive course with significantly shorter progression-free survival. In 75% (n = 6/8) of nonresectable patients, we detected potentially actionable alterations. Financial analysis of the global charges, including NGS codes, indicated 63% reimbursement, which is in line with national (U.S.-based) and international levels of reimbursement. CONCLUSION:Prospective routine clinical genotyping in ACC can identify clinically relevant subsets of patients and is approaching financial sustainability. Demonstrating clinical utility and financial sustainability in an orphan disease (ACC) requires a multiyear and multidimensional program. IMPLICATIONS FOR PRACTICE:Delineation of molecular profiles in adenoid cystic carcinoma (ACC) has been accomplished in the research setting; however, the ability to identify relevant patient subsets in clinical practice has not been assessed. This work presents an approach to perform integrated molecular genotyping of patients with ACC with nonresectable, recurrent, or systemic disease. It was determined that 75% of nonresectable patients harbor potentially actionable alterations and that 63% of charges are reimbursed. This report outlines that orphan diseases such as ACC require a multiyear, multidimensional program to demonstrate utility in clinical practice.

Project description:Adenoid cystic carcinoma (AdCC) of the head and neck originates from salivary glands, with high risks of recurrence and metastasis that account for the poor prognosis of patients. The purpose of this research was to identify key genes related to AdCC for further investigation of their diagnostic and prognostic significance. In our study, the AdCC sample datasets GSE36820, GSE59702 and GSE88804 from the Gene Expression Omnibus (GEO) database were used to explore the abnormal coexpression of genes in AdCC compared with their expression in normal tissue. A total of 115 DEGs were obtained by screening with GEO2R and FunRich software. According to functional annotation analysis using Enrichr, these DEGs were mainly enriched in the SOX2, AR, SMAD and MAPK signaling pathways. A protein-protein network of the DEGs was established by the Search Tool for the Retrieval of Interacting Genes (STRING) and annotated through the WEB-based Gene SeT AnaLysis Toolkit (WebGestalt) and was shown to be enriched with proteins involved in cardiac muscle cell proliferation and extracellular matrix organization. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that ITGA9, LAMB1 and BAMBI were associated with the PI3K-Akt and TGF-β pathways. Furthermore, 36 potential target miRNAs were identified by the OncomiR and miRNA Pathway Dictionary Database (miRPathDB). In conclusion, SLC22A3, FOXP2, Cdc42EP3, COL27A1, DUSP1 and HSPB8 played critical roles according to the enrichment analysis; ITGA9, LAMB1 and BAMBI were involved in significant pathways according to the KEGG analysis; ST3Gal4 is a pivotal component of the PPI network of all the DEGs obtained; SPARC, COL4A2 and PRELP were highly related to multiple malignancies in pan-cancer research; hsa-miR-29-3p, hsa-miR-132-3p and hsa-miR-708-5p were potential regulators in AdCC. The involved pathways, biological processes and miRNAs have been shown to play significant roles in the genesis, growth, invasion and metastasis of AdCC. In this study, these identified DEGs were considered to have a potential influence on AdCC but have not been studied in this disease. The analysis results promote our understanding of the molecular mechanisms and biological processes of AdCC, which might be useful for targeted therapy or diagnosis.

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A Contemporary Review of Molecular Therapeutic Targets for Adenoid Cystic Carcinoma.

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A Contemporary Review of Molecular Therapeutic Targets for Adenoid Cystic Carcinoma.

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