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Updated: Jul 12, 2026
Identification of OTX1 and OTX2 As Two Possible Molecular Markers for Sinonasal Carcinomas and Olfactory Neuroblastomas
Published on: February 28, 2019
Comprehensive multi-omic dissection and AI-prioritized target identification in inverted papilloma-associated
Alka Singh1, Michael Korzinkin2, Viktoria Sarkisova2
1Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA.
Abstract:
Sinonasal squamous cell carcinoma (SNSCC) is a rare malignancy arising de novo or from inverted papilloma (IP), a benign neoplasm with malignant potential. The molecular drivers of IP-associated SNSCC (IP-SNSCC) remain poorly defined, and no effective therapies are available. Progress is hindered by limited preclinical studies and prospective clinical investigations. We performed multi-omic profiling, including whole-exome, RNA, and mitochondrial DNA sequencing (mtDNA-Seq), of matched normal sinonasal epithelium, IP, and SNSCC samples from 11 patients. Analyses revealed a stepwise transcriptional continuum across histological stages, marked by progressive activation of the cell cycle, extracellular matrix remodeling, and metabolic pathways, with suppression of immune and apoptotic signaling. Shared genomic aberrations were detected in only a subset of paired IP and SNSCC specimens, whereas mtDNA-Seq revealed no overlapping mutations, indicating divergent mitochondrial evolution even in clonally related lesions. Given the need for targeted therapies, we applied PandaOmics, an AI-driven target discovery platform, to genes progressively upregulated during IP-SNSCC development. We first prioritized targets with FDA-approved inhibitors, identifying CDK6, EGFR, HDAC, and SRC/YES1 as repurposing candidates, and nominated AURKA, PLK4, TTK, and CDK1/7 as druggable preclinical targets. Together, this study defines the molecular basis of IP-SNSCC and provides a foundation for future translational investigation.
Insights
This study reveals the molecular changes in sinonasal squamous cell carcinoma (SNSCC) linked to inverted papilloma (IP). It identifies potential drug targets for this rare cancer, offering hope for new therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Sinonasal squamous cell carcinoma (SNSCC) is a rare cancer, often developing from inverted papilloma (IP).
- The molecular drivers and effective treatments for IP-associated SNSCC (IP-SNSCC) are poorly understood.
- Limited preclinical and clinical data hinder progress in understanding and treating IP-SNSCC.
Purpose of the Study:
- To elucidate the molecular underpinnings of IP-associated SNSCC.
- To identify potential therapeutic targets for IP-SNSCC using multi-omic profiling and AI-driven analysis.
- To establish a molecular foundation for future translational research in IP-SNSCC.
Main Methods:
- Multi-omic profiling including whole-exome, RNA, and mitochondrial DNA sequencing (mtDNA-Seq) on matched sinonasal epithelium, IP, and SNSCC samples from 11 patients.
- Analysis of transcriptional changes across histological stages to identify molecular pathways involved in IP-SNSCC progression.
- Application of an AI-driven target discovery platform (PandaOmics) to identify druggable targets based on gene expression data.
Main Results:
- A stepwise transcriptional continuum was observed during IP-SNSCC development, characterized by increased cell cycle, ECM remodeling, and metabolic activity, alongside decreased immune and apoptotic signaling.
- Genomic aberrations were inconsistently shared between paired IP and SNSCC, and mitochondrial DNA mutations showed divergent evolution.
- AI analysis identified FDA-approved drug repurposing candidates (e.g., CDK6, EGFR, HDAC, SRC/YES1) and preclinical targets (e.g., AURKA, PLK4, TTK, CDK1/7).
Conclusions:
- This study defines the molecular landscape of IP-associated SNSCC, revealing key pathways driving its progression.
- It highlights the potential for drug repurposing and identifies novel preclinical targets for IP-SNSCC therapy.
- The findings provide a crucial foundation for developing targeted treatments for this rare sinonasal malignancy.
