Comprehensive multi-omic dissection and AI-prioritized target identification in inverted papilloma–associated sinonasal squamous cell carcinoma
10 affiliations
- 1Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL USA
- 2Insilico Medicine Hong Kong Hong Kong Ltd., Hong Kong Science and Technology Park, Hong Kong, China
- 3Division of Pulmonary Critical Care Medicine, Johns Hopkins University, Baltimore, MD USA
- 4Ben May Department for Cancer Research, University of Chicago, Chicago, IL USA
- 5Department of Surgery, University of Chicago, Chicago, IL USA
- 6Department of Pathology, University of Chicago, Chicago, IL USA
- 7Insilico Medicine AI Ltd., Abu Dhabi, UAE
- 8Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD USA
- 9Department of Human Genetics, University of Chicago, Chicago, IL USA
- 10Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University, Baltimore, MD 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.
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BibTeX
@article{singh2026comprehensive,
title = {{Comprehensive multi-omic dissection and AI-prioritized target identification in inverted papilloma–associated sinonasal squamous cell carcinoma}},
author = {Alka Singh and Michael Korzinkin and Viktoria Sarkisova and Ekaterina Vergasova and Ari J. Rosenberg and Karthik Suresh and Vasudha Mishra and Yuxuan Miao and Le Shen and Julia Smolik and Alexander Veviorskiy and Frank W. Pun and Xiangying Cheng and Claudia Wing and Jayant Pinto and Christopher M. Low and Mark W. Lingen and Lisa Rooper and Alexander T. Pearson and Everett E. Vokes and Xuanyao Liu and Nyall London and Alex Zhavoronkov and Nishant Agrawal and Evgeny Izumchenko},
journal = {NPJ Precision Oncology},
year = {2026},
month = jul,
doi = {10.1038/s41698-026-01599-4},
url = {https://doi.org/10.1038/s41698-026-01599-4},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Comprehensive multi-omic dissection and AI-prioritized target identification in inverted papilloma–associated sinonasal squamous cell carcinoma
AU - Alka Singh
AU - Michael Korzinkin
AU - Viktoria Sarkisova
AU - Ekaterina Vergasova
AU - Ari J. Rosenberg
AU - Karthik Suresh
AU - Vasudha Mishra
AU - Yuxuan Miao
AU - Le Shen
AU - Julia Smolik
AU - Alexander Veviorskiy
AU - Frank W. Pun
AU - Xiangying Cheng
AU - Claudia Wing
AU - Jayant Pinto
AU - Christopher M. Low
AU - Mark W. Lingen
AU - Lisa Rooper
AU - Alexander T. Pearson
AU - Everett E. Vokes
AU - Xuanyao Liu
AU - Nyall London
AU - Alex Zhavoronkov
AU - Nishant Agrawal
AU - Evgeny Izumchenko
PY - 2026
DA - 2026/07/10
JO - NPJ Precision Oncology
DO - 10.1038/s41698-026-01599-4
UR - https://doi.org/10.1038/s41698-026-01599-4
AB - 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.
SN - 2397-768X
ER -