Abstract
Abstract Pancreatic ductal adenocarcinoma (PDA) is among the most lethal tumors, with limited treatment options. The absence of reliable screening and diagnostic tools (biomarkers or procedures) significantly contributes to its poor prognosis. Biomarkers that can diagnose PDA, select optimal therapy combinations, and predict the risk of occult metastases are crucial for enhancing treatment outcomes. Previously, we identified methylation signatures capable of predicting outcomes and diagnosing PDA, focusing on genes/proteins with preclinical evidence of influencing key drugs (gemcitabine [Gem], 5-fluorouracil [5FU], oxaliplatin, cisplatin, paclitaxel, and irinotecan) used in treatment. To make these findings more clinically applicable and propose a novel approach for personalized treatment selection between Gem-based (Gem/nab-paclitaxel) and 5FU-based (FOLFIRINOX) combinations, we explored the diagnostic value of genes associated specifically with Gem and 5FU. The objective was to develop a gene signature for diagnosing PDA and aiding in treatment selection. Based on recent literature, we updated our previous gene panels (from 55 to 93 for Gem, and from 20 to 28 for 5FU). We analyzed RNA and gene expression differences between normal (NT) and PDA tissues using TNMplot.com, a web tool that leverages data from the Gene Expression Omnibus (NCBI-GEO), Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories, employing Mann-Whitney or Kruskal-Wallis tests for statistical significance. For the Gem-specific gene panel, the combined RNA expression of 90 out of 93 genes was significantly higher in PDA compared to NT (2.59, p=6.48e-61), while the combined gene expression of 80 out of 93 genes was also significantly higher in PDA tissues (1.62, p=3.48e-29). For the 5FU-specific gene panel, the combined RNA expression of 27 out of 28 genes was significantly elevated in PDA (2.00, p=5.44e-57), and the combined gene expression of 23 out of 28 genes was significantly higher in PDA tissues (1.21, p=1.44e-7). Our preliminary findings suggest that this approach has the potential to serve as an effective tool for diagnosing PDA and guiding treatment selection. However, these results must be validated through larger prospective studies. Additionally, this application could serve as a screening tool for high-risk populations, such as individuals with potentially malignant lesions like intraductal papillary mucinous neoplasms, first-degree relatives of PDA patients, or those with concerning genetic risks (e.g., BRCA1 or BRCA2 mutations). Citation Format: Harshitha Puram, Deepak Sherpally, Sravan Jeepalyam, Ashish Manne. Advanced Gene Signatures for the Diagnosis and Personalized Treatment of Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A013.
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