Abstract 1604: Homeobox transcription regulatory gene HOXA10 in pancreatic cancer treatment response

Abstract Gemcitabine/nab-paclitaxel (GnP) or FOLFIRINOX (FFX) are recommended guidelines for use as first line regimens for pancreatic ductal adenocarcinoma (PDAC) patients. Use of FFX is usually limited to a small subset of younger, fit patients with minimal comorbidities. This underscores the need to focus on efforts to test and develop effective regimens that can be used in a wide range of patients due to potentially minimal toxicity profile and cost. We identified palmatine, a protoberberine alkaloid fulfilling the Lipinski’s 5-rule as a potential candidate drug. We show that relative to gemcitabine, palmatine in combination with gemcitabine was more effective against a panel of human PDAC cultured cells, human ex vivo cultured cells, and human PDAC organoid models. Furthermore, repeated measures linear model changes in bioluminescence at the time of termination from baseline (Log10), showed that gemcitabine alone and in combination with palmatine resulted in significant reduction of tumor burden relative to control KPC orthotopic syngeneic mouse model of PDAC. The combination was tolerated well by the animals. Bulk RNA-sequencing from tumors treated with combination showed that expression of Hoxa10 was significantly reduced. Gene-set enrichment analysis further showed enrichment of B-cell receptor signaling in responding relative to non-responding mice. Spatial transcriptomic analyses of responding and non-responding tumors showed that expression of Hoxa10 was found in the mesenchymal cell population and that HoxA10 expression correlated with differentially expressed genes in B cell population. Exploration of tumor immune microenvironment (TIME) using CellScape revealed increased density of B-cells and decreased regulatory T-cells (Tregs) in tumors from responding but not non-responding mice. The HOXA10-associated gene signature is reported to be prognostic for survival. Recent evidence shows that HOXA10 expression correlates differentially with immune cell populations. We found CD274 (PD-L1), IFNGR1, NFκB1 and STAT3 as potential HOXA10 targets based on ChIP-seq data with HOXA10 pull-down from ENCODE project. In silico analysis of the pancreatic cancer database shows that HOXA10 expression is elevated in human pancreatic tumors and that high expression is associated with increased survival. HOXA10, the homeobox transcription regulatory gene is involved in multiple roles in cancer including cell survival, epithelial mesenchymal transition (EMT), cancer progression, metastasis, and therapeutic resistance and in the context of PDAC it also promotes stromal cell proliferation. Taken together, these findings suggest the potential utility of palmatine in therapeutic sensitization of gemcitabine through deregulation of HOXA10 signaling. Supported in part through VA Merit Award BX003876 (APK). Citation Format: Addanki Pratap Kumar, Amanda Munoz, Xiaoyu Yang, Meagan Marie Ybarra, Joel Michalek, Shaye Hagler, John Baer, Ramya Chengalvala, Sukeshi A. Patel, Danielle Fritze, Glenn Halff, Zhao Lai, Yuji Ikeno, Yidong Chen, Rita Ghosh. Homeobox transcription regulatory gene HOXA10 in pancreatic cancer treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1604.