Abstract 1843: Therapeutic implication of pH/hypoxic responsive nanoencapsulated tunicamycin on pancreatic cancer by targeting K-RasG12D

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading sources of cancer mortality worldwide, including US Veterans. An initial response to chemotherapy, such as Gemcitabine (GEM) alone or in combination with other chemotherapies, is often followed by emergent resistance, reflecting an urgent need for targeted therapies. PDAC cells are highly addicted to oncogenic K-RAS mutations for their growth, progression, immunosuppression, and drug resistance, but mutant K-RAS in PDAC is still tricky to target. A glycosylation inhibitor, Tunicamycin (TM), is a potent killer of PDAC cells. However, free-form TM is found to be very toxic in in vivo implication as a therapy. To repeal the limitation of TM, we have synthesized a pH/Hypoxic-responsive iRGD-tagged biodegradable nano-encapsulated TM (NPTM) that was found to inhibit PDAC cell growth parallel with blocking K-RASG12D expression and its downstream signaling pathways associated with desmoplasia, and program cell death ligand 1 (PD-L1) expression. Moreover, NPTM markedly reduced the xenograft tumor growth, increased intratumoral CD8+ T cells, and increased in overall survival of treated mice. Furthermore, NPTM treatment synergizes with GEM to further regress PDAC growth in a PDAC xenograft model. These studies provide insights into NPTM treatment with a potential clinical application. Citation Format: Axel H. Breier, Debasmita Dutta, Anjali Kambhampati, Inamul Haque, Archana De, Sunil P. Upadhyay, Sushanta K. Banerjee, Mohiuddin Quadir, Snigdha Banerjee. Therapeutic implication of pH/hypoxic responsive nanoencapsulated tunicamycin on pancreatic cancer by targeting K-RasG12D [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 1843.