Abstract B128: Urolithin A enhances chemotherapy efficacy and preserves intestinal barrier integrity in pancreatic ductal adenocarcinoma
Varunkumar Krishnamoorthy, Vineet K. Gupta, Nitu R. Heggade, Siddharth Mehra, Sweta Ghosh, Sana I. Oroumieh, Daysi D. Manrique, Rohan Moniruzzaman, Kamalpreet K. Sandha, Sanjana Shrivatsa, Rimpi Khurana, Venkatakrishna R. Jala, Yuguang Ban, Nipun Merchant, Austin R. Dosch, Peter J. Hosein, Nagaraj NagathihalliAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) is commonly treated with standard chemotherapy regimens such as Gemcitabine/Paclitaxel (Gem+PTX) and FOLFIRINOX (FFX), which are cytotoxic agents. However, treatment-associated gastrointestinal toxicity limits dose intensity and clinical benefit. Urolithin A (UroA), a gut microbiome-derived metabolite that promotes epithelial mitochondrial fitness, is untested as a chemotherapy adjuvant in PDAC. We investigated whether UroA could improve antitumor efficacy while protecting against chemotherapy-induced intestinal injury in preclinical PDAC models.
Methods:
We used genetically engineered PKT (Ptf1a Cre/+ ; LSL-Kras G12D/+ ; Tgfbr2 flox/flox ) or orthotopically implanted KPC6694 cells in C57BL6 mice that were treated with vehicle, UroA, Gem+PTX, or (Gem+PTX)+UroA; parallel studies evaluated FFX±UroA and MRTX1133+(Gem+PTX)+UroA. Pancreatic tumor burden was quantified. Intestinal barrier function was evaluated by measuring colon length, multiplex immunofluorescence, and transepithelial electrical resistance (TEER) plus FITC-dextran permeability in 3D human EpiIntestinal organoids. GeoMx digital spatial transcriptomics was used to assess the tight junction regions. Survival was analyzed by Kaplan-Meier.
Results:
Adding UroA to Gem+PTX significantly reduced pancreatic tumor burden and increased preservation of normal pancreatic parenchyma compared with Gem+PTX alone. Similar antitumor benefits were observed in FFX-treated mice, in which UroA further enhanced therapeutic responses while improving normal pancreatic architecture. Chemotherapy shortened colons, disrupted ZO-1 continuity, and increased inflammatory cell infiltration; UroA restored colon length and ZO-1 architecture, reduced inflammatory cell infiltration, improved barrier function in human organoids as measured by TEER, and normalized FITC-dextran permeability. Colonic spatial profiling revealed UroA-associated normalization of tight junction programs and attenuation of the chemotherapy-driven inflammatory signature. Uro A and Gem+PTX improve survival when compared to mice treated with Gem+PTX alone. The addition of the clinical-stage KRAS inhibitor MRTX1133 further improved outcomes, more than doubling survival compared with Gem+PTX+UroA.
Conclusions:
Urolithin A enhances chemotherapy's antitumor activity, protects the intestinal barrier, and further extends survival when combined with KRAS inhibition, supporting UroA as a translationally ready PDAC-combination adjuvant.
Citation Format:
Varunkumar Krishnamoorthy, Vineet K. Gupta, Nitu R. Heggade, Siddharth Mehra, Sweta Ghosh, Sana I. Oroumieh, Daysi D. Manrique, Rohan Moniruzzaman, Kamalpreet K. Sandha, Sanjana Shrivatsa, Rimpi Khurana, Venkatakrishna R. Jala, Yuguang Ban, Nipun Merchant, Austin R. Dosch, Peter J. Hosein, Nagaraj Nagathihalli. Urolithin A enhances chemotherapy efficacy and preserves intestinal barrier integrity in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B128.