Abstract LB299: Identification of key regulators for nuclear protein export inhibitor and chemotherapy combination in pancreatic cancer using spatial genomics approach

Abstract Background: All patients with pancreatic ductal adenocarcinoma (PDAC) experience disease progression after gemcitabine-nab-paclitaxel (GemPac) treatment with a median time to progression of just under 6 months. There is an urgent need for more effective combination therapies for this highly recalcitrant disease. Previously we showed that the selective inhibitor of nuclear export (SINE) selinexor (Sel) against XPO1 in combination with GemPac enhanced the survival of LSL-Kras G12D/+; Trp53 fl/+; Pdx1-Cre (KPC) mice. The Sel-GemPac combination also showed evaluable response in PDAC patients in a Phase I study. Here we identified key regulatory molecules involved in the synergy of the Sel-GemPac combination, utilizing KPC mouse tumors and patient biopsy samples. We also evaluated the efficacy of this combination in a Phase II study. Methods: The activity of Sel-GemPac was evaluated in KPC mouse derived 2D cell line and 3D spheroid models. RNA-seq was performed to evaluate transcriptional differences associated with synergy. The identified differentially expressed genes (DEG) were validated in vitro through siRNA mediated silencing, qPCR, cytotoxicity, and related assays. The molecular mechanism of synergy was also evaluated in KPC mice tumors and in biopsies from patients enrolled in the Phase I portion of the trial using spatial transcriptomic and proteomic analysis. The efficacy of Sel-Gem was evaluated in a Phase II study in patients with metastatic PDAC (NCT02178436). Results: In a KPC tumor derived cell line, Sel inhibited cell growth and suppressed spheroid formation. Sel synergized with GemPac (CI<1) leading to superior inhibition of cell proliferation and suppressed long term growth (colonies). GSEA of RNA-seq showed inhibition of protein transport mechanism after treatment. In spatial transcriptomic analysis, marked suppression of stroma supporting markers were observed in tumor and stromal compartments of KPC tumors. In the treated cancer and stromal cells, 197 and 42 genes were differentially expressed respectively out of a total 11,650 genes, affecting 16 pathways. The top upregulated genes included Mt2, Nrn1, Gpihbp1 and Pals2 and the top downregulated genes include Chil3, Pglyrp1, Ear10 and Prap1. In the Phase II portion of the trial, 4 patients were given Sel (60 mg oral) with Gem (1000 mg/m2 i.v.) on days 1, 8, and 15 of the 28-day cycle. One patient from Phase II showed stable reduction of tumor lesion from 38.3 × 33.2 cm (before) to 33.2 × 26.9 cm (after). The best response based on RECIST 1.1 was minus 25%. This patient had an overall survival of 16 months. In patient biopsies, spatial transcriptomic analysis of malignant ductal tissues, detected 346 and 487 DEG between a responder and a non-responder at baseline, affecting more than 29 pathways. Most important the top DEG included S100P, B2M, CXCL5 and HP. Conclusions: Collectively, our studies show that XPO1 may be a valid therapeutic target in PDAC and Sel-GemPac is a combination warranting further investigation. Citation Format: Md. Hafiz Uddin, Sahar F. Bannoura, Husain Y. Khan, Amro Aboukameel, Yiwei Li, Ibrahim Azar, Eliza W. Bael, Miguel Tobon, Donald Weaver, Steve Kim, Tanya Odisho, Amr Mohammed, Gregory Dyson, Rafic Beydoun, Ramzi M. Mohammad, Herbert Chen, Bassel El-Rayes, Philip A. Philip, Mohammad N. Al-Hallak, Asfar S. Azmi. Identification of key regulators for nuclear protein export inhibitor and chemotherapy combination in pancreatic cancer using spatial genomics approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB299.