Abstract C45: NT219, a novel bispecific inhibitor of STAT3 and IRS1/2, combined with chemotherapy or MEK inhibitor in gemcitabine-resistant pancreatic tumors, induced tumor regression

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, with poor outcome of current treatments. Major contributors to therapeutic resistance in PDAC include Kras mutations, a dense desmoplastic stroma, and activation of feedback signaling pathways. STAT3 and Insulin Receptor Substrate 1/2 (IRS1/2) regulate tumor survival and metastasis, the crosstalk of the tumor and its microenvironment, and play major role in drug resistance. NT219 is a novel bispecific inhibitor of IRS1/2 and STAT3, leading to IRS1/2 elimination and STAT3 dephosphorylation. The purpose of this study was to assess NT219 activity in PDAC PDX models and define schedule and regimens and combinations to overcome resistance to optimize future clinical protocols. Methods: Patient-derived tumor xenograft (PDX) models of mutated KRAS pancreatic cancer were used to test the efficacy of NT219 in combination with gemcitabine, trametinib, and folfirinox. RNAseq was used to analyze the pharmacodynamic effect of NT219. Pharmacokinetic profile of NT219 was tested. Results: Chemoresistent tumors of 4 PDAC PDX models were exposed to NT219 with gemcitabine demonstrated reversal of pre-existing resistance. One of these models demonstrated complete response in 5 out of 10 mice upon addition of NT219 to gemcitabine. Similar results were observed when NT219 was combined with trametinib (a MEK inhibitor) and with folfirinox (chemotherapy). There was a correlative dose-escalation response of both plasma and tumor levels and the therapeutic effect. NT219 delivered prior to gemcitabine showed a much better response than the inverse schedule/drug administration. RNAseq analysis of the tumors revealed that the combined treatment with NT219 and gemcitabine lowered the levels of IRS1 to 20% of the control group. Similar reductions were observed for STAT3-regulated genes, as well as for Ki67 (a proliferation marker), cyclin D (prognostic marker), and TGFβ (driver of epithelial to mesenchymal transition). Conclusion: NT219 overcomes gemcitabine acquired resistance in PDAC. The combination of NT219 with modern chemotherapy in pancreatic cancer may enhance efficacy and delay acquired resistance in this fatal disease. Citation Format: Hadas Reuveni, Lana Kupershmidt, Neta Moskovits, Evgeny Solomonov, Salomon M Stemmer, Izhak Haviv. NT219, a novel bispecific inhibitor of STAT3 and IRS1/2, combined with chemotherapy or MEK inhibitor in gemcitabine-resistant pancreatic tumors, induced tumor regression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C45.