Pharmacological Inhibition of Insulin Growth Factor-1 Receptor (IGF-1R) Alone or in Combination With Ruxolitinib Shows Therapeutic Efficacy in Preclinical Myeloproliferative Neoplasm Models

Titiksha Basu; Hannah Bertrand; Nikolaos Karantzelis; Albert Gründer; Heike L Pahl

doi:10.1097/HS9.0000000000000565

Pharmacological Inhibition of Insulin Growth Factor-1 Receptor (IGF-1R) Alone or in Combination With Ruxolitinib Shows Therapeutic Efficacy in Preclinical Myeloproliferative Neoplasm Models

Hemasphere. 2021 Apr 30;5(5):e565. doi: 10.1097/HS9.0000000000000565. eCollection 2021 May.

Authors

Titiksha Basu¹, Hannah Bertrand¹, Nikolaos Karantzelis¹, Albert Gründer¹, Heike L Pahl¹

Affiliation

¹ Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Germany.

Abstract

Even after development of the JAK1/JAK2 inhibitor ruxolitinib, myeloproliferative neoplasm (MPN) patients require novel therapeutic options. While ruxolitinib can considerably improve quality of life and prolong survival, it does not modify the natural disease course in most patients. Moreover, resistance develops with prolonged use. Therefore, various combination treatments are currently being investigated. Published data provide a compelling rationale for the inhibition of insulin growth factor-1 receptor (IGF-1R) signaling in MPN. Here we report that genetic and pharmacological inhibition of IGF-1R selectively reduced Jak2^V617F-driven cytokine-independent proliferation ex vivo. Two different structurally unrelated IGF-1R inhibitors ameliorated disease phenotype in a murine MPN model and significantly prolonged survival. Moreover, in mice, low-dose ruxolitinib synergized with IGF-1R inhibition to increase survival. Our data demonstrate preclinical efficacy of IGF-1R inhibition in a murine MPN model.