Molecular Target Characterization and Antimyeloma Activity of the Novel, Insulin-like Growth Factor 1 Receptor Inhibitor, GTx-134

Abstract

Purpose: Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of cancers including multiple myeloma (MM). In this study, we describe GTx-134, a novel small-molecule inhibitor of IGF-1R and insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM. Experimental Design: The activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples. Downstream effector proteins and correlation with apoptosis was evaluated. Cytotoxcity in bone marrow stroma coculture experiments was assessed. Finally, the in vivo efficacy was evaluated in a human myeloma xenograft model. Results: GTx-134 inhibited the growth of 10 of 14 myeloma cell lines (<5 μmol/L) and induced apoptosis. Sensitivity to GTx-134 correlated with IGF-1R signal inhibition. Expression of MDR-1 and CD45 were associated with resistance to GTx-134. Coculture with insulin-growth factor-1 (IGF-1) or adherence to bone marrow stroma conferred modest resistance, but did not overcome GTx-134–induced cytotoxicity. GTx-134 showed in vitro synergies when combined with dexamethasone or lenalidomide. Further, GTx-134 enhanced the activity of PD173074, a fibroblast growth factor receptor 3 (FGFR3) inhibitor, against t(4;14) myeloma cells. Therapeutic efficacy of GTx-134 was shown against primary cells and xenograft tumors. Although dysregulation of glucose homeostasis was observed in GTx-134–treated mice, impairment of glucose tolerance was modest. Conclusions: These studies support the potential therapeutic efficacy of GTx-134 in MM. Further, they provide a rationale for clinical application in combination with established antimyeloma treatments and novel targeted therapies. Clin Cancer Res; 17(14); 4693–704. ©2011 AACR.

Discovery and Preclinical Characterization of Novel Small Molecule TRK and ROS1 Tyrosine Kinase Inhibitors for the Treatment of Cancer and Inflammation

“…GTx186 is an imidazo[4,5-f]isoindole derivative related to previously the disclosed novel RTKI GTx-134 [28]. To leverage the oncology, inflammatory, and nociceptive roles of TRK-A and ROS1 tyrosine kinases, we built a library of small molecules that selectively inhibits the kinases in the phylogenetic branch containing TRK-A and ROS1.…”

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

“…IGF-IR monoclonal antibodies prevent binding of the ligand to the receptor and induce receptor internalization and degradation, whereas TKIs decrease receptor activity by competing with ATP for binding the kinase domain and IGF monoclonal antibodies prevent ligand binding and activation of the receptor by neutralizing IGFs. Many of these agents have been preclinically tested in MM with very encouraging results [114, 144, 174]. Among the numerous other cancer cell lines, human MM cell lines are the most sensitive for IGF-IR inhibition [175].…”

“…Targeting the IGF-IR using picropodophyllin or the clinically relevant dual IGF-IR and IR TKI OSI-906 overcame this resistance both in vitro and in vivo [108]. Finally, Liang et al reported potent preclinical anti-myeloma activity (both as a single agent and when combined with lenalidomide or dexamethasone) for yet another novel small-molecule inhibitor of IGF-IR and IR, GTx-134 [174]. …”

Functional Investigation of IGF1R Mutations in Multiple Myeloma

“…Although IGF1R is supposed to be an important oncogene in MM and other malignant diseases [30][31][32] and promising findings were made in vitro [33][34][35][36], significant clinical responses to monotherapies with IGF1R inhibitors have not been achieved in patients [37,38]. This might be due to compensation mechanisms employing other growth factors, e.g., through the ability of IGF1R to form hybrid receptors [37][38][39].…”