Abstract 3647: Targeting cancer-induced anemia with hepcidin lowering ALK2 inhibitors

Abstract

Abstract Anemia of cancer (AOC) is a cytokine driven condition that frequently occurs in patients due to chronic inflammation associated with cancer development. It differs from chemotherapy-induced anemia because the anemia is a result of the disease itself and not a side effect of a treatment regimen, although the both causes can work in concert. AOC is caused by high levels of the liver peptide hormone, hepcidin, which sequesters iron in epithelial cells and macrophages, thereby limiting bioavailable iron required for erythropoiesis. Reducing elevated hepcidin levels in cancer patients can reverse the hypoferremia and anemia seen in AOC. Hepcidin levels are controlled by inflammatory cytokines through pathways dependent on bone morphogenetic proteins (BMP). BMPs up-regulate hepcidin by activating the SMAD signaling pathway through the activin-like kinase receptor 2 (ALK2). Therefore, ALK2 has emerged as an attractive therapeutic target to modulate hepcidin levels in cancer patients and treat their AOC. We have developed novel small molecule ALK2 inhibitors which have shown promising results in tissue culture models as well as a preclinical cancer model of AOC. The two most promising compounds downregulate hepcidin expression in BMP-induced cell culture studies at concentrations of 100 nM or lower. Importantly, this activity was observed at concentrations that exhibited little cytotoxicity suggesting the compounds have a clean selectivity profile. The two compounds have been tested in a TC-1 syngeneic mouse model of AOC where anemia is induced after tumor formation, in a manner similar to human cancer caused anemia. Treatment with the lead candidates reversed the induction of hepcidin expression and also decreased the symptoms of anemia as measured by serum iron and red blood cell levels. From these data, we have nominated a candidate to advance into IND-enabling studies that has favorable drug-like properties. We anticipate a clinical development strategy that focuses on AOC. Citation Format: Peter W. Peterson. Targeting cancer-induced anemia with hepcidin lowering ALK2 inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3647. doi:10.1158/1538-7445.AM2015-3647