Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway.
Bottom Line: Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma.Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development.The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib.
Affiliation: Lilly Deutschland GmbH, Bad Homburg, Germany.
Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.
No MeSH data available.
Related in: MedlinePlus
Mentions: Since the discovery of the cytokine transforming growth factor-beta 1 (TGF-β1),1 a diverse family of ligands, corresponding receptors, and signal transduction proteins known as the TGF-β superfamily were identified (Table 1).2 Although the members of the TGF-β superfamily share genetic and protein structures, some of these members have different physiological functions and play distinct roles in diseases, including cancer (Figure 1). For example, the activin receptor-like kinase 1 (ALK1) receptor and the ALK5 receptor, also known as TGF-β receptor type I (TGF-βRI), can both promote angiogenesis but have different intracellular activation pathways with different effects on angiogenesis (for details, see the section TGF-β/ALK5 signaling pathway and its role in cancer). Here, we will focus on the role of the TGF-β/ALK5-mediated pathway and describe the experiences of developing galunisertib.
No MeSH data available.