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.
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Mentions: In the early 1980s, TGF-β was biochemically isolated from tumor cells and was named after its ability to transform normal rat kidney fibroblasts.1 This approximately 13 kDa polypeptide was later designated as TGF-β1.3 TGF-β ligands include TGF-β1, TGF-β2, and TGF-β3 (Table 1), all of which regulate diverse biological functions.4,5 All three ligands can independently engage the specific receptor TGF-βRI/ALK5, which then undergoes dimerization with TGF-β receptor type II (TGF-βRII).6 Recent studies have shown that two TGF-β ligand molecules bind as homodimers to two TGF-βRI and two TGF-βRII molecules (ie, a homodimer bound to a heterotetramer), creating a heterodimer complex consisting of six distinct molecules.7 For simplicity reasons, figures often do not show the duplicity of the heterodimer (Figure 2). This heterodimer complex phosphorylates the intracellular proteins SMAD2 and SMAD3, activating a signaling cascade to induce several nuclear transduction proteins. The induction of these proteins leads to cellular proliferation, differentiation, motility, survival, and apoptosis in tumor cells.8 This TGF-β/ALK5 signaling pathway is commonly referred to as the canonical signaling pathway (Figure 1). In addition to this canonical pathway, a number of accessory receptors have been identified, which can separately interact with the TGF-RI and TGF-RII. One example is the TGF-βRIII, to which the glycoprotein endoglin (CD105) can bind with high affinity.9
No MeSH data available.