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Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth
Stephan Herbertz1, J Scott Sawyer2, Anja J Stauber2
1Lilly Deutschland GmbH, Bad Homburg, Germany.
Abstract:
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.
Insights
Transforming growth factor-beta (TGF-β) is crucial in cancer. Galunisertib, a TGF-β inhibitor, shows antitumor activity but requires careful dosing to manage toxicity in clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Transforming growth factor-beta (TGF-β) signaling is integral to biological processes and cancer progression.
- TGF-β contributes to tumor proliferation, invasion, metastasis, angiogenesis, and immune evasion.
- Pharmacological strategies to inhibit TGF-β signaling are actively explored for cancer therapy.
Purpose of the Study:
- To review pharmacological treatments for blocking TGF-β signaling.
- To highlight the development and clinical investigation of galunisertib, a TGF-β receptor I kinase inhibitor.
- To summarize experiences enabling galunisertib's use in cancer patients.
Main Methods:
- Galunisertib inhibits TGF-β receptor I kinase, downregulating SMAD2 phosphorylation and canonical pathway activation.
- Antitumor activity of galunisertib was demonstrated in preclinical animal models.
- Pharmacokinetic/pharmacodynamic (PK/PD) modeling was employed to establish a safe and effective dosing strategy.
Main Results:
- Galunisertib exhibits antitumor effects in various cancer models.
- PK/PD modeling identified a therapeutic window and informed an intermittent dosing regimen (14 days on/14 days off).
- This strategy mitigated cardiac toxicities observed with continuous exposure, facilitating clinical trials.
Conclusions:
- Galunisertib is a promising TGF-β inhibitor investigated in clinical trials for cancers with high unmet needs.
- An intermittent dosing regimen, guided by PK/PD modeling, is crucial for its safe and effective clinical application.
- The review consolidates knowledge on pharmacological interventions that support galunisertib's development in oncology.
