ly-2157299 and Heart-Diseases

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.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Discovery; Heart Diseases; Molecular Structure; Molecular Targeted Therapy; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad2 Protein; Treatment Outcome; Xenograft Model Antitumor Assays

Transforming growth factor-beta (TGF-β) signaling plays an important role in the fetal development of cardiovascular organs and in the repair mechanisms of the heart. Hence, inhibitors of the TGF-β signaling pathway require a careful identification of a safe therapeutic window and a comprehensive monitoring of the cardiovascular system. Seventy-nine cancer patients (67 glioma and 12 solid tumor) enrolled in a first-in-human dose study and received the TGF-β inhibitor LY2157299 monohydrate (LY2157299) as monotherapy (n = 53) or in combination with lomustine (n = 26). All patients were monitored using 2D echocardiography/color and Spectral Doppler (2D Echo with Doppler) every 2 months, monthly electrocardiograms, thorax computer tomography scans every 6 months, and monthly serum brain natriuretic peptide (BNP), troponin I, cystatin C, high-sensitivity C-reactive protein (hs-CRP). Administration of LY2157299 was not associated with medically relevant cardiovascular toxicities, including patients treated ≥6 months (n = 13). There were no increases of troponin I, BNP, or hs-CRP or reduction in cystatin C levels, which may have been considered as signs of cardiovascular injury. Blood pressure was generally stable during treatment. Imaging with echocardiography/Doppler showed an increase in mitral and tricuspid valve regurgitation by two grades of severity in only one patient with no concurrent clinical symptoms of cardiovascular injury. Overall, this comprehensive cardiovascular monitoring for the TGF-β inhibitor LY2157299 did not detect medically relevant cardiac toxicity and hence supports the evaluation of LY2157299 in future clinical trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Blood Pressure; Echocardiography, Doppler; Electrocardiography; Female; Heart Diseases; Humans; Lomustine; Male; Middle Aged; Neoplasms; Prospective Studies; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Risk Assessment; Risk Factors; Signal Transduction; Spain; Time Factors; Treatment Outcome; Young Adult

Cardiac fibrosis is a significant component of pathological heart remodeling, yet it is not directly targeted by existing drugs. Systems pharmacology approaches have the potential to provide mechanistic frameworks with which to predict and understand how drugs modulate biological systems. Here, we combine network modeling of the fibroblast signaling network with 36 unique drug-target interactions from DrugBank to predict drugs that modulate fibroblast phenotype and fibrosis. Galunisertib was predicted to decrease collagen and α-SMA expression, which we validated in human cardiac fibroblasts. In vivo fibrosis data from the literature validated predictions for 10 drugs. Further, the model was used to identify network mechanisms by which these drugs work. Arsenic trioxide was predicted to induce fibrosis by AP1-driven TGFβ expression and MMP2-driven TGFβ activation. Entresto (valsartan/sacubitril) was predicted to suppress fibrosis by valsartan suppression of ERK signaling and sacubitril enhancement of PKG activity, both of which decreased Smad3 activity. Overall, this study provides a framework for integrating drug-target mechanisms with logic-based network models, which can drive further studies both in cardiac fibrosis and other conditions.

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Animals; Arsenic Trioxide; Biphenyl Compounds; Computer Simulation; Drug Combinations; Fibroblasts; Fibrosis; Heart Diseases; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Models, Animal; Network Pharmacology; Pyrazoles; Quaternary Ammonium Compounds; Quinolines; Rats; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad3 Protein; Thioctic Acid; Valsartan