Brain perfusion and permeability in patients with advanced, refractory glioblastoma treated with lomustine and the transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate

Sepúlveda‐Sánchez, Juan Manuel; Ramos, Ana; Hilario, Amaya; Velasco, Guillermo de; Castellano, Daniel; Torre, Marta García de la; Rodón, Jordi; Lahn, Michael

doi:10.3892/ol.2015.3106

Cited by 7 publications

(6 citation statements)

References 34 publications

(29 reference statements)

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“…Traditionally, TGF-β 2 has been the preferred isoform for its role in glioma genesis and clinical trials specifically targeting this isoform have been carried out [ 25 ]. However, this treatment strategy seems to have lost the interest of researchers to the benefit of LY2157299, a TGF-β receptor 1 kinase inhibitor, which has yet to prove its efficiency ( identifier NCT01220271) [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Differential Expression and Clinical Significance of Transforming Growth Factor-Beta Isoforms in GBM Tumors

Roy

Poirier

Fortin

2018

IJMS

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Glioblastoma (GBM) represents the most common and aggressive malignant primary brain tumors in adults. Response to standard treatment is transitory and the survival of clinical trial cohorts are little more than 14 months. GBM are characterized by excessive proliferation, invasiveness, and radio-/chemoresistance features; which are strongly upregulated by transforming growth factor-beta (TGF-β). We hypothesized that TGF-β gene expression could correlate with overall survival (OS) and serve as a prognostic biomarker. TGF-β1 and -β2 expression were analyzed by qPCR in 159 GBM tumor specimens. Kaplan–Meier and multivariate analyses were used to correlate expression with OS and progression-free survival (PFS). In GBM, TGF-β1 and -β2 levels were 33- and 11-fold higher respectively than in non-tumoral samples. Kaplan–Meier and multivariate analyses revealed that high to moderate expressions of TGF-β1 significantly conferred a strikingly poorer OS and PFS in newly diagnosed patients. Interestingly, at relapse, neither isoforms had meaningful impact on clinical evolution. We demonstrate that TGF-β1 is the dominant isoform in newly diagnosed GBM rather than the previously acknowledged TGF-β2. We believe our study is the first to unveil a significant relationship between TGF-β1 expression and OS or PFS in newly diagnosed GBM. TGF-β1 could serve as a prognostic biomarker or target affecting treatment planning and patient follow-up.

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Section: Discussionmentioning

confidence: 99%

Differential Expression and Clinical Significance of Transforming Growth Factor-Beta Isoforms in GBM Tumors

Roy

Poirier

Fortin

2018

IJMS

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“…Also, in two patients with radiographic responses, a site-specific imaging study found that tumor blood flow was changed, similar to that seen with antiangiogenic agents. 104 However, compared with other antiangiogenic drugs, the blood flow changes occurred at a later time.…”

Section: Fhd Study and Early Clinical Development Of Galunisertib In mentioning

confidence: 99%

Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway

Herbertz

Sawyer

Stauber

et al. 2015

DDDT

276

120

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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.

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“…The small molecule inhibitor (SMI) galunisertib (LY2157299 monohydrate) showed anti-tumor effects in glioblastoma animal models and also in patients [ 10 , 11 , 12 , 13 , 14 , 15 ]. Galunisertib targets the serine-threonine kinase of the TGF-βRI and abrogates the phosphorylation of SMAD2, the initial intracellular protein of the TGF-β signaling pathway [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine

Capper

Deimling

Brandes

et al. 2017

IJMS

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Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2+ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H+ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3+ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4+ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker.

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Brain perfusion and permeability in patients with advanced, refractory glioblastoma treated with lomustine and the transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate

Cited by 7 publications

References 34 publications

Differential Expression and Clinical Significance of Transforming Growth Factor-Beta Isoforms in GBM Tumors

Differential Expression and Clinical Significance of Transforming Growth Factor-Beta Isoforms in GBM Tumors

Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway

Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine

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