Pharmacodynamic monitoring of BAY 43‐9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells

Tong, Frances; Chow, Sue; Hedley, David W.

doi:10.1002/cyto.b.20092

Cited by 52 publications

(41 citation statements)

References 20 publications

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“…Due to the small number of patients with dose‐limiting toxicities reported in our original clinical trial,9 we were unable to perform an exposure‐toxicity assessment. However, in accordance with previously reported clinical trials in patients with AML, a lower dose of sorafenib is associated with enhanced tolerability 19, 20. Recently, another observational study has shown that sorafenib‐related adverse events were associated with a relatively higher exposure of the N‐oxide metabolite after 400 mg b.i.d.…”

Section: Discussionsupporting

confidence: 85%

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

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Sorafenib administered at the approved dose continuously is not tolerated long‐term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure‐response relationship in patients with AML. A one‐compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS‐like tyrosine kinase 3 (FLT3)‐ITD and extracellular signal‐regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax) model. Sorafenib could inhibit FLT3‐ITD activity by 100% with an IC50 of 69.3 ng/mL and ERK activity by 84% with an IC50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure‐response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3‐ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML.

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Section: Discussionsupporting

confidence: 85%

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

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“…Moreover, control cells were completely insensitive to the inhibitor (James et al, 2003). A phase I clinical trial addressed the question of efficacy of Sorafenib (BAY43-9006), a Raf-1 kinase inhibitor, in AML patients (Tong et al, 2006).…”

Section: Ras/raf/mek/erkmentioning

confidence: 99%

Targeting receptor tyrosine kinase signaling in acute myeloid leukemia

Doepfner¹,

Boller²,

Arcaro³

2007

Critical Reviews in Oncology/Hematology

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Targeting receptor tyrosine kinase signaling in acute myeloid leukemia The main goal of this work was therefore aimed at gaining deeper insight into RTK signaling in a panel of AML cell lines and patient blast cells. A broad potein expression analysis was set up in order to identify cancer-specific expression patterns of signaling molecules and to uncover potential molecular targets. Using different approaches the molecular function and the feasibility of targeting the candidate proteins was investigated. Novel specific inhibitors were tested and neutralizing antibodies and RNA interference (RNAi) were used to block or down-regulate the individual proteins. Our study of the IGF-IR/PI3K signaling system in AML cells uncovered a novel role for autocrine IGF-I signaling in the growth and survival of these cancer cells. Besides, we could show that targeting this signaling branch in combination with commonly used chemotherapeutical agents represents an interesting novel approach for AML therapy.As protein expression analysis revealed highly variable expression levels of the mammalian target of rapamycin (mTOR) in the panel of cells analyzed, further interest was laid on the role of mTOR in AML. Cells expressing low levels of mTOR were compared to cells expressing high levels of this protein and a siRNA screen was aimed at uncovering human kinases that modulate the sensitivity to the mTOR inhibitor rapamycin. Preliminary results suggest that mTOR plays a crucial role in cell growth and survival in a subset of AML cells and that rapamycin in combination with certain RTK or Syk/ZAP70 inhibitors has potential for AML therapy. In summary, our study of the RTK/PI3K signaling system in distinct human cancers has provided novel insights into the importance and the complexity of this network for tumor growth and survival. Moreover, the analysis of specific components of this crucial signaling network has uncovered potential molecular targets for future cancer therapy.

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“…Indeed, voices were raised against the use of sorafenib for the treatment of immunogenic tumors or the use of sorafenib in combination with The measure of PMA-induced ERK phosphorylation in PBLs has been suggested to be a useful biomarker for measuring and predicting the effects of sorafenib (12). In this respect, Tong et al reported that ERK phosphorylation on PMA treatment was not affected in PBLs from sorafenibtreated patients (13); others, however, observed a complete loss of phospho-ERK inducibility on sorafenib treatment (14). Our presented data support the latter finding because sorafenib concentrations comparable with patient's plasma levels efficiently inhibited ERK phosphorylation on PMA treatment.…”

Section: Discussionmentioning

confidence: 99%

“…To date, it is still unclear whether PMA induced ERK phosphorylation in T lymphocytes is impaired in patients treated with sorafenib. Indeed, contradictory reports have been published (13,14). Therefore, we analyzed the level of ERK phosphorylation in PBLs following PMA stimulation in the presence of 1, 5, and 25 Ag/mL sorafenib corresponding to 2.15, 10.75, and 53.75 Amol/L, respectively.…”

Section: Inhibition Of Pma-stimulated Induction Of Erk Phosphorylatiomentioning

confidence: 99%

“…At present, the multikinase inhibitor sorafenib is evaluated for the treatment of a wide variety of cancers either as monotherapy or in combinations in >100 different clinical trials. 1 In this context, it has been suggested that phospho-ERK in peripheral blood lymphocytes (PBL) may be a useful biomarker for measuring and predicting the effects of sorafenib (12,13). In this respect, a lost ability to stimulate ERK phosphorylation by phorbol myristate acetate (PMA) in PBLs of patients under sorafenib has been reported (14).…”

Section: Introductionmentioning

confidence: 99%

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MAPK-independent impairment of T-cell responses by the multikinase inhibitor sorafenib

Houben

Voigt

Noelke

et al. 2009

Molecular Cancer Therapeutics

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Sorafenib, originally developed as CRAF inhibitor but soon recognized as a multikinase inhibitor, is currently widely tested for the treatment of different cancers either alone or in combination therapy. However, the clinical success, particularly in immunogenic tumors such as melanoma, was less than anticipated. Because T-cell activation is tightly regulated by a multitude of kinases, we scrutinized effects of sorafenib on immune responses. To this end, comprehensive in vitro studies revealed that the presence of sorafenib concentrations comparable with observed plasma levels in patients strongly impairs the activation of T cells. Notably, even established tumor-specific immune responses are influenced by sorafenib. Indeed, ELISPOT data of peripheral blood lymphocytes obtained from melanoma patients vaccinated against survivin show markedly diminished survivin-specific immune responses in the presence of sorafenib. Surprisingly, inhibition of T-cell activation was not associated with reduced extracellular signal-regulated kinase phosphorylation. In fact, on T-cell receptor stimulation phospho-extracellular signalregulated kinase and phospho-mitogen-activated protein kinase kinase levels were found to be elevated in the presence of sorafenib, showing the complexity of signal transduction events following T-cell receptor stimulation. In conclusion, our data show that T-cell function is sensitive toward the multikinase inhibitor sorafenib in a mitogen-activated protein kinase-independent fashion. This observation has important implications for the use of sorafenib as therapy for immunogenic cancers.

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Pharmacodynamic monitoring of BAY 43‐9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells

Cited by 52 publications

References 20 publications

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Targeting receptor tyrosine kinase signaling in acute myeloid leukemia

MAPK-independent impairment of T-cell responses by the multikinase inhibitor sorafenib

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