Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766) in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma

Schmieder, Roberta; Puehler, Florian; Neuhaus, Roland; Kissel, Maria; Adjei, Alex A.; Miner, Jeffrey N.; Mumberg, Dominik; Ziegelbauer, Karl; Scholz, Arne

doi:10.1593/neo.13812

Cited by 55 publications

(45 citation statements)

References 33 publications

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“…A similar targeted approach is being taken with the MEK-inhibitor refametinib (BAY 86-9766) in Ras-mutated HCC. Refametinib, a highly selective and potent small molecule allosteric (non-ATP-competitive) inhibitor of MEK 1 and MEK 2, showed potent single agent antitumor activity and acted synergistically in combination with sorafenib in preclinical HCC models, albeit with potential application for only a small subgroup of HCC patients [89][90][91] . Refa- …”

Section: Treatment Of Hccmentioning

confidence: 99%

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

Deng

Zeng

Shen

2015

WJH

147

121

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Section: Treatment Of Hccmentioning

confidence: 99%

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

Deng

Zeng

Shen

2015

WJH

147

121

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“…15). Sorafenib (Nexavar Ò ; Bayer Pharma AG) is an oral multikinase inhibitor with potent activity against Raf-1 and wild-type and mutant BRAF, and with antiangiogenic activity mediated by inhibition of vascular endothelial growth factor receptors and platelet-derived growth factors (16).…”

Section: Introductionmentioning

confidence: 99%

A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer

Adjei

Richards

El-Khoueiry

et al. 2016

Clinical Cancer Research

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Purpose: To assess the safety and tolerability of the smallmolecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies.Experimental Design: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation.Results: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatmentrelated toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of $16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year.Conclusions: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368-76. Ó2015 AACR.

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“…On the other hand, brivanib, which targets VEGFR, PDGFR and FGFR, also failed to prolong OS (Table 1) in a phase III trial conducted to investigate its efficacy as a first line therapy even though it had a more favorable toxicity profile than sorafenib [89,90]. Moreover, another phase III, randomized, placebo-controlled study investigated the efficacy of brivanib after sorafenib failure and the authors reported that, in comparison to placebo, brivanib resulted in a longer median TTP but insignificant increase in the OS (Table 1) [91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108].…”

Section: Anti-angiogenic Agentsmentioning

confidence: 99%

“…Essentially, pharmacodynamic studies showed that selumetinib was able to block MEK signal ing by preventing phosphorylation of ERK and MEK [101]. On the other hand, refametinib is a potent non-ATP competitive inhibitor of MEK 1 and MEK 2 [102]. Preclinical studies have demonstrated its activity as a single agent and in combination with sorafenib.…”

Section: Mapk Inhibitorsmentioning

confidence: 99%

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

Mekuria¹,

Abdi²

2017

J Cancer Sci Ther

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Hepatocellular Carcinoma (HCC) is a common type of primary liver cancer. According to the recent world cancer report, the disease ranked as the sixth most common cancer worldwide and the third largest cause of cancer-related death. Deregulation of numerous signaling pathways have been implicate in pathogenesis of HCC, including IGF, EGF/TGF, HGF/cMet, WNT, Hedgehog, notch, hippo, VEGF, PDGF, and FGF. Besides, intracellular mediators such as MAPK and PI3K/AKT/mTOR play a role in HCC development and progression. Currently sorafenib is the only molecularly targeted drug available to treat advanced HCC. It only extends survival by a matter of months. Moreover, there is no alternative agent for patients progressing under treatment with sorafenib. Thus, there remains a critical need for both continued molecular characterization and aggressive drug development. This review provided and updated appraisal of the deregulated signaling and epigenetic pathways, targeted therapeutics that is being investigated and possible challenges in drug development for HCC. Nevertheless, c-Met over-expression was reported to be related to increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition [26]. Pathways related to neo-angiogenesisHigh vascularization is a hallmark of human HCC [8]. This angiogenesis process relies on autocrine and paracrine interactions between tumor cells, vascular endothelial cells, and pericytes. Tumor cells release pro-angiogenic factors in response to hypoxic conditions and nutrient deprivation and thus activate endothelial cells [27]. Activated endothelial cells break down extracellular matrix and basement membrane which result in a release of angiogenic factors which includes VEGF, FGF, PDGF, and TGF β [16]. These angiogenic factors in turn activate endothelial cells through TKR and their intracellular mediator's MAPK and PI3K/Akt/mTOR pathways, which lead to proliferation and migration of endothelial cells to form a new tubular structure and lumen for new vessels and finally, pericytes are activated and recruited to stabilize the new blood vessels [27,28]. has become a potential investigating area of research to identify target(s) to inhibit proliferation of HCC and metastasis. IGF pathwayThe pathway consists of circulating ligands IGF-I, IGF-II, and the receptor IGF-IR. It has been known for its involvement in the regulation of cell growth and energy metabolism [17]. According to studies, overexpression of IGF-II and IGF-IR has been implicated in cell proliferation and inhibition of apoptosis [18]. In support of this, low expression of IGF I and progressive increase in the level of expression of IGF-IR, IGF-II, and IGF substrates during the hepatocarcinogenesis process was detected at mRNA and protein level, which was associated with cell increased proliferation and reduced apoptosis has been observed in HCC cell lines and rat models as well as in human HCC samples [18]. Other studies also indicated that the major tumorpromoting e...

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Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766) in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma

Abstract: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.

Cited by 55 publications

References 33 publications

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

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