First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway

Hagel, Margit; Miduturu, Chandra; Sheets, Michael P.; Rubin, Nooreen; Weng, Weifan; Stransky, Nicolas; Bifulco, Neil; Kim, Joseph L.; Hodous, Brian L.; Brooijmans, Natasja; Shutes, Adam; Winter, Christopher; Lengauer, Christoph; Kohl, Nancy E.; Guzi, Timothy J.

doi:10.1158/2159-8290.cd-14-1029

Cited by 271 publications

(302 citation statements)

References 35 publications

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“…This includes AZD4547 , BGJ398 (Guagnano et al, 2011), LY2874455 (Zhao et al, 2011), TAS-120 (Ochiiwa et al, 2014), ARQ 087 (Dransfield et al, 2014), PD 173074 (Dimitroff et al, 1999), JNJ-42756493 (Tabernero et al, 2015), BLU9931 (Hagel et al, 2015), DEBIO 1347 (Nakanishi et al, 2014), FGF401 (Repana et al, 2015) and BAY-1163877 (Heroult et al, 2014). Due to the large amount of drugs we will only focus on those who are being evaluated in clinical trials (Table 2).…”

Section: Selective Fgfr Tkismentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

179

162

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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Section: Selective Fgfr Tkismentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

179

162

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“…Hagel and colleagues ( 2 ) report the design and the activity of an FGFR4-specifi c inhibitor, BLU9931, in several models of hepatocellular carcinoma (HCC). This group utilized structure-based drug design to create a compound that binds covalently to Cys552 in the hinge region of FGFR4.…”

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confidence: 99%

Paralog-Specific Kinase Inhibition of FGFR4: Adding to the Arsenal of Anti-FGFR Agents

Packer

Pollock

2015

Cancer Discovery

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Summary:In this issue of Cancer Discovery , Hagel and colleagues report the design and the in vitro and in vivo activity of a novel, irreversible, paralog-specifi c kinase inhibitor of FGFR4, BLU9931. This compound binds covalently to a cysteine residue in the hinge region of FGFR4 but not in FGFR1-3. BLU9931 induces tumor shrinkage in hepatocellular carcinoma models that express a functioning ligand/receptor complex consisting of FGF19/ FGFR4/KLB and adds to a growing list of anti-FGFR4 agents. Cancer Discov; 5(4); ©2015 AACR . Hagel et al., p. 424 (2). See related article byAlongside the identifi cation of cancers driven by FGFR activation, the past few years have delivered multiple second-and third-generation anti-FGFR agents. These include inhibitors with greater selectivity (e.g., AZD4547 and NVP-BGJ398), irreversible FGFR kinase inhibitors (FIIN-1, FIIN-2), mAbs specifi c to each family member (FGFR1-4), as well as allosteric inhibitors targeting the extracellular domain that inhibit receptor internalization (SSR128129E). With respect to the competitive kinase inhibitors, the search for greater FGFR selectivity was driven, to some extent, by the desire to reduce toxicity associated with VEGFR2 inhibition. However, the selection against VEGFR2 was accompanied by a loss of selectivity against FGFR4. As a result, almost all the competitive FGFR kinase inhibitors currently in phase I/II trials (AZD4547, NVP-BGJ398, JNJ-42756493, BAY1163877, Debio 1347, and LY2874455) show at least a 4-fold greater selectivity toward FGFR1-3 over FGFR4 ( 1 ).Hagel and colleagues ( 2 ) report the design and the activity of an FGFR4-specifi c inhibitor, BLU9931, in several models of hepatocellular carcinoma (HCC). This group utilized structure-based drug design to create a compound that binds covalently to Cys552 in the hinge region of FGFR4. This cysteine is unique to FGFR4, as FGFR1-3 possess a bulky tyrosine residue that clashes with BLU9931. As a result of modifying Cys552, BLU9931 is a potent and selective FGFR4 inhibitor (IC 50 = 3 nmol/L) with only weak activity against FGFR1-3 (IC 50 values range from ∼150 to 600 nmol/L). Furthermore, BLU9931 was unable to inhibit the six other kinases that also have a cysteine at the corresponding position within the hinge region.The group at Blueprint Medicines shows that BLU9931 inhibits FGFR4 and blocks phosphorylation of its substrates FRS2α, MAPK, and AKT at 10 to 30 nmol/L in the MDA-MB-453 breast cancer cell line carrying an activating Y367C mutation in FGFR4 , but not in DMS-11 lung cancer cells carrying amplifi cation of FGFR1 . With regard to HCC, they confi rmed previous reports with pan-FGFR inhibitors showing only cells expressing a fully functional receptor complex comprised of FGFR4, its coreceptor Klotho-β (KLB), and FGF19 respond to BLU9931 ( 3 ). Of the 11 HCC cell lines they tested, 4 cell lines expressed all three components, and 3 of these, all with FGF19 amplifi cation, were sensitive to BLU9931. The authors report that twice-daily 30-mg/kg doses led to tumor shrink...

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“…The blood supply will change, followed by increased nodular arterial blood supply and decreased portal vein blood supply. If there are no more new blood vessels, the tumor diameter will not be more than 3 mm, eventually developing into SHCC (14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

Study on the diagnosis of small hepatocellular carcinoma caused by hepatitis B cirrhosis via multi‑slice spiral CT and MRI

et al. 2017

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Abstract. The present study compared the diagnostic accuracy of multi-slice spiral computed tomography (CT) and magnetic resonance imaging (MRI) on small hepatocellular carcinoma (SHCC) caused by hepatitis B cirrhosis. A total of 160 patients with hepatitis B cirrhosis were selected between January 2012 and April 2016, and 183 SHCC lesions were included in the present retrospective study. Patients were divided into the SHCC group (T stage) and the micro hepatocellular carcinoma (MHCC) group (T1 stage). There were a total of 129 SHCC lesions and 54 MHCC lesions identified. All patients underwent multiphasic CT and MRI imaging. The liver acquisition with volume acquisition (LAVA) technique was utilized for MRI. Furthermore, SPSS 20.0 was used for statistical analyses. LAVA in the arterial phase and CT in the arterial phase revealed significantly higher diagnostic rates for the diagnoses of 183 lesions. In addition, standard CT scan exhibited significantly reduced diagnostic rates in SHCC lesions. Results indicated that LAVA in the equilibrium phase had the lowest diagnostic rate in MHCC lesions, which was statistically significant (P<0.05). Overall, the diagnostic rate of CT (79.63%) for MHCC was significantly lower than that of MRI (96.29%) (P<0.05). However, the diagnostic rate of CT for SHCC (96.12%) was significantly higher than that for MHCC (79.63%) (P<0.05). MRI-LAVA in the arterial phase has the highest diagnostic rate for SHCC and MHCC. However, the diagnostic capability of MRI for MHCC lesions is superior to that of CT. IntroductionLiver cancer is one of the most common malignant tumors of the digestive system. It has high incidence rates and ranks second in cancer mortality in China (1). It has multiple causes, such as liver cirrhosis, viral infection, chemical carcinogens, alcohol and tobacco, water pollution, and genetic factors (2). Liver cancer caused by hepatitis B infection and cirrhosis is highly prevalent, although it lacks the typical clinical manifestations of liver cancer Moreover, it is particularly important to improve the diagnostic rate of early liver cancer (3). The clinical diagnosis of the hepatocellular cancer involves multiple approaches. Important clinical symptoms like abdominal distension, liver pain, fever, emaciation, debilitation, and jaundice confirms the middle and advanced stage of the disease. The clinically well-established factor being utilized for liver cancer is cirrhosis (4). The diagnosis of hepatocellular carcinoma could frequently, and uniquely, be made on characteristic multiphase contrast based cross-sectional imaging rather than strict need for tissue sampling. Epigentics is another new area showing good potential in clincal diagnosis of liver cancer. Promising results from microRNA (miRNA/miR) profiling and hypermethylation of selected genes have raised hopes of identifying new biomarkers (5). Furthermore, miR-122, a completely conserved liver-specific miRNA in vertebrates, is essential for the maintenance of liver homeostasis. miR-122 is also being explored for...

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First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway

Cited by 271 publications

References 35 publications

FGFR a promising druggable target in cancer: Molecular biology and new drugs

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Paralog-Specific Kinase Inhibition of FGFR4: Adding to the Arsenal of Anti-FGFR Agents

Study on the diagnosis of small hepatocellular carcinoma caused by hepatitis B cirrhosis via multi‑slice spiral CT and MRI

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