Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation

Hall, T.M.T.; Yu, Yi; Eathiraj, Sudharshan; Wang, Yunxia; Savage, Ronald E.; Lapierre, Jean‐Marc; Schwartz, Brian; Abbadessa, Giovanni

doi:10.1371/journal.pone.0162594

Cited by 76 publications

(69 citation statements)

References 54 publications

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“…Preclinical activity of ARQ-087 was tested in a group of different cancers cell lines showing positive relation between ARQ-087 concentration and cancer cell death (Hall et al, 2016). Currently there are not a lot of data on this drug but the latest studies have shown specific activity inducing cell cycle arrest and apoptosis correlated to the level of FGFR2, a clinical development plan including a patient selection strategy is defined and the drug is currently in a Phase I/II clinical trial (NCT01752920).…”

Section: Arq-087mentioning

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

177

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: Arq-087mentioning

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

177

162

View full text Add to dashboard Cite

show abstract

“…Preclinical and phase I studies have suggested that these compounds have potent and selective anti-tumor activity against FGFRmutated cancers (80)(81)(82)(83). A recently developed monoclonal antibody against FGFR2 (BAY1179470) showed tumor suppressive potential in tumors with high FGFR2 expression (84).…”

Section: Fgfr2 Fusionsmentioning

confidence: 99%

Current biologics for treatment of biliary tract cancers

Zhao

Lim

2017

J. Gastrointest. Oncol.

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Biliary tract cancers (BTC) is a group of malignancies that arise from the epithelial cells of the biliary tree. These cancers are typically classified by anatomic site of origin: intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). To date, complete surgical resection remains the mainstay of treatment especially for earlier stage disease. Unfortunately, most patients present with advanced or metastatic disease, when systemic chemotherapy is the only treatment option. Due to the paucity of effective treatments, BTCs have a dismal prognosis. There is a tremendous need to better understand the disease biology, discover new therapies, and improve clinical outcomes for this challenging disease. Next-generation sequencing has produced a more accurate and detailed picture of the molecular signatures in BTCs. The three BTC histologic subtypes are, in fact, quite molecularly distinct.IHCC commonly contain FGFR2 fusions and IDH 1 and 2 mutations, whereas EHCC and GBC tend to carry mutations in EGFR, HER2, and MAPK pathway. In light of this emerging knowledge, clinical trials have become more biomarker-driven, which allows capturing of subsets of patients that are most likely to respond to certain therapies. Many new and promising targeted therapeutics are currently in the pipeline.Here we review the genetic landscape of BTCs while focusing on new molecular targets and targeted therapeutics currently being investigated in biomarker-driven clinical trials.

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“…The precise reason for the higher ARQ 087 levels is incompletely understood, and may be due to alterations in the absorption and metabolism of the combined agents. In addition, this may be the cause for the increased toxicity observed in the animals dosed with both compounds; however it is notable that ARQ 087 concentrations as high as those observed in the combo group have been seen in previous xenograft studies without any increased toxicity 28. The toxicity data suggests that continuous dosing of both agents may be suboptimal.…”

Section: Discussionmentioning

confidence: 93%

“…In previous studies, we have demonstrated that ARQ 092 and ARQ 087 as single agents suppressed tumor growth in the AN3CA xenograft model 6,28. Mice bearing AN3CA tumors were treated with various doses of ARQ 092 and ARQ 087.…”

Section: Resultsmentioning

confidence: 99%