A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression

Mason, Warren P.; Bélanger, Karl; Nicholas, Garth; Vallières, Isabelle; Mathieu, David; Kavan, Petr; Desjardins, Annick; Omuro, Antonio; Reymond, D.

doi:10.1007/s11060-011-0747-6

Cited by 40 publications

(18 citation statements)

References 17 publications

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“…Higher PDSs were associated with bad prognosis on both datasets for all but two pathways. Many of the other 35 pathways (SI Appendix, Table S3) make biological sense: Some are related to angiogenesis, critical to glioblastoma progression (such as VEGF signaling, Fibrinolysis, PDGFRβ signaling, α4β1 integrin signaling, and hypoxia-inducible factor 2-α pathway); many are known key players in glioblastoma and cancer, have a prognostic value, and are promising drug targets [such as MAP kinase (22,23), Insulin signaling and its components (24), RET tyrosine kinase (25), EGFR/ERBB signaling (26), PDGF signaling (27), and integrins (28)]. SI Appendix gives the full list of other survival-related pathways and their roles in glioblastoma.…”

Section: Pathway-based Substratification Of Gbm Has Important Clinicalmentioning

confidence: 99%

Pathway-based personalized analysis of cancer

Drier

Sheffer

Domany

2013

Proc. Natl. Acad. Sci. U.S.A.

312

359

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We introduce Pathifier, an algorithm that infers pathway deregulation scores for each tumor sample on the basis of expression data. This score is determined, in a context-specific manner, for every particular dataset and type of cancer that is being investigated. The algorithm transforms gene-level information into pathway-level information, generating a compact and biologically relevant representation of each sample. We demonstrate the algorithm's performance on three colorectal cancer datasets and two glioblastoma multiforme datasets and show that our multipathway-based representation is reproducible, preserves much of the original information, and allows inference of complex biologically significant information. We discovered several pathways that were significantly associated with survival of glioblastoma patients and two whose scores are predictive of survival in colorectal cancer: CXCR3-mediated signaling and oxidative phosphorylation. We also identified a subclass of proneural and neural glioblastoma with significantly better survival, and an EGF receptor-deregulated subclass of colon cancers.computational biology | systems biology | oncogenomics | principal curve T he operation of many important pathways is altered during cancer initiation and progression. Identifying the involved pathways and quantifying their deregulation is a very important step toward understanding the malignancy process (1-5). Because advanced therapies target specific pathways, pathway-level understanding is a key step also for developing personalized cancer treatments. Indeed, many methods, such as those described in refs. 5-10, were developed for pathway analysis of high-throughput data. Nearly all methods characterize a pathway's activity for an entire sample set and do not provide information on its deregulation in a particular tumor. One prominent exception is Pathway Recognition Algorithm using Data Integration on Genomic Models (PARADIGM) (11), a tool that deduces for each pathway and sample a score using the pathway's known connectivity and functional structure. Hence, it may not work well for many complex pathways that play significant roles in cancer, for which either the mechanism of pathway activity is not well known or essential relevant data (such as protein abundance and phosphorylation status) are unavailable.We introduce a method to calculate, independently for every pathway, a score that represents the extent to which the pathway is deregulated in every individual sample. We quantify the level of deregulation of a pathway in a sample by measuring the deviation of the sample from normal behavior. We do not need detailed reliable knowledge of the network or wiring diagram that underlies the pathway's activity. Hence, our estimates of pathway deregulation in a given sample are not restricted to only simple pathways. The method is knowledge-based, because we use generally well-known external information on the identity of the genes that belong to each pathway. Since the detailed interactions in each pathway are largel...

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Section: Pathway-based Substratification Of Gbm Has Important Clinicalmentioning

confidence: 99%

Pathway-based personalized analysis of cancer

Drier

Sheffer

Domany

2013

Proc. Natl. Acad. Sci. U.S.A.

312

359

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“…110 These compounds have been evaluated in a number of clinical trials with varying results. 111–113 …”

Section: High-throughput Screeningmentioning

confidence: 99%

Targeting Mutant KRAS for Anticancer Therapeutics: A Review of Novel Small Molecule Modulators

et al. 2013

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The RAS proteins play a role in cell differentiation, proliferation, and survival. Aberrant RAS signaling has been found to play a role in 30% of all cancers. KRAS, a key member of the RAS protein family, is an attractive cancer target, as frequent point mutations in the KRAS gene render the protein constitutively active. A number of attempts have been made to target aberrant KRAS signaling by identifying small molecule compounds that (1) are synthetic lethal to mutant KRAS, (2) block KRAS/GEF interactions, (3) inhibit downstream KRAS effectors, or (4) inhibit the post-translational processing of RAS proteins. In addition, inhibition of novel targets outside the main KRAS signaling pathway, specifically the cell cycle related kinase PLK1, has been shown have an effect in cells that harbor mutant KRAS. Herein we review the use of various high-throughput screening assays utilized to identify new small-molecule compounds capable of targeting mutant KRAS-driven cancers.

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“…As BU-4664L accumulates in implanted gliomas by binding to the peripheral benzodiazepine receptor, it is expected as a new anticancer drug for glioblastoma, although the initial phase II trial was unsuccessful [28]. Based on the proposed biosynthetic pathway, precursor directed biosynthesis has been attempted to produce unnatural BU-4664L analogues [29].…”

Section: Bu-4664l a Cell Migration Inhibitor From Micromonospora Spmentioning

confidence: 99%

Antitumor Compounds from Actinomycetes in Deep-sea Water of Toyama Bay

Igarashi

2014

Handbook of Anticancer Drugs From Marine Origin

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Actinomycetes are the richest source of bioactive small molecules with high structural complexity and diversity which have been an inspiration to drug development. After the intensive screening efforts from soil-derived actinomycetes over a half century, it became necessary to exploit new microbial resources for discovering new drug leads. The deep-sea water in Toyama Bay is known as the 'specific deep-sea water of Japan Sea' because Sea of Japan is almost enclosed from the Pacific Ocean and the water exchanges very slowly with the neighboring seas. Furthermore, high dissolved oxygen concentration in this sea water gives rise to high biological productivity. As a part of investigation on the deep-sea water in Toyama Bay, we undertook the isolation of actinomycetes from deep-sea water for evaluation of bioactive compound production. This chapter summarizes the chemistry and biology of antitumor compounds produced by actinomycetes collected from the deep-sea water in Toyama Bay.Keywords Actinomycetes · Micromonospora · Deep-sea water · Antitumor compounds IntroductionToyama Bay is located in the northern shores of Honshu, Japan, and faced to Sea of Japan. The sea water present deeper than 300 m is called 'deep-sea water', which occupies about 60 % of the total volume of Toyama Bay. The deep-sea water of Toyama Bay has a low temperature, annually stable around 2 °C. The salinity is also stable at 34.0-34.1 g/kg, higher than that of surface sea water (32-33 g/kg). Utilization of the deep-sea water is being studied for commercial/industrial purposes such as aquatic culture of cold-water shrimps. As a part of investigation on the deep-sea water in Toyama Bay, we undertook the isolation of actinomycetes from

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A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression

Cited by 40 publications

References 17 publications

Pathway-based personalized analysis of cancer

Pathway-based personalized analysis of cancer

Targeting Mutant KRAS for Anticancer Therapeutics: A Review of Novel Small Molecule Modulators

Antitumor Compounds from Actinomycetes in Deep-sea Water of Toyama Bay

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