Phase I study and pharmacokinetic of CHS-828, a guanidino-containing compound, administered orally as a single dose every 3weeks in solid tumours: An ECSG/EORTC study

Ravaud, Alain; Cerny, Thomas; Terret, C.; Wanders, J.; Bui, Binh; Hess, Dagmar; Droz, Jean‐Pierre; Fumoleau, P.; Twelves, Chris

doi:10.1016/j.ejca.2004.12.023

Cited by 99 publications

(75 citation statements)

References 4 publications

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“…Most probable the deviation in our trial from the tolerance pattern previously published relates to the low number of patients included in our trial and their baseline characteristics rather than to treatment schedule and dosing. In our study these were somewhere in between those used in the studies by Hovstadius and Ravaud et al and that showed fairly consistent patterns of adverse events [19,20].…”

Section: Discussionsupporting

confidence: 74%

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Heideman

Berglund

Larsson

et al. 2009

Cancer Chemother Pharmacol

160

150

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2 AbstractPurpose Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials. Conclusions Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low. Methods

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Section: Discussionsupporting

confidence: 74%

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Heideman

Berglund

Larsson

et al. 2009

Cancer Chemother Pharmacol

160

150

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“…4B). In addition, and consistent with activated JNK signaling, we also observed high concentrations of the phosphorylated forms of the AP-1 transcription factors subunits c-Jun and Atf2 (6,7,24) in the nuclear extracts of CARD11(L225LI)-transgenic cells (Fig. 4C).…”

Section: Card11(l225li)-induced Lymphoproliferation Is Strictly Depenmentioning

confidence: 65%

“…Canonical NF-κB signaling is regulated by IκB kinase β (IKKβ), which induces proteolytic degradation of inhibitory IκB proteins by their phosphorylation and thereby allows translocation of NF-κB transcription factors into the nucleus. Although small molecule inhibitors of IKKβ efficiently block the growth of ABC-DLBCL cells in vitro (5), clinical trials failed due to highly toxic side effects (NCT00003979) (6,7).…”

mentioning

confidence: 99%

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Knies

Alankus

Weilemann

et al. 2015

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

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The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.

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“…Three NAMPT inhibitors of two distinct structural classes have entered clinical trials for cancer, APO866 (formerly FK866; ref. 8), GMX1778 (formerly CHS828), and a prodrug of GMX1778, GMX1777 (9)(10)(11). In these trials, thrombocytopenia and gastrointestinal toxicity were the most common adverse events, with thrombocytopenia being the dose-limiting toxicity (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors

Shames¹,

Elkins²,

Walter³

et al. 2013

Clinical Cancer Research

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Purpose: We sought to identify predictive biomarkers for a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor.Experimental Design: We use a NAMPT inhibitor, GNE-617, to evaluate nicotinic acid rescue status in a panel of more than 400 cancer cell lines. Using correlative analysis and RNA interference (RNAi), we identify a specific biomarker for nicotinic acid rescue status. We next determine the mechanism of regulation of expression of the biomarker. Finally, we develop immunohistochemical (IHC) and DNA methylation assays and evaluate cancer tissue for prevalence of the biomarker across indications.Results: Nicotinate phosphoribosyltransferase (NAPRT1) is necessary for nicotinic acid rescue and its expression is the major determinant of rescue status. We demonstrate that NAPRT1 promoter methylation accounts for NAPRT1 deficiency in cancer cells, and NAPRT1 methylation is predictive of rescue status in cancer cell lines. Bisulfite next-generation sequencing mapping of the NAPRT1 promoter identified tumor-specific sites of NAPRT1 DNA methylation and enabled the development of a quantitative methylation-specific PCR (QMSP) assay suitable for use on archival formalin-fixed paraffin-embedded tumor tissue.Conclusions: Tumor-specific promoter hypermethylation of NAPRT1 inactivates one of two NAD salvage pathways, resulting in synthetic lethality with the coadministration of a NAMPT inhibitor. NAPRT1 expression is lost due to promoter hypermethylation in most cancer types evaluated at frequencies ranging from 5% to 65%. NAPRT1-specific immunohistochemical or DNA methylation assays can be used on archival formalin paraffin-embedded cancer tissue to identify patients likely to benefit from coadministration of a Nampt inhibitor and nicotinic acid.

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Phase I study and pharmacokinetic of CHS-828, a guanidino-containing compound, administered orally as a single dose every 3weeks in solid tumours: An ECSG/EORTC study

Cited by 99 publications

References 4 publications

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data

Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation

Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors

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