A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma

Gallerani, Elisa; Zucchetti, Massimo; Brunelli, Dario; Marangon, Elena; Noberasco, Cristina; Hess, Dagmar; Delmonte, Angelo; Martinelli, Giovanni; Böhm, Steffen; Driessen, Christoph; Braud, Filippo de; Marsoni, Silvia; Cereda, Roberta; Sala, Federica; D’Incalci, Maurizio; Sessa, Cristiana

doi:10.1016/j.ejca.2012.09.009

Cited by 71 publications

(47 citation statements)

References 11 publications

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“…The proteasome is a possible therapeutic target for regulating the amount of iron stored in the liver and other ZIP14-containing organs when the standard iron deficiency treatment, such as dietary replacement or exogenous iron supplements, is inadequate to restore body iron or when patients need rapid restitution of iron stores. Proteasome inhibition has been developed and tested broadly for antitumor activities (36)(37)(38)(39), but the potential to treat iron deficiency has not been explored. By inhibiting the proteasomal activity, iron-depleted cells might be able to preserve the function of ZIP14 to obtain iron for maintaining proper cellular function.…”

Section: Discussionmentioning

confidence: 99%

An iron-regulated and glycosylation-dependent proteasomal degradation pathway for the plasma membrane metal transporter ZIP14

Zhao

Zhang

Worthen

et al. 2014

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

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Protein degradation is instrumental in regulating cellular function. Plasma membrane proteins targeted for degradation are internalized and sorted to multivesicular bodies, which fuse with lysosomes, where they are degraded. ZIP14 is a newly identified iron transporter with multitransmembrane domains. In an attempt to dissect the molecular mechanisms by which iron regulates ZIP14 levels, we found that ZIP14 is endocytosed, extracted from membranes, deglycosylated, and degraded by proteasomes. This pathway did not depend on the retrograde trafficking to the endoplasmic reticulum and thus did not involve the well-defined endoplasmic reticulum-associated protein degradation pathway. Iron inhibited membrane extraction of internalized ZIP14, resulting in higher steady-state levels of ZIP14. Asparagine-linked (N-linked) glycosylation of ZIP14, particularly the glycosylation at N102, was required for efficient membrane extraction of ZIP14 and therefore is necessary for its iron sensitivity. These findings highlight the importance of proteasomes in the degradation of endocytosed plasma membrane proteins.

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Section: Discussionmentioning

confidence: 99%

An iron-regulated and glycosylation-dependent proteasomal degradation pathway for the plasma membrane metal transporter ZIP14

Zhao

Zhang

Worthen

et al. 2014

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

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“…The half-life of the drug was rather long, 62 hrs, with linear PK. The degree of proteasome inhibition was lower than that described for BTZ or CFZ (45%), and rash occurred in over half of patients [186]. It remains to be determined whether the drug will have meaningful anti-MM activity in BTZ-resistant patients.…”

Section: Other Second Generation Proteasome Inhibitors In Clinical Dementioning

confidence: 99%

Overview of Proteasome Inhibitor-Based Anti-cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors versus Future Generation Inhibitors of Ubiquitin-Proteasome System

Dou¹,

Zonder²

2014

CCDT

233

203

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Over the past ten years, proteasome inhibition has emerged as an effective therapeutic strategy for treating multiple myeloma (MM) and some lymphomas. In 2003, Bortezomib (BTZ) became the first proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA). BTZ-based therapies have become a staple for the treatment of MM at all stages of the disease. The survival rate of MM patients has improved significantly since clinical introduction of BTZ and other immunomodulatory drugs. However, BTZ has several limitations. Not all patients respond to BTZ-based therapies and relapse occurs in many patients who initially responded. Solid tumors, in particular, are often resistant to BTZ. Furthermore, BTZ can induce dose-limiting peripheral neuropathy (PN). The second generation proteasome inhibitor Carfizomib (CFZ; U.S. FDA approved in August 2012) induces responses in a minority of MM patients relapsed from or refractory to BTZ. There is less PN compared to BTZ. Four other second-generation proteasome inhibitors (Ixazomib, Delanzomib, Oprozomib and Marizomib) with different pharmacologic properties and broader anticancer activities, have also shown some clinical activity in bortezomib-resistant cancers. While the mechanism of resistance to bortezomib in human cancers still remains to be fully understood, targeting the immunoproteasome, ubiquitin E3 ligases, the 19S proteasome and deubiquitinases in pre-clinical studies represents possible directions for future generation inhibitors of ubiquitin-proteasome system in the treatment of MM and other cancers.

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“…Based on the preclinical results of the compounds tested in our study, delanzomib holds most promise to be effective in the clinical setting for GIST patients. Two early phase clinical trials testing delanzomib in multiple myeloma and solid tumors indeed reported that delanzomib treatment was feasible 20,41 . Importantly, no neurotoxicity, the most severe adverse effect of bortezomib, was reported.…”

Section: Kitmentioning

confidence: 99%

“…Importantly, no neurotoxicity, the most severe adverse effect of bortezomib, was reported. While a few partial responses were seen, however, the best result for most delanzomib-treated patients was stable disease 20,41 .…”

Section: Kitmentioning

confidence: 99%

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells

Rausch

Ali

Lee

et al. 2019

Preprint

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The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but can show high inter-and intratumoral heterogeneity.Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug's adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitinproteasome machinery as therapeutic target.

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A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma

Cited by 71 publications

References 11 publications

An iron-regulated and glycosylation-dependent proteasomal degradation pathway for the plasma membrane metal transporter ZIP14

An iron-regulated and glycosylation-dependent proteasomal degradation pathway for the plasma membrane metal transporter ZIP14

Overview of Proteasome Inhibitor-Based Anti-cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors versus Future Generation Inhibitors of Ubiquitin-Proteasome System

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells

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