A phase 1 clinical trial evaluating marizomib, pomalidomide and low‐dose dexamethasone in relapsed and refractory multiple myeloma (<scp>NPI</scp>‐0052‐107): final study results

Spencer, Andrew; Harrison, Simon; Zonder, Jeffrey A.; Badros, Ashraf; Laubach, Jacob P.; Bergin, Krystal; Khot, Amit; Zimmerman, Todd; Chauhan, Dharminder; Levin, Nancy K.; MacLaren, Ann; Reich, Steven D.; Trikha, Mohit; Richardson, Paul G.

doi:10.1111/bjh.14987

Cited by 63 publications

(38 citation statements)

References 41 publications

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“…Phase III for MM Marizomib 371 A novel proteasome inhibitor that exhibits effects in patients with refractory and relapsed MM.…”

Section: Nanog Ubiquitinationmentioning

confidence: 99%

“…370 Additionally, marizomib exhibits synergistic effects with bortezomib and lenalidomide or pomalidomide and low-dose dexamethasone in patients with refractory and relapsed MM. 362,371 In addition, marizomib has the ability to penetrate the blood-brain barrier and induce apoptosis in glioma cells with low toxicity on normal cells. 372 Thus, it has been applied in newly diagnosed glioblastoma (NCT03345095).…”

Section: Preclinical/researchmentioning

confidence: 99%

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The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

424

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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“…Phase III for MM Marizomib 371 A novel proteasome inhibitor that exhibits effects in patients with refractory and relapsed MM.…”

Section: Nanog Ubiquitinationmentioning

confidence: 99%

Section: Preclinical/researchmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

424

308

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“…Marizomib was shown to selectively affect the cell viability of MM and Lymphocytic Leukaemia (CLL) cancer cells and have less toxicity on normal cells as compared to BTZ [215,217]. Marizomib was also effective in killing MM cells derived from patients with resistance to BTZ [124,215,218]. Clinical trials in patients with refractory or relapsed MM showed an overall response rate of 11% when marizomib was used as monotherapy [128], with the rate increasing to 53% when the drug was combined with pomalidomide and low-dose dexamethasone [218].…”

Section: Marizomibmentioning

confidence: 99%

“…Marizomib was also effective in killing MM cells derived from patients with resistance to BTZ [124,215,218]. Clinical trials in patients with refractory or relapsed MM showed an overall response rate of 11% when marizomib was used as monotherapy [128], with the rate increasing to 53% when the drug was combined with pomalidomide and low-dose dexamethasone [218]. Note worthily, marizomib treatment has been associated with some central neurotoxicity and has been shown to induce apoptosis glioma cells, these effects indicating that the drug penetrates the blood-brain barrier and that its use would be worth exploring as a potential treatment for brain cancer [124,219].…”

Section: Marizomibmentioning

confidence: 99%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22]. The NF-κB p105 is the precursor of NF-κB p50. It is evident that NF-κB p105 is cleaved and selectively degraded at the C-terminus by proteasome, generating the active form of NF-κB p50 [23]. Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases [24]. Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitin-proteasome pathway by breaking down shorter peptides (<5 residues) into even smaller fragments [25]. Many, but not all, of aminopeptidases, are zinc metalloenzymes, such as leucine aminopeptidases (lAPs) and methionine aminopeptidases (metAPs) [26,27]. Studies showed that blocking the activity of the aminopeptidases by inhibitor of bestatin could generate a major accumulation of peptides which are ∼2-5 residues long [28].The 26S proteasome contains one/two 19S regulatory particles (19S RP) which mainly regulate the translocation of ubiquitinated proteins to the 20S CP and one 20S core particle (20S CP) in which proteolysis finally occurs [29,30]. In general, two main processes are associated with the process of degradation of proteins by the UPS: (1) tagging the to-be-degraded proteins by polyubiquitination (normally more than four ubiquitins), and (2) proteolytic degradation of the polyubiquitinated protein by the 26S proteasome complex [31,32]. Each step incorporates an intricate and complex spectrum of protein interaction...

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“…Marizomib is currently being tested in multiple phase I, II, and III clinical trials for refractory multiple myeloma, leukemia, lymphoma, glioblastoma, and malignant glioma (NCT03345095, NCT02330562, NCT02103335, NCT02903069), both as a single agent and in combination therapies. The results from these clinical trials show that Mzb (both as a monotherapy and in combination therapy) is well-tolerated, and demonstrate its promising activity in multiple cancer types (51). Our pre-clinical data in this study generated using a range of in vitro and in vivo TNBC models provide a strong rationale to translate Mzb into a clinical trial in combination with standard-of-care chemotherapy for primary and metastatic TNBC patients.…”

Section: Molecular Analysis Of Primary 4t1br4 Tumors Revealed That Mzmentioning

confidence: 81%

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

Raninga

Lee

Sinha

et al. 2019

Preprint

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AbstractLacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive with development of metastasis especially brain, and remains clinically challenging breast cancer subtype to treat. Despite the survival dependency on the proteasome pathway genes, FDA-approved proteasome inhibitors induced minimal clinical response in breast cancer patients due to weak proteasome inhibition. Here, we show that a potent proteasome inhibitor Marizomib (Mzb) inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Mzb reduces lung and brain metastases by reducing the number of circulating tumor cells and the expression of multiple genes involved in the epithelial-to-mesenchymal transition. Furthermore, Mzb-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and, hence, combined inhibition of glycolysis with Mzb exposure leads to a synergistic anti-cancer activity. Collectively, our data provide a strong rationale for a clinical evaluation of Mzb in primary and metastatic TNBC patients.One Sentence SummaryMarizomib inhibits primary tumor growth, and also reduces lung and brain metastases in pre-clinical models of triple-negative breast cancer.

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A phase 1 clinical trial evaluating marizomib, pomalidomide and low‐dose dexamethasone in relapsed and refractory multiple myeloma (NPI‐0052‐107): final study results

Cited by 63 publications

References 41 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

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