marizomib (NPI-0052) / Triphase Accelerator Corporation, BMS - LARVOL DELTA

Exploring the in vitro and in vivo antileishmanial potential of Marizomib against Leishmania amazonensis and Leishmania infantum. (PubMed, Antimicrob Agents Chemother) - "Importantly, Marizomib, in the treatment regimens used, did not cause renal and hepatic acute toxicity to infected animals. These results highlight the antileishmanial potential of Marizomib, encouraging us to conduct preclinical tests in other animal models, as well as clinical trials."

Journal • Preclinical • Dermatology • Infectious Disease • Oncology

Marizomib in the therapy of brain tumors-how far did we go and where do we stand? (PubMed, Pharmacol Rep) - "Despite an indisputable therapeutic potential of MZB, it has yet failed to be successfully introduced to the clinics as a ready-to-use chemotherapy for GBM-suffering patients. Therefore, in this work we describe the potential of PIs as candidates for neuro-oncological drugs, present results of preclinical and clinical investigations concerning MZB in brain tumors, discuss possible reasons of failure of MZB-based therapies and delineate future directions of MZB-related studies."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome. (PubMed, Molecules) - "This structure reveals the binding mode of MZB to all six catalytic subunits within the two β-rings of the 20S proteasome, providing a detailed molecular understanding of its irreversible inhibitory mechanism. These findings enhance the therapeutic potential of MZB for both cancer and parasitic diseases at the molecular level and highlight marine-derived natural products in targeting the proteasome for therapeutic applications."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • Targeted Protein Degradation

Structural insights into Salinosporamide A mediated inhibition of the human 20S proteasome. (PubMed, bioRxiv) - "This structure reveals the binding mode of MZB to all six catalytic subunits within the two β-rings of the 20S proteasome, providing a detailed molecular understanding of its irreversible inhibitory mechanism. These findings explain the therapeutic potential of MZB at the molecular level and highlight marine-derived natural products in targeting the proteasome for anticancer treatment."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • Targeted Protein Degradation

Marizomib Promotes Senescence or Long-Term Apoptosis in Melanoma Cancer Cells. (PubMed, Molecules) - "After 96 h from inhibitor removal, the G361 line presented signs of senescence (increased level of SA-β-galactosidase, IL-8, P-P53, G2/M and S phases of cell cycle, decreased lamin B1 and cleaved lamin B1), while the A375 line demonstrated more signs of apoptosis (increased subG1 phase, P-P53, cleaved lamin B1). The gathered findings suggest that MZB resulted in the induction of cellular senescence (line G361) or enhanced apoptosis (line A375) in the melanoma cell lines tested here and could be a promising therapeutic factor in malignant melanoma treatment."

Journal • Melanoma • Oncology • Solid Tumor • CDKN1A • CXCL8 • LMNB1 • TP53

Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors. (PubMed, Nat Commun) - "Notably, the marizomib (MZB) inhibits all catalytic subunits of Tv20S, while the peptide inhibitor carmaphycin-17 (CP-17) specifically targets β2 and β5...These findings explain MZB's low specificity for Tv20S compared to the human proteasome and demonstrate CP-17's higher specificity. Overall, these data provide a structure-based strategy for the development of specific Tv20S inhibitors to treat trichomoniasis."

Journal • Infectious Disease

The Proteasome Inhibitor Marizomib Evokes Endoplasmic Reticulum Stress and Promotes Apoptosis in Human Glioblastoma Cells. (PubMed, Pharmaceuticals (Basel)) - "On the contrary, overproduction of ROS or increased expressions of ERO1α, LC3 II, Beclin 1, and ATG5 were not detected, suggesting that neither oxidative stress nor autophagy were involved in the process of MZB-induced cell death. Thus, marizomib represents a potentially promising compound for facilitating further progress in brain cancer therapy."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • ATF4 • ATG5 • BECN1 • CASP3 • CASP7 • ERO1A • HSPA5 • PARP1

Marizomib (Salinosporamide A) Promotes Apoptosis in A375 and G361 Melanoma Cancer Cells. (PubMed, Mar Drugs) - "A Western blot analysis presented an increase in the expression of proteins related to endoplasmic reticulum (ER) stress as well as markers of the apoptosis. The gathered findings suggest that marizomib induced the ER stress in the examined melanoma cancer cells and directed them towards the apoptosis pathway."

Journal • Melanoma • Oncology • Solid Tumor • ANXA5

Marizomib Central Nervous System (CNS) (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Dana-Farber Cancer Institute | N=30 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Hematological Malignancies • Multiple Myeloma • Oncology

Efficacy of combined Proteasome and HDAC inhibitors treatment in glioblastoma cells (EACR 2024) - "Cleaved PARP, caspase 3 and p-histone H2Ax were detected, indicative of apoptosis activation and DNA damage as likely mediators of cytotoxicity.Conclusion Marizomib and vorinostat have a strong synergistic activity in T98G cells and GSCs and evidence suggests the involvement of the UPR as a mediator of cell death. More detailed studies are in progress to further study the potency and underlying mechanisms of action of this combined treatment."

Clinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CASP3

A scheme to underpin key mediator(s) in Salinosporamide(s) against pan-tumor via systems biology concept. (PubMed, J Transl Med) - No abstract available

Journal • Pan tumor • Oncology

Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease. (PubMed, Front Cell Infect Microbiol) - "The drugs Montelukast (targeting the MMP15 gene) and MARIZOMIB (targeting the PSMA4 gene) may reduce the risk of spirometry-defined COPD. Our findings identified 22 potential drug targets for COPD and lung function. Prioritizing clinical trials that target these identified druggable genes with existing drugs or novel medications will be beneficial for the development of COPD treatments."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • APH1A • ERBB3

Inhibiting elements of the proteasome recovery pathway sensitizes glioblastoma to proteasome inhibitors (AACR 2024) - "Despite robust preclinical evaluations for the usage of proteosome inhibitors against GBM, most tested proteosome inhibitors failed in phase II and III trials, indicating resistance. We conducted an unbiased genome wide CRISPR-Cas9 screen in human HAP1 cells treated with the proteosome inhibitor, Bortezomib (BTZ), to identify genes that may lead to a BTZ-resistant phenotype. The generation of NGLY-1, DDI2, and NFE2L1 KO cell lines demonstrated functional sensitivity to the proteosome inhibitor Marizomib (MZB) as observed through a significant reduction of the IC50 in the KO cell lines compared to a control. Functional evaluation also revealed a reduction in proliferation capacity as well as sphere formation in these genetically modified GBM lines. Ongoing in vivo work will aim to evaluate the mitigation of this resistant pathway in our NSG mouse models orthotopically transplanted with these patient derived KO cell lines."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Marizomib for patients with newly diagnosed glioblastoma: a randomized phase 3 trial. (PubMed, Neuro Oncol) - "Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma."

Journal • P3 data • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • MGMT

Phase I Study of Marizomib + Panobinostat for Children With DIPG (clinicaltrials.gov) - P1 | N=4 | Terminated | Sponsor: Dana-Farber Cancer Institute | N=45 ➔ 4 | Trial completion date: Dec 2024 ➔ Feb 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jun 2024 ➔ Feb 2024; Withdrawal of support from BMS

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Gliosarcoma • Oncology • Pediatrics • Sarcoma • Solid Tumor

MIRAGE: A Phase III Trial of With Marizomib in Patients With Newly Diagnosed Glioblastoma (clinicaltrials.gov) - P3 | N=749 | Completed | Sponsor: European Organisation for Research and Treatment of Cancer - EORTC | Active, not recruiting ➔ Completed

Trial completion • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Phase I Study of Marizomib + Panobinostat for Children With DIPG (clinicaltrials.gov) - P1 | N=45 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial primary completion date: Dec 2023 ➔ Jun 2024

Combination therapy • Trial primary completion date • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Gliosarcoma • Oncology • Pediatrics • Sarcoma • Solid Tumor

The Relative Efficacy of Available Proteasome Inhibitors in Preventing Muscle Contractures Following Neonatal Brachial Plexus Injury. (PubMed, J Bone Joint Surg Am) - "Although PIs offer unique opportunities to establish critical mechanistic insights into contracture pathophysiology, their clinical use is contraindicated in patients with NPBI at this time."

Journal • Targeted Protein Degradation

Integrated proteomics spotlight the proteasome as a therapeutic vulnerability in Embryonal Tumors with Multilayered Rosettes. (PubMed, Neuro Oncol) - "In summary, histomorphology stipulates the proteome signatures of ETMR, and proteasome regulatory proteins are pervasively abundant in these tumors. As validated in vitro, proteasome inhibition poses a promising therapeutic option in ETMR."

Journal • Brain Cancer • Embryonal Tumor • Oncology • Pediatrics • Solid Tumor

Proteasome Inhibitors against Glioblastoma-Overview of Molecular Mechanisms of Cytotoxicity, Progress in Clinical Trials, and Perspective for Use in Personalized Medicine. (PubMed, Curr Oncol) - "The accumulation of cell cycle inhibitors p21 and p27, and decreased levels of prosurvival molecules NFKB, survivin, and MGMT, underlie proteasome inhibitors' cytotoxicity when used alone or in combination with the anti-GBM cytostatic drug temozolomide (TMZ). The evidence gathered in preclinical studies substantiated the design of clinical trials that employed the two most promising proteasome inhibitors, bortezomib and marizomib...The data from this phase III study indicate that marizomib does not improve the PFS and OS of GBM patients; however, further analysis of the genetic and epigenetic background of each patient tumor may shed some light on the sensitivity of individual patients to proteasome inhibition. The mutational and epigenetic makeup of GBM cells, like genetic alterations to TP53 and PTEN, or MGMT promoter methylation levels may actually determine the response to proteasome inhibition."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • BIRC5 • MGMT • PTEN • TP53

Targeting non-catalytic activators of the proteasome decreases tumor growth and enhances antigen presentation in glioblastoma. (SNO 2023) - "Indeed, adverse neurological symptoms were prevalent in phase III clinical trials for the brain penetrant proteasome inhibitor, Marizomib, which may be linked to the vital role of proteasome subunits in non-malignant neural counterparts...We are further investigating enhanced antigen presentation by targeting these proteasome activator subunits and examining changes in the tumor microenvironment and survival in syngeneic immunocompetent models of GBM. Further understanding of this mechanism may provide novel targets for GBM treatment or improve immunotherapies in GBM."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • IFNG

Updated results and molecular subgroup analyses from the randomized phase 3 MIRAGE trial on marizomib in patients with newly diagnosed glioblastoma (SNO 2023) - "The addition of marizomib to standard temozolomide-based radiochemotherapy was associated with more toxicity but did not confer a survival benefit in glioblastoma patients, independent of the MGMT promoter methylation status."

Clinical • P3 data • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • MGMT

PHASE 1 TRIAL OF MARIZOMIB ALONE AND IN COMBINATION WITH PANOBINOSTAT IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) (EANO 2023) - "CONCLUSIONChildren with DIPG tolerated single agent MRZ at a dose of 0.6 mg/m2/dose on Days 1 and 15 and in combination with panobinostat without any DLT or CNS toxicity. Target dose levels were not evaluated as clinical development program for marizomib ended and the study was discontinued early."

Clinical • Combination therapy • P1 data • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor

Proteasome inhibitors as anticancer agents. (PubMed, Expert Opin Ther Pat) - "This review covers the progress made in the field of proteasome inhibitors, ranging from the first-generation bortezomib to the latest second-generation inhibitors such as carfilzomib and ixazomib as well as the proteasome inhibitors in clinical phase such as oprozomib and marizomib. The extension of proteasome inhibitors for the treatment of solid tumors, and their ability to pass the blood-brain barrier open new possibilities for treating central nervous system cancers. However, managing adverse effects, particularly those affecting the central nervous system, remains a critical consideration and a strategic 'working on' aspect for the near future."

Journal • Review • Brain Cancer • CNS Tumor • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor • Targeted Protein Degradation

Marizomib Central Nervous System (CNS) (clinicaltrials.gov) - P2 | N=30 | Not yet recruiting | Sponsor: Dana-Farber Cancer Institute | Trial completion date: Dec 2025 ➔ Dec 2027 | Trial primary completion date: Dec 2023 ➔ Dec 2025

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology