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

Marine-Derived Anticancer Compounds and their Clinical Status. (PubMed, Anticancer Agents Med Chem) - "Marine sources offer a wide variety of compounds, and modifying them provides researchers with new opportunities for drug development. Many marine-derived compounds have already shown strong pharmacological effects, with some even proven in clinical use. New studies suggest that marine compounds could also play an important role in anticancer drug delivery systems, making them a promising option for future treatments."

Journal • Oncology

From Deep-Sea Natural Product to Optimized Therapeutics: Computational Design of Marizomib Analogs. (PubMed, Int J Mol Sci) - "This integrative computational study identifies MZBMOD-77 and MZBMOD-79 as promising next-generation proteasome β5 inhibitors. These analogs mimic and enhance the inhibitory mechanism of native MZB, offering potential candidates for further optimization and preclinical development in glioblastoma therapy."

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

Lost in translation: Do preclinical studies predict clinical failure in GBM? (SNO 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Solid Tumor

Lost in translation: Do preclinical studies predict clinical failure in GBM? (SNO 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Solid Tumor

Lost in translation: Do preclinical studies predict clinical failure in GBM? (WFNOS 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

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

Lost in translation: Do preclinical studies predict clinical failure in GBM? (WFNOS 2025) - "For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%...The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide...The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into..."

Preclinical • Brain Cancer • CNS Disorders • Glioblastoma • Glioma • Oncology • Solid Tumor

A functional precision medicine clinical trial in Relapsed/Refractory multiple myeloma: Prospective study of a high throughput drug sensitivity assay on correlation of drug sensitivity scores with treatment response (ASH 2025) - P=N/A | "All patients (100%) had prior exposure to lenalidomide, 97.5% to bortezomib, 85% to carfilzomib, 82% to daratumumab, 77.5% to pomalidomide, and 12.5% BCMA CAR-T therapy...From Oncopanel2 v1, the top drugs by DSS included bortezomib (median DSS 47.7), carfilzomib (median DSS 47.3), panobinostat (median DSS 47), and romidepsin (median DSS 45.4). From Oncopanel2 v2, the top drugs by DSS were marizomib (an investigational PI, with median DSS 46.1), carfilzomib (median DSS 40.2), ixazomib (median DSS 37.2), and oprozomib (an investigational PI, with median DSS 31.6)... The use of a high throughput drug sensitivity assay was feasible among patients with relapsed/refractory MM. In our analysis of drug-specific DSS thresholds for bortezomib and Selinexor, DSS performance varied by agent, highlighting the need for drug-specific threshold optimization. In the patients who received Selinexor, there was a non-significant tendency toward higher DSS scores in responders,..."

Clinical • IO biomarker • Hematological Malignancies • Leukemia • Multiple Myeloma • Plasma Cell Leukemia • Plasmacytoma • SDC1

Marizomib-induced neurological toxicities: regional brain differences in proteasome inhibition, synaptic alterations, and neurotransmitter release (SNO 2025) - "Our findings reveal distinct brain regional and cellular effects of marizomib, providing mechanistic insight into its neurological toxicities observed in glioblastoma patients. Alterations in neurotransmitter release in the prefrontal cortex and cerebellum, as well as reductions in dendritic spine density, neuronal arborization, and proteasomal activity, may contribute to marizomib-associated adverse toxicities. Further research is warranted to determine the relationship between functional neural changes and response to marizomib treatment."

Alzheimer's Disease • Ataxia • Brain Cancer • CNS Disorders • Cognitive Disorders • Glioblastoma • Mental Retardation • Movement Disorders • Solid Tumor

Mitochondrial Protease LonP1 Drives Resistance to Proteasome Inhibitors in Glioblastoma and Offers a Novel Therapeutic Target (SNO 2025) - "Proteasome inhibitors like bortezomib and marizomib although demonstrated encouraging results in preclinical studies, neither drug achieved success in clinical trials for the treatment of glioblastoma. Conversely, genetic or pharmacological inhibition of LonP1 restores proteasome inhibitors sensitivity, synergistically inducing apoptosis via ROS accumulation and impaired mitochondrial metabolism. These findings establish LonP1 as a critical central driver of proteasome inhibitors resistance and provide a rationale for co-targeting LonP1 and the proteasome to overcome therapeutic resistance in cancer and advocate for dual targeting strategies to improve therapeutic outcomes."

Brain Cancer • Glioblastoma • Glioma • Metabolic Disorders • Solid Tumor • LONP1

Identifying common transcriptional mechanisms in treatment-resistant glioma. (SNO 2025) - "Background: Glioma, the most common primary brain tumor, shows poor prognosis and resistance to first-line therapies, like temozolomide (TMZ), lomustine (LOM) and panobinostat-marizomib (PM), complicating treatment and diminishing disease-free survival. RNA-sequencing identified common genes linked to TMZ, LOM, and PM chemoresistance, revealing key genetic networks involved in acquiring and maintaining drug resistance. Targeting these pathways, along with epigenetic silencing and/or combinatorial therapies, may resensitize chemoresistant cells and allow for effective treatment of glioma."

Brain Cancer • Glioma • High Grade Glioma • Solid Tumor • ERBB4 • FOXA1 • PDGFRA • SOX2

Identifying common transcriptional mechanisms in treatment-resistant glioma. (WFNOS 2025) - "Background: Glioma, the most common primary brain tumor, shows poor prognosis and resistance to first-line therapies, like temozolomide (TMZ), lomustine (LOM) and panobinostat-marizomib (PM), complicating treatment and diminishing disease-free survival. RNA-sequencing identified common genes linked to TMZ, LOM, and PM chemoresistance, revealing key genetic networks involved in acquiring and maintaining drug resistance. Targeting these pathways, along with epigenetic silencing and/or combinatorial therapies, may resensitize chemoresistant cells and allow for effective treatment of glioma."

Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • ERBB4 • FOXA1 • PDGFRA • SOX2

Marizomib-induced neurological toxicities: regional brain differences in proteasome inhibition, synaptic alterations, and neurotransmitter release (WFNOS 2025) - "Our findings reveal distinct brain regional and cellular effects of marizomib, providing mechanistic insight into its neurological toxicities observed in glioblastoma patients. Alterations in neurotransmitter release in the prefrontal cortex and cerebellum, as well as reductions in dendritic spine density, neuronal arborization, and proteasomal activity, may contribute to marizomib-associated adverse toxicities. Further research is warranted to determine the relationship between functional neural changes and response to marizomib treatment."

Alzheimer's Disease • Ataxia • Brain Cancer • CNS Disorders • Cognitive Disorders • Glioblastoma • Mental Retardation • Movement Disorders • Psychiatry • Solid Tumor

Mitochondrial Protease LonP1 Drives Resistance to Proteasome Inhibitors in Glioblastoma and Offers a Novel Therapeutic Target (WFNOS 2025) - "Proteasome inhibitors like bortezomib and marizomib although demonstrated encouraging results in preclinical studies, neither drug achieved success in clinical trials for the treatment of glioblastoma. Conversely, genetic or pharmacological inhibition of LonP1 restores proteasome inhibitors sensitivity, synergistically inducing apoptosis via ROS accumulation and impaired mitochondrial metabolism. These findings establish LonP1 as a critical central driver of proteasome inhibitors resistance and provide a rationale for co-targeting LonP1 and the proteasome to overcome therapeutic resistance in cancer and advocate for dual targeting strategies to improve therapeutic outcomes."

Brain Cancer • CNS Tumor • Glioblastoma • Metabolic Disorders • Oncology • Solid Tumor • LONP1

Recombinant proteasome provides new avenues for anti-malarial drug development. (PubMed, bioRxiv) - "Clinical proteasome inhibitors, bortezomib, carfilzomib and marizomib were potent but lacked Pf20S selectivity. Further evaluation of novel Pf20S-selective inhibitors such as the reversible TDI-8304 and irreversible analogs 8304-vinyl sulfone and 8304-epoxyketone confirmed their potency and selectivity over the human constitutive proteasome. This recombinant Pf20S platform facilitates detailed biochemical and structural studies, accelerating the development of selective antimalarial therapeutics."

Journal • Infectious Disease

Quality assurance in the randomized multicentre phase III trial EORTC-1709-BTG/CCTG CE.8 (MIRAGE) for glioblastoma: Results of the radiotherapy delineation benchmark case procedure. (PubMed, Radiother Oncol) - P3 | "Variations in the delineation of target volumes and organs at risk were frequently judged as "unacceptable" during the RTQA review process. Besides a significant increase of CTV coverage, the impact of variations on organ at risk dosimetry was minor, suggesting a potentially negligible effect on toxicity outcomes. Quantitative metrics to assess delineation variations should be explored to improve the RTQA process in clinical trials and routine practice, aiming to flag delineation variations that confer an effect on tumour control or toxicity."

Journal • P3 data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

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