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

Functional Precision Medicine Using Ex Vivo Drug Sensitivity Profiling to Guide Therapy Selection in Relapsed/Refractory Multiple Myeloma: Results of a Prospective Clinical Trial (IMS 2026) - P=N/A | "Prior exposure included lenalidomide (100%), bortezomib (97.5%), carfilzomib (85%), daratumumab (82%), pomalidomide (77.5%), and BCMA CAR-T (12.5%). Top-ranked agents by DSS in v1 included bortezomib (median DSS 47.7), carfilzomib (47.3), panobinostat (47.0), and romidepsin (45.4). In v2, leading agents were marizomib ( 46.1), carfilzomib (40.2), ixazomib (37.2), and oprozomib (31.6)...ROC analysis for bortezomib (n=12) and selinexor (n=8) yielded AUCs of 0.471 and 0.462, respectively... High-throughput drug sensitivity testing was feasible in heavily pretreated RRMM and generated actionable results in nearly all patients. DSS-based prediction varied across agents, highlighting the need for drug-specific thresholds and larger validation cohorts. These findings support further development of functional precision medicine as a complementary tool to refine therapeutic decision-making in RRMM"

Late-breaking abstract • Preclinical • Hematological Malignancies • Leukemia • Multiple Myeloma • Plasma Cell Leukemia • Plasmacytoma • SDC1

Uninvolved-brain mean dose in radiotherapy is associated with survival and toxicity burden in the EORTC-1709-BTG MIRAGE trial: an exploratory analysis (EANO 2026) - "Using centrally available planning data from the EORTC 1709 (MIRAGE) trial on the role of marizomib in patients with newly diagnosed glioblastoma, an exploratory analysis was performed to assess whether uninvolved-brain dose is associated with survival outcomes and overall toxicity burden, alongside standard RTQA compliance reporting.Material and Overall, 672 patients were included in the RTQA analyses... In this large dataset, categorical compliance did not correlate with clinical outcomes; whereas higher dose to uninvolved brain exhibits a correlation to both survival outcomes and overall toxicity burden. These findings support prospective pre-specification of uninvolved-brain dose metrics as quantitative RTQA endpoints in GBM, although prospective validation is needed. Clinically, preserving uninvolved-brain dose reserve may be particularly important at recurrence, to maintain tolerability and keep re-irradiation as a feasible option in selected patients."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Prognostic associations of the G8 geriatric screening tool in the EORTC Brain Tumor Group trials 1608 and 1709 in patients with newly diagnosed glioblastoma. (ASCO 2026) - P1, P3 | " Data from 99 patients aged 70 or older enrolled in the 1608 STEAM trial on the multikinase inhibitor zotiraciclib (NCT 03224104) (n = 23) or the 1709 MIRAGE trial on the proteasome inhibitor marizomib (NCT 03345095) (n = 76) were analyzed. The G8 score may be a powerful tool for prognostic assessment and for patient stratification in old and frail patients with glioblastoma. It may help to identify patients in need of early involvement of a palliative care team."

Clinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Identification of a Small-Molecule Modulator of Astrocyte Reactivity for Optic Nerve Protection. (PubMed, Invest Ophthalmol Vis Sci) - "We developed a small-scale drug-screening platform and identified Marizomib as a modulator of astrocyte phenotypes. Its therapeutic potential was validated both in vitro and in vivo, providing a new chemical tool to modulate astrocyte reactivity for future therapeutic exploration."

Journal • GBP2

Targeting the proteasome in cancer therapy: development and future opportunities in natural products. (PubMed, Front Pharmacol) - "We also discuss the clinical progress of marizomib, the only natural product-derived PI, that has advanced to clinical trials...The development of novel natural product-derived PIs and rational combination strategies offers promising opportunities for overcoming resistance in cancer therapy. Although challenges remain, the remarkable structural diversity of natural products provides a rich reservoir for drug discovery, underscoring the importance of continued exploration and innovation in this field."

Journal • Review • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation

Efficacy and safety of targeted therapies for glioblastoma: a systematic review and network meta-analysis. (PubMed, BMC Cancer) - "Bevacizumab was associated with improved PFS, but not OS compared to standard therapy and other targeted therapies in newly diagnosed GBM patients. Exploratory subgroup findings suggested that nivolumab may be associated with less favorable OS and PFS estimates in MGMT-unmethylated patients. SUCRA rankings should be interpreted as exploratory because most interventions were supported by limited trial evidence. However, certain targeted drugs exhibit inadequate safety profiles, and careful risk-benefit assessment is required. Future research should further explore safer and more effective multi-targeted combination strategies to overcome GBM's survival bottleneck."

Journal • Retrospective data • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • MGMT

Nanoparticle-Based delivery of proteasome inhibitors for glioblastoma Therapy: Strategies to overcome Blood-Brain barrier and therapeutic resistance. (PubMed, Biochem Pharmacol) - "Glioblastoma (GBM), the most malignant primary brain tumor, has a poor prognosis despite surgical resection, radiation, and temozolomide-based chemotherapy...Thus, proteasome inhibitors (PIs) such bortezomib (BTZ), carfilzomib, ixazomib, and marizomib are promising treatments...To improve glioblastoma clinical outcomes with nanomedicine and proteasome inhibition, we also explore translational difficulties and prospects. This review provides the UPS's biological role in GBM, proteasome inhibitors and their limitations, and nanoparticle-enabled delivery techniques to bypass BBB barriers and treatment resistance."

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

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

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