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The most common (≥3 % of patients overall) drug-related grade ≥3 AEs, overall and within the dose-escalation and expansion cohorts
Source publication
Purpose:
Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies.
Methods:
Patients received IV ixazomib twi...
Context in source publication
Similar publications
Background
Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome...
Citations
... The mean priority of these drugs was 31.9 compared to docetaxel's priority of 85.1. In clinical trials, poziotinib, litronesib, ninlaro, and temsirolimus each positively affected HNC progression [30][31][32][33] . Additionally, previously published in vitro and in vivo studies present evidence of anti-HNC activity for YM-155, BGT226, and SN-38 [34][35][36] . ...
Due to cancer’s complex nature and variable response to therapy, precision oncology informed by omics sequence analysis has become the current standard of care. However, the amount of data produced for each patient makes it difficult to quickly identify the best treatment regimen. Moreover, limited data availability has hindered computational methods’ abilities to learn patterns associated with effective drug-cell line pairs. In this work, we propose the use of contrastive learning to improve learned drug and cell line representations by preserving relationship structures associated with drug mechanisms of action and cell line cancer types. In addition to achieving enhanced performance relative to a state-of-the-art method, we find that classifiers using our learned representations exhibit a more balanced reliance on drug- and cell line-derived features when making predictions. This facilitates more personalized drug prioritizations that are informed by signals related to drug resistance.
... The comparisons between bortezomib and ixazomib showed that ixazomib own better clinical efficacy in tumor suppression (19). Furthermore, MLN2238 has already shown significant inhibitory effects on tumor growth in melanoma, colorectal cancer and so on (20,21). And the main function of MLN2238 was to regulate target gene MCL-1, NOXA expression (22,23). ...
... Because the studies in the literature on HPV-positive HNSC cancer are insu cient, we examined the drugs without considering HPV status to be on the safe side, and the drugs that have ever been associated with HNSC cancer were not considered novel in this study.The literature search shows that the majority of drug candidates have already been associated with HNSC cancer. That is, all the drug targets of mCDKN2A proteins have already been associated with HNSC cancer [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. Of the total 5 drug targets uncovered for mMCM5, 3 were not associated with HNSC cancer and were novel. ...
Human papillomavirus (HPV) infection is one of the causative factors in the development of head and neck squamous cell carcinoma (HNSC). One in four HNSC cases is positive for HPV infection, and HPV16 is the most common infection in HNSC cancer. HPV-positive and HPV-negative HNSC patients differ significantly in their molecular profiles and clinical features. Although the diagnosis and treatment strategies of HNSC patients should differ depending on the HPV status of the patient, there are no specific treatment regimens for these patients today. Given the enormous variation in HNSC cancers depending on HPV status, the 3P framework is of great importance specifically for these patients. In this study we present systemic biomarkers and treatment options tailored to the patient's HPV status. Gene expression levels of HPV16-positive and -negative cancer patients were used as proxies, and the differential interactome algorithm was employed to identify the differential interacting proteins (DIPs) around which significant changes occur at protein-protein interactome level. By assessing the prognostic capabilities and druggabilities of DIPs and their interacting partners (DIP-centered modules), we were able to introduce eight DIP-centered modules as potential systems biomarkers specialized for either HPV16-positive or HPV16-negative phenotype. The prognostic power of three modules specific for HPV16-positive phenotype was also validated by an independent cohort study. Finally, raloxifene was repositioned as a drug candidate for the treatment of HPV16-positive HNSC patients. With this study, we open new perspectives for the development of effective prognostic and treatment strategies for HNSC patients depending on their HPV16 status.
... Moreover, some preclinical studies have indicated that MLN9708 displayed an antitumor activity in solid tumor cells [24,25] . ...
Background
Ixazomib (MLN9708) shows a better pharmacodynamic and pharmacokinetic feature than bortezomib as a second-generation proteasome inhibitor. Our study aims to examine the cytotoxic effects of MLN9708 alone or in combination with fluorouracil (5-FU) or gemcitabine in pancreatic cancer cells, and explore the possible molecular mechanism with MLN9708 in pancreatic cancer.
Materials
In this preclinical study, three pancreatic cancer cell lines were selected to perform the cell proliferation assays, colony formation assays and anchorage-independent growth assays to examine the cytotoxicity of MLN9708 alone or mixed with gemcitabine or 5-FU. Next-generation RNA sequencing was then used to identify differentially expressed (DE) mRNAs from different treatment groups in BxPC-3 and PANC-1. Quantitative reverse transcription PCR (RT-qPCR) assay was performed to validate the accuracy of the RNA-seq results. Furthermore, UALCAN website and Kaplan-Meier survival analysis were used to determine predicting value of DE expression genes and levels.
Results
MLN9708 demonstrated inhibitory effects on pancreatic cancer cell lines. The combinational therapy leads to greater inhibition of cell proliferation in PANC-1 and BxPC-3 than the monotherapy. A total of 157 commonly DE genes were identified. Among them, top five upregulated DE genes were picked out. RT-qPCR assay showed that ATP6V0D2, Matrix Metalloproteinases-1 (MMP-1) and RNF103-CHMP3 were significant differences. According to UALCAN website and Kaplan-Meier survival analysis, overexpression of ATP6V0D2, MMP-1 and RNF103-CHMP3 was associated with worse prognosis of PC patients; and overexpression of MMP-1 and RNF103-CHMP3 predicted shorter relapse-free survival in pancreatic cancer patients. Furthermore, ATP6V0D2 and MMP-1 demonstrated high expressions in pancreatic cancer samples.
Conclusions
Our experiments suggested MLN9708’s antitumor effects in pancreatic cancer, which sensitizes PANC-1 and BxPC-3 to gemcitabine and 5-FU, especially for 5-FU treatment. MMP-1 overexpression is closely associated with molecular mechanisms of MLN9708 in pancreatic cancer.
... Ixazomib selectively binds to and inhibits the b5 chymotrypsinlike proteolytic site of the 20S proteasome, as well as the b1 caspase-like and b2 trypsin-like subunits [2,4e6]. Additionally, it upregulates the pharmacodynamic markers of proteasome inhibition in tumor tissues, including the activation of tumor activated transcription factor 3, growth arrest, and DNA damage-inducible protein 34, which are usually upregulated during endoplasmic reticulum stress and activation of unfolded protein responses [2,4,7]. The ubiquitin proteasome system (UPS) uses K48-linked polyubiquitin chains to target and mark damaged or misfolded proteins for degradation [8e11]. ...
Purpose
Ixazomib is a selective, effective, and reversible inhibitor of 20S proteasome and is approved for the treatment of multiple myeloma. Ubiquitin-conjugating enzyme E2 (UBE2K) is involved in the synthesis of K48-linked ubiquitin chains and is the target of certain drugs used for the treatment of tumors. The purpose of this study was to investigate the relationship between ixazomib and UBE2K in myeloma cells.
Methods
We used CCK-8 and Annexin V-FITC/propidium iodide kit to detect the effects of ixazomib on survival and apoptosis of RPMI-8226 and U-266 myeloma cell lines. Quantitative polymerase chain reaction and western blot were used to detect the change in gene and protein expression levels of myeloma cells treated with ixazomib. Furthermore, the regulatory effects of ixazomib on UBE2K and its downstream targets were investigated following the overexpression of UBE2K.
Results
In myeloma cells, ixazomib decreased cell survival and increased apoptosis in a dose-dependent manner. Ixazomib significantly increased the expression of HIST1H2BD, MNAT1, NEK3, and TARS2, while decreasing the expression of HSPA1B and UBE2K. In addition, ixazomib inhibited the proliferation of myeloma cells, blocked cell cycle, induced cell apoptosis, and increased the production of reactive oxygen species by inhibiting UBE2K expression. Lastly, ixazomib regulates mitosis- and apoptosis-related genes by lowering UBE2K expression.
Conclusion
In summary, ixazomib leads to impaired proliferation of myeloma cells by targeting UBE2K.
... MLN2238 is a proteasome inhibitor with improved pharmacodynamic profile and antitumor activity in vitro and in vivo compared to bortezomib [65]. A phase I study of intravenous MLN2238 showed manageable safety profile, limited antitumor activity and C max of up to 1400 nM at maximum tolerated dose [66]. The C max from that study was higher than the GR50s from our data, and C ss for the same dose was within 30-300 nM, which is comparable to our data. ...
Sarcomas are a heterogeneous group of mesenchymal orphan cancers and new treatment alternatives beyond traditional chemotherapeutic regimes are much needed. So far, tumor mutation analysis has not led to significant treatment advances, and we have attempted to bypass this limitation by performing direct drug testing of a library of 353 anti-cancer compounds that are either FDA-approved, in clinical trial, or in advanced stages of preclinical development on a panel of 13 liposarcoma cell lines. We identified and validated six drugs, targeting different mechanisms and with good efficiency across the cell lines: MLN2238 –a proteasome inhibitor, GSK2126458 –a PI3K/mTOR inhibitor, JNJ-26481585 –a histone deacetylase inhibitor, triptolide–a multi-target drug, YM155 –a survivin inhibitor, and APO866 (FK866)–a nicotinamide phosphoribosyl transferase inhibitor. GR50s for those drugs were mostly in the nanomolar range, and in many cases below 10 nM. These drugs had long-lasting effect upon drug withdrawal, limited toxicity to normal cells and good efficacy also against tumor explants. Finally, we identified potential genomic biomarkers of their efficacy. Being approved or in clinical trials, these drugs are promising candidates for liposarcoma treatment.
... The overall ixazomib exposure, as determined by the area under the curve (AUC) (last) , was found to increase with dose, with median values of 1,236, 1,957, and 5,025 ng/mL per hour in the 2.3-mg, 3-mg, and 4-mg cohorts, respectively. The elimination half-life and the AUC (last) values were similar to those previously reported for ixazomib monotherapy administered twice weekly when pharmacokinetic data were analyzed using noncompartmental analysis [25]. However, the elimination half-life values in this study were shorter than the cited mean elimination half-life of 9.5 days (228 hours) [13,26]. ...
Lessons learned:
Fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models.
Background:
Fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models.
Methods:
This is a single-center phase Ib study with a 3+3 design of fulvestrant and the proteasome inhibitor ixazomib (MLN9708) in patients with advanced ER+ breast cancer that was progressing on fulvestrant. A dose-escalation design allowed establishment of the ixazomib maximum tolerated dose (MTD). Secondary objectives included progression-free survival, pharmacokinetics, and tumor molecular analyses.
Results:
Among nine evaluable subjects, treatment was well-tolerated without dose-limiting toxicities The MTD of ixazomib was 4 mg in combination with fulvestrant. Plasma concentrations of the active form of ixazomib (MLN2238) in the 4-mg dose cohort had a median (range) Cmax of 155 (122-171) ng/mL; Tmax of 1 (1-1.5) h; terminal elimination half-life of 66.6 (57.3-102.6) hr after initial dose; AUC of 5,025 (4,160-5,345) ng*h/mL. One partial response was observed, and median progression-free survival was 51 days (range 47-137).
Conclusion:
This drug combination has a favorable safety profile and anti-tumor activity in patients with fulvestrant-resistant advanced ER+ breast cancer that justifies future testing.
... Several studies are currently investigating the activity of ixazomib in patients with immunoglobulin light chain (AL) amyloidosis, Waldestrom Macroglobulinemia, bone plasmocytome and other nonhaematological malignancies (Smith et al., 2015;Smolewski and Rydygier, 2019;clinical trials.gov). Until now the best results were obtained in a phase 1/2 study which evaluated the safety, tolerability, and preliminary efficacy of ixazomib in patients with relapsed/refractory AL amyloidosis, paving the road to a phase 3 study which is currently ongoing (NCT01659658) (Sanchorawala et al., 2017;Smolewski and Rydygier, 2019). ...
Ubiquitin Proteasome System (UPS) is an adaptable and finely tuned system that sustains proteostasis network under a large variety of physiopathological conditions. Its dysregulation is often associated with the onset and progression of human diseases; hence, UPS modulation has emerged as a promising new avenue for the development of treatments of several relevant pathologies, such as cancer and neurodegeneration. The clinical interest in proteasome inhibition has considerably increased after the FDA approval in 2003 of bortezomib for relapsed/refractory multiple myeloma, which is now used in the front-line setting. Thereafter, two other proteasome inhibitors (carfilzomib and ixazomib), designed to overcome resistance to bortezomib, have been approved for treatment-experienced patients, and a variety of novel inhibitors are currently under preclinical and clinical investigation not only for haematological malignancies but also for solid tumours. However, since UPS collapse leads to toxic misfolded proteins accumulation, proteasome is attracting even more interest as a target for the care of neurodegenerative diseases, which are sustained by UPS impairment. Thus, conceptually, proteasome activation represents an innovative and largely unexplored target for drug development. According to a multidisciplinary approach, spanning from chemistry, biochemistry, molecular biology to pharmacology, this review will summarize the most recent available literature regarding different aspects of proteasome biology, focusing on structure, function and regulation of proteasome in physiological and pathological processes, mostly cancer and neurodegenerative diseases, connecting biochemical features and clinical studies of proteasome targeting drugs.
... Initially, this phenomenon was blamed on poor tumor penetration of the drug, based on studies from bortezomib [17]. However, ixazomib, which exhibits better tumor penetration, has not fared well in clinical trials with solid tumors [18]. A more recent view is that proteasome inhibitors need to be used in combination with other drugs to increase their efficacy in solid tumors [19]. ...
Currently, proteasome inhibitors bortezomib, carfilzomib, and ixazomib are successfully used in clinics to treat multiple myeloma. However, these agents show limited efficacy against solid tumors. Identification of drugs that can potentiate the action of proteasome inhibitors could help expand the use of this therapeutic modality to solid tumors. Here, we found that bromodomain extra-terminal (BET) family protein inhibitors such as JQ1, I-BET762, and I-BET151 synergize with carfilzomib in multiple solid tumor cell lines. Mechanistically, BET inhibitors attenuated the ability of the transcription factor Nrf1 to induce proteasome genes in response to proteasome inhibition, thus, impeding the bounce-back response of proteasome activity, a critical pathway by which cells cope with proteotoxic stress. Moreover, we found that treatment with BET inhibitors or depletion of Nrf1 exacerbated the unfolded protein response (UPR), signaling that was initiated by proteasome inhibition. Taken together, our work provides a mechanistic explanation behind the synergy between proteasome and BET inhibitors in cancer cell lines and could prompt future preclinical and clinical studies aimed at further investigating this combination.
... 2020, 21, 327 2 of 14 Carfilzomib (CFZ) and Ixazomib (IXZ) are approved for relapsed and refractory multiple myeloma (RRMM). In general, hematologic tumors cells have proven more sensitive to PI-induced apoptosis than solid tumors [6][7][8]. The major difference between these PIs, aside from their route of delivery (intravenous for BTZ and CFZ; oral for IXZ), is the mechanism by which they inhibit the proteasome. ...
... Solid tumors, like breast cancer, have been historically less sensitive to treatment with proteasome inhibitors [7,8]. We reasoned that DDI2 depletion could sensitize these cancer cells to CFZ-induced apoptosis via inhibition of the NRF1-mediated bounce-back response. ...
Proteasome inhibition is used therapeutically to induce proteotoxic stress and trigger apoptosis in cancer cells that are highly dependent on the proteasome. As a mechanism of resistance, inhibition of the cellular proteasome induces the synthesis of new, uninhibited proteasomes to restore proteasome activity and relieve proteotoxic stress in the cell, thus evading apoptosis. This evolutionarily conserved compensatory mechanism is referred to as the proteasome-bounce back response and is orchestrated in mammalian cells by nuclear factor erythroid derived 2-related factor 1 (NRF1), a transcription factor and master regulator of proteasome subunit genes. Upon synthesis, NRF1 is cotranslationally inserted into the endoplasmic reticulum (ER), then is rapidly retrotranslocated into the cytosol and degraded by the proteasome. In contrast, during conditions of proteasome inhibition or insufficiency, NRF1 escapes degradation, is proteolytically cleaved by the aspartyl protease DNA damage inducible 1 homolog 2 (DDI2) to its active form, and enters the nucleus as an active transcription factor. Despite these insights, the cellular compartment where the proteolytic processing step occurs remains unclear. Here we further probed this pathway and found that NRF1 can be completely retrotranslocated into the cytosol where it is then cleaved and activated by DDI2. Furthermore, using a triple-negative breast cancer cell line MDA-MB-231, we investigated the therapeutic utility of attenuating DDI2 function. We found that DDI2 depletion attenuated NRF1 activation and potentiated the cytotoxic effects of the proteasome inhibitor carfilzomib. More importantly, expression of a point-mutant of DDI2 that is protease-dead recapitulated these effects. Taken together, our results provide a strong rationale for a combinational therapy that utilizes inhibition of the proteasome and the protease function of DDI2. This approach could expand the repertoire of cancer types that can be successfully treated with proteasome inhibitors in the clinic.
