133 results found
Richard S, Chari A, Delimpasi S, et al., 2021, Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: Outcomes by cytogenetic risk, AMERICAN JOURNAL OF HEMATOLOGY, ISSN: 0361-8609
Sanchez L, Leleu X, Beaumont JL, et al., 2021, Peripheral neuropathy symptoms, pain, and functioning in previously treated multiple myeloma patients treated with selinexor, bortezomib, and dexamethasone, American Journal of Hematology, ISSN: 0361-8609
Mateos MV, Gavriatopoulou M, Facon T, et al., 2021, Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma, Journal of Hematology and Oncology, Vol: 14, ISSN: 1756-8722
Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.
Auner HW, Gavriatopoulou M, Delimpasi S, et al., 2021, Effect of age and frailty on the efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 96, Pages: 708-718, ISSN: 0361-8609
Yong KL, Hinsley S, Auner HW, et al., 2021, Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone followed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multi-centre, phase II, randomized, controlled trial (MUKfive)., Haematologica: the hematology journal, ISSN: 0390-6078
The proteasome inhibitors (PIs), carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these PIs in combination with cyclophosphamide and dexamethasone (KCd vs VCd) in second line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomised patients (2:1) to KCd (201) or VCd (99); responding patients on carfilzomib were randomised to maintenance carfilzomib (69) or no further treatment (72). Primary endpoints were (i) very good partial response (VGPR, non-inferiority, OR 0.8) at 24 weeks, and (ii) progression-free survival (PFS). More participants achieved ≥VGPR with carfilzomib compared to bortezomib (40.2% vs. 31.9%, OR=1.48, 90%CI:0.95,2.31; non-inferior), with a trend for particular benefit in adverse risk disease. KCd was associated with higher overall response (≥PR, 84.0% vs. 68.1%, OR=2.72, 90%CI:1.62,4.55, p=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, p.
Saavedra-Garcia P, Roman-Trufero M, Al-Sadah HA, et al., 2021, Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs, Proceedings of the National Academy of Sciences of USA, Vol: 118, ISSN: 0027-8424
Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known.Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stressresolution in multiple myeloma cells recovering from proteasome inhibition. Our observations definelayered and protracted programmes for stress resolution that encompass extensive changes acrossthe transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibitioninvolved protracted and dynamic changes of glucose and lipid metabolism and suppression ofmitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insultsthan acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellularresponse to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptomeanalysis pipeline, we further show that GCN2 is also a stress-independent bona fide target intranscriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus,identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumour cellsmay reveal new therapeutic targets and routes for cancer therapy optimisation.
Ponnusamy K, Tzioni MM, Begum M, et al., 2021, The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma., Haematologica
Multiple myeloma is a malignancy of plasma cells (PC) initiated and driven by primary and secondary genetic events. Nevertheless, myeloma PC survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B cell development in both human and mouse cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma PC, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the PC lineage-defining transcription factor IRF4, and thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.
Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al., 2021, Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition), Autophagy, Vol: 17, Pages: 1-382, ISSN: 1554-8627
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
Caputo VS, Trasanidis N, Xiao X, et al., 2021, Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro, iScience, Vol: 24, Pages: 1-31, ISSN: 2589-0042
Osteoclast development in response to RANKL is critical for bone homeostasis in health and in disease. The early and direct chromatin regulatory changes imparted by the BET chromatin readers Brd2-4 and osteoclast-affiliated transcription factors (TF) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early osteoclast development entails regulation of two alternative cell fate transcriptional programmes, osteoclast vs macrophage, with repression of the latter following activation of the former. Both programmes are regulated in a non-redundant manner by increased chromatin binding of Brd2 at promoters and of Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, regulates osteoclast development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TF. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation.
Grosicki S, Simonova M, Spicka I, et al., 2020, Once-weekly selinexor, bortezomib, and dexamethasone versus twice-weekly bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label phase 3 trial, The Lancet, Vol: 396, Pages: P1563-1573, ISSN: 0140-6736
Background Selinexor with dexamethasone has demonstrated activity in patients with heavily pretreated multiple myeloma (MM). In a phase 1b/2 study, the combination of oral selinexor with the proteasome inhibitor (PI) bortezomib, and dexamethasone (SVd) induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. The aim of this trial was to evaluate the clinical benefit of weekly SVd versus standard bortezomib and dexamethasone (Vd) in patients with previously treated MM.Methods This phase 3, randomised, open label trial was conducted at 123 sites in 21 countries. Patients who were previously treated with one to three lines of therapy, including PIs were randomised (1:1) to selinexor (100 mg once-weekly) plus bortezomib (1·3 mg/m2 once-weekly) and dexamethasone (20 mg twice-weekly) [SVd] or bortezomib (1·3 mg/m2 twice-weekly) and dexamethasone (20 mg 4 times per week) [Vd]. Randomisation was done using interactive response technology and stratified by previous PI therapy, lines of treatment, and MM stage. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562.Findings Between June 2017 and February 2019, 402 patients were randomised: 195 to SVd and 207 to Vd. Median PFS was 13·93 (95% CI 11·73–NE) with SVd versus 9·46 months (8·11–10·78) with Vd; HR 0·70, [95% CI 0·53–0·93]; P=0.0075. Most frequent grade ≥3 adverse events (SVd vs Vd) were thrombocytopenia (77 [40%] vs 35 [17%]), fatigue (26 [13%] vs 2 [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy rates (overall, 32·3% vs 47·1%; OR 0·52, [95% CI 0·35-0·79]; P=0.0010 and grade ≥2, 21&middo
Auner HW, Gavriatopoulou M, Delimpasi S, et al., 2020, Once Weekly Selinexor, Bortezomib, and Dexamethasone Versus Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Age and Frailty Subgroup Analyses from the Phase 3 Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Mateos M, Gavriatopoulou M, Facon T, et al., 2020, Effect of Prior Treatment with Proteasome Inhibitors on the Efficacy and Safety of Once-Weekly Selinexor, Bortezomib, and Dexamethasone in Comparison with Twice-Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Subgroup Analysis from the Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Richard S, Chari A, Delimpasi S, et al., 2020, Once Weekly Selinexor, Bortezomib, and Dexamethasone (SVd) Versus Twice Weekly Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma: High-Risk Cytogenetic Risk Planned Subgroup Analyses from the Phase 3 Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Sanchez L, Leleu X, Beaumont J, et al., 2020, Peripheral Neuropathy Symptoms, Pain and Functioning in Relapsed or Refractory Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Mateos M, Jagannath S, Delimpasi S, et al., 2020, Impact of Prior Therapies on the Safety and Efficacy of Once Weekly Selinexor, Bortezomib, and Dexamethasone Compared with Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Results from the Boston Study, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Hinsley S, Walker K, Sherratt D, et al., 2020, The MUK eight protocol: A randomised phase II trial of Cyclophosphamide and Dexamethasone in combination with Ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor, Trials, Vol: 21, ISSN: 1745-6215
BackgroundMultiple myeloma is a plasma cell tumour with approximately 5500 new cases in the UK each year. Ixazomib is a next generation inhibitor of the 20S proteasome and is thought to be an effective treatment for those who have relapsed from bortezomib. The combination of cyclophosphamide and dexamethasone (CD) is a recognised treatment option for patients with relapsed refractory multiple myeloma (RRMM) who have relapsed after treatment with bortezomib and lenalidomide, whilst also often being combined with newer proteasome inhibitors. The most apparent combination for ixazomib is therefore with CD.MethodsMUK eight is a randomised, controlled, open, parallel group, multi-centre phase II trial that will recruit patients with RRMM who have relapsed after treatment with thalidomide, lenalidomide, and a proteasome inhibitor. The primary objective of the trial is to evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improved clinical activity compared to CD in terms of progression-free survival (PFS). Secondary objectives include comparing toxicity profiles and the activity and cost-effectiveness of both treatments. Since opening, the trial has been amended to allow all participants who experience disease progression (as per the IMWG criteria) on the CD arm to subsequently switch to receive ICD treatment, once progression has been confirmed with two clinical members of the Trial Management Group (TMG). This ‘switch’ phase of the study is exploratory and will assess second progression-free survival measured from randomisation to second disease progression (PFS2) and progression-free survival from the point of switching to second disease progression (PFS Switch) in participants who switch from CD to ICD treatment.DiscussionDevelopment of ixazomib offers the opportunity to further investigate the value of proteasome inhibition through oral administration in the treatment of RRMM. Previous studies investigating the safe
Dimopoulos MA, Delimpasi S, Simonova M, et al., 2020, Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: Initial results of the phase III BOSTON study., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Saavedra-Garcia P, Martini F, Auner HW, 2020, Proteasome inhibition in multiple myeloma: lessons for other cancers, AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, Vol: 318, Pages: C451-C462, ISSN: 0363-6143
Morris C, Chabannon C, Masszi T, et al., 2020, Results from a multi-center, non-interventional registry study for multiple myeloma patients who received stem cell mobilization regimens with and without plerixafor, Bone Marrow Transplantation, Vol: 55, Pages: 356-366, ISSN: 1476-5365
Plerixafor plus granulocyte-colony stimulating factor (G-CSF) enhances the mobilization of haematopoietic stem cells (HSCs) for collection and subsequent autologous haematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma (MM).This international, multicenter, non-interventional registry study (NCT01362972), evaluated long-term outcomes for MM patients who received plerixafor versus other mobilization regimens. The comparisons were: G-CSF+plerixafor (G-CSF+P) versus G-CSF-; G-CSF+P versus G-CSF+chemotherapy (G-CSF+C); and G-CSF+P+C versus G-CSF+C. Propensity score matching was used to balance groups. Primary outcome measures were progression free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR) after transplantation. After propensity matching, 77 versus 41 patients in the G-CSF+P versus G-CSF cohorts, 129 versus 129 in the G-CSF+P versus G-CSF+C cohort and 117 versus 117 in the G-CSF+P+C versus G-CSF+C cohort, were matched, respectively. Propensity score matching resulted in a smaller sample size and imbalances were not completely overcome. For both PFS and OS, the upper limits of the hazard ratio 95% confidence intervals exceeded pre-specified boundaries; non-inferiority was not demonstrated. CIR rates were higher in the plerixafor cohorts. G-CSF+P remains an option for the mobilization of HSCs in poor-mobilizers with MM with no substantial differences in PFS, OS and CIR in comparison with other regimens.
Graziani G, Herget G, Ihorst G, et al., 2020, Time from first symptom onset to the final diagnosis of Multiple Myeloma (MM) - possible risks and future solutions: retrospective and prospective ‘Deutsche Studiengruppe MM’ (DSMM) and ‘European Myeloma Network’ (EMN) analysis, Leukemia and Lymphoma, Vol: 61, Pages: 875-886, ISSN: 1026-8022
Multiple Myeloma (MM) often presents with unspecific symptoms and is challenging to diagnose. We performed this DSMM/EMN-analysis via test-(retro-) and validation (prospective) study to determine the time interval from the onset of first symptoms to the diagnosis of MM. The retrospective and prospective analyses were performed in 101 and 176 patients, respectively. The median time from first symptoms to the MM diagnosis in both cohorts was 4 and 6 months, respectively. Frequencies of MM-related pathologic bone fractures, renal and infectious complications at diagnosis occurred in 41%, 35% and 16% of patients, respectively. Our MM-questionnaire determined that 39% of patients were dissatisfied with the diagnostic process. PFS and OS proved insignificantly different with shorter (≤6) and longer (>6 months) latency periods. In conclusion, our in depth studies demonstrate that delays in diagnosis do not decrease PFS or OS, but induce MM-related complications and influence patients' satisfaction with their medical care.
Ponnusamy K, Tzioni M-M, Begum M, et al., 2019, Novel ZBP1-IRF3 Dependency in Multiple Myeloma Mediated By IRF3-Driven Regulation of Cell Cycle Genes, BLOOD, Vol: 134, ISSN: 0006-4971
Saavedra-Garcia P, Al-Sadah HA, Penfold L, et al., 2019, Integrated Systems Level Examination of Proteasome Inhibitor Stress Recovery in Myeloma Cells Reveals Druggable Vulnerabilities Linked to Multiple Metabolic Processes, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Trasanidis N, Alvarez-Benayas J, Katsarou A, et al., 2019, Distinct Chromatin Accessibility Changes, Aberrant Transcription Factor Networks Combined with Novel Oncogenic Enhancers Characterise Myeloma-Initiating Genetic Events, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Caputo VS, Trasanidis N, Xiao X, et al., 2019, Myc and Bet Proteins Orchestrate the Early Regulatory Genome Changes Required for Osteoclast Lineage Commitment, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Brown SR, Hall A, Kendall J, et al., 2019, Muktwelve: A Randomized Phase II Trial of Selinexor, Cyclophosphamide and Prednisolone Vs Cyclophosphamide and Prednisolone in Relapsed or Refractory Multiple Myeloma (RRMM) Patients, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Trasanidis N, Katsarou A, Bergonia B, et al., 2019, PBX1 Co-Operates with FOXM1 to Regulate Myeloma Cell Proliferation and to Define an Ultra High-Risk chr1q Gain Myeloma Patient Subgroup, BLOOD, Vol: 134, ISSN: 0006-4971
Bringhen S, Milan A, D'Agostino M, et al., 2019, Prevention, monitoring and treatment of cardiovascular adverse events in myeloma patients receiving carfilzomib - A Consensus Paper by the European Myeloma Network and the Italian Society of Arterial Hypertension, Journal of Internal Medicine, Vol: 286, Pages: 63-74, ISSN: 0954-6820
The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies in relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib. An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome, the risk-benefit ratio of diagnostic and therapeutic tools and thereby to achieve myeloma response with novel combination approaches, while preventing CVAEs. Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment. A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions. This article is protected by copyright. All rights reserved.
Tornatore L, Capece D, D'Andrea D, et al., 2019, Clinical proof of concept for a safe and effective NF-κB-targeting strategy in multiple myeloma, British Journal of Haematology, Vol: 185, Pages: 588-592, ISSN: 1365-2141
Tornatore L, Capece D, D'Andrea D, et al., 2019, Preclinical toxicology and safety pharmacology of the first-in-class GADD45β/MKK7 inhibitor and clinical candidate, DTP3, Toxicology Reports, Vol: 6, Pages: 369-379, ISSN: 2214-7500
Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)β/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)β/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo, ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers.
Parzych K, Saavedra Garcia P, Valbuena G, et al., 2019, The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation, Oncogene, Vol: 38, Pages: 3216-3231, ISSN: 0950-9232
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.
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