1 Introduction
2 Proteasome inhibitors in leukemia
Class | Compounds | Binding to proteasome | Specificity and mechanisms |
---|---|---|---|
Peptide aldehydes | MG-132, ALLnL, ALLnM, LLnV, PSI | Reversible | Interact with the catalytic threonine residue of the proteasome. |
Peptide boronates | Bortezomib, MG-262, PS273 CEP-18770 (delanzomib) MLN9708/MLN2238 (ixazomib citrate/ixazomib) | Reversible | Selective proteasome inhibitors. Interact with the catalytic threonine residue of the proteasome. |
Peptide vinyl sulfones | NLVS, YLVS | Irreversible | Interact with β-subunits of the proteasome. |
Peptide epoxyketones | Dihydroeponemycin Epoxomycin PR-171 (carfilzomib) PR-047 (ONX 0912, oprozomib) | Irreversible | Selective proteasome inhibitors. Bind specifically to β5-subunit of the proteasome. |
PR-957 (ONX 0914) PR-924 | Selective immune proteasome inhibitors. Bind to immune β-subunits of the proteasome. | ||
β-Lactones | Lactacystin | Irreversible | Relatively specific but weak proteasome inhibitors. Binds to β-subunits of the proteasome. |
NPI-0052 (marizomib) | Irreversible | Binds to β-subunits of the proteasome. |
Proteasome inhibitors | Leukemic cells | Study results and mechanisms involved | Refs. |
---|---|---|---|
Several | AML cell line HL60 | Induction of apoptosis. Increase of p27Kip1. Activation of cysteine proteases. | [49] |
PSI | CML, AML, and ALL cell lines | Induction of apoptosis in all cell lines. Enhanced taxol and cisplatinum cytotoxicity. PSI was more active on leukemic than on normal CD34+ bone marrow progenitors. | [50] |
Lactacystin | AML cell line U937 | Lactacystin combined with PKC activator bryostatin enhanced apoptosis. | [51] |
Lactacystin, MG-132 | Primary CLL cells | Induction of apoptosis in both GC sensitive and resistant cells. Activation of cysteine proteases. Apoptosis is blocked by caspase antagonist zVADfmk. Inhibition of NF-κB. | [52] |
MG-132, LLnL, lactacystin | AML and ALL cell lines, primary AML cells | Synergistic interactions between PI and cyclin-dependent kinase inhibitors flavopiridol and roscovitine. Downregulation of XIAP, p21CIP1, and Mcl-1. | [53] |
Bortezomib | Primary CLL cells | Induction of apoptosis associated with release of SMAC and cytochrome c. | [54] |
Bortezomib | CML, AML, and ALL cell lines | Synergistic with flavopiridol. Blockade of the IκB/NF-κB pathway. Activation of the SAPK/JNK cascade. Reduction in activity of STAT3 and STAT5. | [55] |
Bortezomib | Primary CLL cells | Dose-dependent cytotoxicity of bortezomib. Additive effect with purine nucleoside analogues cladribine and fludaribine. CLL cells more sensitive than normal lymphocytes. | [56] |
Bortezomib | AML and ALL cell lines, primary pediatric AML and ALL cells | Lymphoblastoid, CML and AML cell lines. Bortezomib induced apoptosis and acted at least additive with dexamethasone, vincristine, asparaginase, cytarabine, doxorubicin, geldanamycin, HA14.1, and trichostatin A. | [57] |
Bortezomib | AML cell lines | Synergistic with tipifarnib. The combination overcomes cell adhesion-mediated drug resistance. | [58] |
Bortezomib | Pediatric ALL xenocraft model |
In vitro and in vivo activity of bortezomib against primary pediatric ALL cells in a xenocraft mouse model. | [59] |
Bortezomib, PSI | CML and AML cell lines | PSI enhanced toxicity of daunoblastin, taxol, cisplatinum, and bortezomib. PSI and bortezomib suppressed clonogenic potential of AML and CML more than that of normal bone marrow (NBM) progenitors. Bortezomib inhibited the clonogenic potential of CML and NBM more effectively. | [60] |
Carfizomib | Primary AML and ALL cells | Inhibits proliferation and induces apoptosis AML, inhibits proliferation in ALL. | [61] |
Carfilzomib, bortezomib | AML cell lines and primary AML cells | Synergistic effect on proteotoxic stress together with the protease inhibitors ritonavir, nelfinavir, saquinavir, and lopinavir. | [62] |
Carfilzomib, bortezomib | ALL cell lines in vitro and in xenograft model | Proteasome inhibitors evoke latent tumor suppression programs in pro-B MLL leukemia through MLL-AF4. | [63] |
Carfilzomib | MM, AML, Burkitt’s lymphoma cell lines | Induces proapoptotic sequelae, including proteasome substrate accumulation, Noxa and caspase 3/7 induction, and phospho-eIF2α suppression. | [13] |
Marizomib | ALL, AML, and CML cell lines and in xenograft model | Induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors. | |
Marizomib, bortezomib | AML and ALL cell lines | Anti-leukemic activity, synergistic in combination with bortezomib. | [31] |
ONX 0914 | AML and ALL cell lines | Growth inhibition, proteasome inhibitor-induced apoptosis, activation of PARP cleavage and accumulation of polyubiquitinated proteins. | [16] |
PR-924 | AML and ALL cell lines | Growth inhibition, immune proteasome inhibition, apoptosis, activation of PARP cleavage. | [29] |
Ixazomib | Primary CLL cells | Annexin-V staining, PARP1 and caspase-3 cleavage and an increase in mitochondrial membrane permeability, apoptosis was only partially blocked by the pan-caspase inhibitor z-VAD-fmk. | [66] |
3 Markers for PI (BTZ) sensitivity/resistance in leukemia cell lines
3.1 Upregulation of proteasomal subunits
3.2 PSMB5 mutations
3.3 Alternative protein disposal
3.4 Activation of pro-survival pathways
3.5 X-box binding protein 1 (XBP1)
3.6 Drug efflux transporters
4 Markers for PI (BTZ) sensitivity/resistance in primary leukemia samples
4.1 Proteasome levels and subunit composition
4.2 PSMB5 mutations
4.3 MARCKS
5 Clinical trials with proteasome inhibitors in leukemia
Study drugs | Cohort | Number | Phase | Study results and mechanisms involved | Refs. |
---|---|---|---|---|---|
BTZ | Several hematologic malignancies | 27 | I | Bortezomib was given twice weekly for 4 weeks every 6 weeks. The MTD was 1.04 mg/m2. CR in 1 MM patient. PR in 1 patient with MCL and 1 with FL. | [128] |
BTZ | Refractory or relapsed acute leukemia | 15 | I | Bortezomib was given twice weekly for 4 weeks every 6 weeks. The MTD was 1.25 mg/m2. No ≥grade 3 toxicities. 5 patients showed hematological improvement. No CR achieved. | [129] |
BTZ, PegLD | AML, MM, and NHL | 42 | I | Bortezomib was given on days 1, 4, 8, and 11 and PedLD on day 4. MTD of BTZ 1.3 mg/m2. No significant pharmacokinetic and pharmacodynamic interactions between bortezomib and PegLD. 16 of 22 MM patients achieved CR, near-CR or PR. 1 CR and 1 PR in NHL patients. 2 of 2 AML patients achieved a PR. | [130] |
BTZ | Recurrent childhood ALL, AML, blastic phase CML, M3 | 12 | I | Bortezomib was administered twice weekly for 2 weeks followed by a 1-week rest. MTD of bortezomib was 1.3 mg/m2/dose. 5 patients were fully evaluable. DLT’s occurred in 2 patients at the 1.7 mg/m2 dose level. No OR achieved. | [131] |
BTZ, IDA, AraC | AML | 31 | I | Addition of BTZ to AML induction chemotherapy. Bortezomib added on days 1, 4, 8, and 11. 19 CR, 3 CRp, 2 PR and 7 no response. BTZ was well-tolerated up to 1.5 mg/m2. | [132] |
BTZ, VCR, DEX, PegAspa, DOX | Recurrent childhood ALL | 10 | I | Combination of bortezomib (1.3 mg/m2) with ALL induction therapy is active with acceptable toxicity. 6 patients achieved CR. | [133] |
BTZ, VCR, DEX, PegAspa, DOX | Recurrent childhood ALL | 22 | II | 14 patients achieved CR, and 2 achieved CRp, 3 patients died from bacterial infections, 2 of 2 included T cell ALL patients did not respond. | [134] |
BTZ, tipifarnib | Relapsed or refractory ALL(26) or AML (1) | 27 | I | Combination well tolerated. 2 patients achieved CRp and 5 SD. | [135] |
BTZ, DNR, AraC | AML (age > 65) | 95 | I/II | Combination was tolerated. 62 patients achieved CR and 4 patients CRp. | [136] |
BTZ, 17-AAG | Relapsed or refractory AML | 11 | I | The combination of 17-AAG and BTZ led to toxicity without measurable response in patients with relapsed or refractory AML. | [137] |
BTZ, DAC | Poor-risk AML | 19 | I | Combination was tolerable and active in this cohort of AML patients; 7 of 19 patients had CR or CRi. 5 of 10 patients > 65 years had CR. | [138] |
BTZ, LEN | 14 MDS/CMML 9 AML | 23 | I | MTD of BTZ 1.3 mg/m2 was tolerable in this regimen. Responses were seen in patients with MDS and AML. Two fatal infections occurred. | [139] |
BTZ, IDA | Relapsed AML (7) or AML > 60 years (13) | 20 | I | 4 patients achieved complete remission. 1 treatment-related death. Overall the combination was well tolerated. | [140] |
BTZ, AZA | Relapsed or refractory AML | 23 | I | Dose of 1.3 mg/m2 BTZ was reached without dose-limiting toxicities. 5 out of 23 patients achieved CR. | [141] |
BTZ, MIDO vs BTZ, MIDO, DHAD, etoposide, AraC | Relapsed/refractory AML | 21 | I | 56.5% CR rate and 82.5% overall response rate (CR + CR with incomplete neutrophil or platelet count recovery). Combination is active but is associated with expected drug-related toxicities. DLTs were peripheral neuropathy, decrease in ejection fraction and diarrhea. | [142] |
CFZ + dexamethasone | Refractory or relapsed acute leukemia | 18 | I | CFZ was given twice weekly for 4 weeks with a maximal of 6 cycles. Prior to CFZ dexamethasone was given. The MTD was not established, because no DLTs were observed (36–46 mg/m2). PR in 2/10 patients and 4/10 SD. | [143] |
CFZ + dexamethasone | Previously treated patient with CLL or SLL | 19 | I | CFZ was given twice weekly for 3 weeks in a 28-day cycle. Prior to CFZ dexamethasone was given. No DLTs observed and all available patients for evaluation had SD (including patients with Del(17p13.1) and fludarabine-resistant disease. | [144] |
BTZ, cytarabine, idarubicin vs BTZ, cytarabine etoposide | Children with relapsed, refractory, or secondary AML | 37 | II | BTZ, 1 or 1.3 mg/m2, was given at days 1, 4, and 8 in combination with idarubicin and cytarabine (arm A) or with etoposide and high dose cytarabine (arm B). Hypokalemia incidence was high, 17%. Four deaths occur, 3 infectious deaths and one from PD. Both arms failed to meet predetermined efficacy thresholds (CRi was not included). Arm A: CR = 21.4%, CRp + CRi = 35.6%, PR = 14.3%. Arm B: CR = 34.8%, CRp + CRi = 13% and one death. | [145] |
BTZ | Relapsed/refractory ATL | 15 | II | BTZ, 1.3 mg/m2, was given at days 1, 4, 8, and 11. After stage 1, all patients discontinued treatment (PD = 11, AEs = 3) and the study was terminated because BTZ was not considered promising enough as a single agent. 12 patients had Gr 3/4 drug-related AEs of which 2 Gr3/4 peripheral neuropathy. Overall responses: PR = 1, SD = 5. ORR = 6.7%, PFS = 38 days (8–122). | [146] |
BTZ, DEX, DOX vs BTZ, DEX, cyclophosphamide | Newly diagnosed primary plasma cell leukemia | 39 | II | Four alternating cycles of BTZ (1.3 mg/m2 on days 1, 4, 8, and 11), DEX plus DOX, or cyclophosphamide was given. 35 patients completed the 4 cycles. ORR = 69%, CR = 10%, VGPR = 26%, PR = 23%. 10 were refractory to the induction phase, and 2 deaths due to sepsis occur. 25 patients underwent HDM/ASCT and 1 a syngeneic allograft. After ASCT: ORR = 92% CR = 34%, VGPR = 38%, PR = 16%, PD = 8%. In the intention-to-treat population, the median PFS = 15.1 months and overall survival = 36.3 months. | [147] |
Study drugs | Time period | Number | Phase | Cohort | Age | Sponsor | Clinical trial identifier |
---|---|---|---|---|---|---|---|
BTZ + intensive reinduction chemotherapy | Mar 2009 Sept 2014 | 60 | II | Relapsed ALL | 1–31 | National Cancer Institute (USA) | NCT00873093 |
BTZ, DEX, VCR, MTX | Sep 2009 Jul 2014 | 24 | II | Relapsed/refractory ALL | 0.5–19 | Erasmus Medical Center (Rotterdam, The Netherlands) | NTR1881a
|
BTZ, ATO | May 2013 May 2018 | 30 | II | Relapsed acute promyelocytic leukemia (APL) | 1–75 | Christian Medical College (Vellore, India) | NCT01950611 |
Standard leukemia chemotherapy ± BTZ | Apr 2014 Feb 2019 | 1400 | III | T cell ALL or stages II–IV T cell lymphoblastic lymphoma | 2–30 | National Cancer Institute (USA) | NCT02112916 |
BTZ, SAHA + reinduction chemotherapy | Apr 2015 Apr 2019 | 30 | II | Refractory or relapsed MLL rearranged leukemia | < 21 | St Jude Children’s Research Hospital (Memphis, TN, USA) | NTC 02419755 |
BTZ, PANO + reinduction chemotherapy | Dec 2015 Apr 2019 | 40 | II | Relapsed T cell leukemia or lymphoma | < 21 | St Jude Children’s Research Hospital (Memphis, TN, USA) | NCT02518750 |
BTZ + induction chemotherapy | Oct 2015 Oct 2020 | 50 | I/II | Infant leukemia and lymphoblastic lymphoma | < 1 | St Jude Children’s Research Hospital (Memphis, TN, USA) | NCT02553460 |
BTZ + reinduction chemotherapy | July 2015 Apr 2019 | 20 | II | Refractory or relapsed leukemia and lymphoblastic lymphoma | 1–39 | Children’s Mercy Hospital (Kansas City) | NCT02535806 |
BTZ + HR reinduction chemotherapy | Aug 2015 Aug 2018 | 250 | II | High-risk (HR) relapsed ALL | < 18 | Charité - Universitätsmedizin (Berlin, Germany) | EudraCT number: 2012–000810-12a
|
Study drugs | Time period | Number | Phase | Cohort | Age | Sponsor | Clinical trial ID |
---|---|---|---|---|---|---|---|
BTZ, DHAD, VP16, AraC | Jan 2006 Sept 2016 | 55 | I/II | Relapsed/refractory acute leukemia | > 18 | Thomas Jefferson University (PA, USA) | NCT00410423 |
BTZ, FLAG, IDA | Apr 2008 Jan 2013 | 40 | I/II | Refractory or relapsed AML | > 18 | PETHEMA Foundation | NCT00651781 |
BTZ, SAHA, SFN | Feb 2010 Sept 2016 | 38 | I/II | Poor-risk AML | > 18 | Indiana University (IN, USA) | NCT01534260 |
BTZ, BEL | May 2010 Feb 2014 | 24 | I | Relapsed/refractory acute leukemia | > 18 | Virginia Commonwealth University (VA, USA) | NCT01075425 |
BTZ, NFV | July 2010 Mar 2013 | 18 | I | Relapsed or progressive advanced hematologic cancer | > 18 | Swiss Group for Clinical Cancer Research (Switzerland) | NCT01164709 |
BTZ, DHAD, VP16, AraC | July 2010 May 2014 | 34 | I | Relapsed/refractory AML | 18–70 | Case Comprehensive Cancer Center (OH, USA) | NCT01127009 |
Several drugs in randomization arms ± BTZ | June 2011 June 2017 | 1250 | III | Initial AML | > 29 | National Cancer Institute (USA) | NCT01371981 |
DAC vs BTZ, DAC | Nov 2011 June 2015 | 172 | II | AML | > 60 | National Cancer Institute (USA) | NCT01420926 |
BTZ, DOX, PegAspa, VCR, DEX, AraC, MTX | Mar 2013 July 2017 | 17 | II | Relapsed/refractory ALL | > 18 | National Cancer Institute (USA) | NCT01769209 |
BTZ, SFN, DAC | July 2013 Dec 2016 | 30 | I | AML | > 60 | National Cancer Institute (USA) | NCT01861314 |
BTZ, DOX | Mar 2015 Mar 2017 | 30 | II | AML | 18–80 | University of California, Davis (CA, USA) | NCT01736943 |
BTZ, LEN | Mar 2015 Aug 2018 | 24 | I | Relapsed AML and MDS after Alllo SCT | > 18 | Massachusetts General Hospital (MA, USA) | NCT023121 |
Study drugs | Time period | Number | Phase | Cohort | Age | Sponsor | Clinical trial ID |
---|---|---|---|---|---|---|---|
CFZ | Sept 2010 Jul 2015 | 18 | I | Relapsed/refractory ALL and AML | > 18 | Washington University School of Medicine (MO, USA) | NCT01137747 |
IXA, DHAD, VP16, AraC | May 2014 Nov 2017 | 30 | I | Relapsed/refractory AML | 18–70 | Case Comprehensive Cancer Center; National Cancer Institute (NCI) | NCT02070458 |
IXA | Mar 2014 Mar 2016 | 16 | II | Relapsed/refractory AML | > 18 | Stanford university/National Cancer Institute (NCI) | NCT02030405 |
IXA, DHAD, VP16, AraC | Oct 2014 Nov 2018 | 30 | I | Relapsed/refractory AML | 18–70 | Case Comprehensive Cancer Center (USA) | NCT 02070458 |
CFZ, DEX, DHAD, PegAspa, VCR | Dec 2014 Jul 2017 | 39 | I/II | Relapsed/refractory AML | < 18 | Onyx Therapeutics Inc. (CA, USA) | NCT02303821 |
CFZ, CYCLO, VP16 | Jul 2015 Dec 2017 | 50 | I | Relapsed leukemia and solid tumors | 6–29 | Phoenix Children’s Hospital (AZ, USA) | NCT 02512926 |
IXA + induction and consolidation chemotherapy | Nov 2015 Feb 2022 | 54 | I | AML | > 60 | Massachusetts General Hospital (MA, USA) | NCT02582359 |