Preclinical and clinical studies of pevonedistat
| Malignancy | Key Effects | Reference |
|---|---|---|
| Acute lymphoblastic leukemia | Preclinical efficacy in T-ALL models via induction of nucleolar stress signaling | Han et al., 2016 |
| Preclinical efficacy in ALL models via ER stress and synergistic effects with dexamethasone, doxorubicin, and cytarabine | Leclerc et al., 2016 | |
| Inhibition of the MEK/ERK pathway sensitizes ALL to pevonedistat in vitro and in vivo | Zheng et al., 2017a | |
| Acute myeloid leukemia | Preclinical efficacy via NF-κB pathway inhibition, DNA damage, and ROS generation | Swords et al., 2010 |
| Sensitization of AML cell lines to retinoic acid differentiation therapy | Tan et al., 2011 | |
| Preclinical efficacy in FLT3-ITD AML models via NF-κB inhibition and downregulation of miR-155 | Khalife et al., 2015 | |
| Antitumor effects in AML cells via Noxa upregulation as well as synergistic effects with Bcl-2 inhibitors | Knorr et al., 2015 | |
| Synergistic antileukemic effects with cytarabine in AML cells and mouse models via disruption of nucleotide metabolism | Nawrocki et al., 2015 | |
| Phase 1 clinical trial showing tolerability and modest clinical activity in patients with AML and MDS | Swords et al., 2015 | |
| Synergistic effects with the IAP antagonist T-3256336 in cell lines and in vivo | Sumi et al., 2016 | |
| Synergistic combination with azacytidine in preclinical models of AML via antagonizing RRM2 | Visconte et al., 2016 | |
| Synergistic combination with belinostat in preclinical models of AML/MDS by reciprocal inhibition of specific DNA repair pathways | Zhou et al., 2016 | |
| Synergistic combination with the LSD1 inhibitor T-3775440 in preclinical models of AML via trans-differentiation and DNA re-replication | Ishikawa et al., 2017 | |
| Expanded safety analysis of pevonedistat in patients with AML/MDS with serious toxicity (e.g., hepatotoxicity and sepsis syndromes with multiorgan failure) only observed at doses beyond 100 mg/m2 | Swords et al., 2017 | |
| Phase 1b clinical trial of pevonedistat in combination with azacytidine showing tolerability and potential benefit | Swords et al., 2018 | |
| Breast cancer | Radiosensitization of breast cancer cells via induction of p21 accumulation | Yang et al., 2012 |
| Cervical carcinoma | Preclinical efficacy in models of CC as well as potentiation of cisplatin cytotoxicity | Lin et al., 2015 |
| Cholangiocarcinoma | Preclinical efficacy in ICC models and additive effects with cisplatin | Gao et al., 2014 |
| Chronic lymphocytic leukemia | Antitumor effects in primary CLL B cells cocultured with stromal cells via NF-κB pathway inhibition | Godbersen et al., 2014 |
| Antitumor effects in primary CLL B cells cocultured with stromal cells via CDT1 accumulation and sensitization of cells to alkylating agents | Paiva et al., 2015 | |
| Sensitization of primary CLL cells cocultured with stromal cells to death receptor agonists by enhancing death receptor signaling | Paiva et al., 2017 | |
| Chronic myeloid leukemia | Preclinical efficacy in CML models associated with p27 accumulation and overcoming mutation- and LSC-driven imatinib resistance | Liu et al., 2018 |
| Colorectal cancer | Antitumor effects via DNA re-replication in CRC cell lines | Lin et al., 2010 |
| Preclinical efficacy in models of poorly differentiated, clinically aggressive CRC with a transcriptional signature associated with pevonedistat sensitivity | Picco et al., 2016 | |
| Sensitization of CRC cells to oxaliplatin via induction of DNA damage and CHK2 phosphorylation | Zheng et al., 2017b | |
| Esophageal cancer | Preclinical efficacy in ESCC models via ATF4-CHOP-DR5 axis-mediated extrinsic apoptosis | Chen et al., 2016a |
| Ewing sarcoma | Preclinical efficacy in ES models via WEE1 accumulation and deregulation of S-phase proteins | Mackintosh et al., 2013 |
| Gastric cancer | Antitumor effects in gastric cancer cells associated with protective p27 upregulation | Zhang et al., 2015b |
| Antitumor effects in gastric cancer cells associated with DNA damage induction, senescence, and autophagy | Lan et al., 2016 | |
| Glioblastoma | Preclinical efficacy in models of GBM associated with induction of apoptosis and senescence | Hua et al., 2015 |
| Pevonedistat promotes migration of GBM cells via induction of caveolin-1 phosphorylation | Park et al., 2018 | |
| Upregulation of PD-L1 expression and synergism with anti–PD-L1 therapy in GBM models | Zhou et al., 2019b | |
| Head and neck cancer | Antitumor effects in combination with TRAIL via promoting c-FLIP degradation in HNSCC cell lines | Zhao et al., 2011 |
| Preclinical efficacy in HNSCC models and radiosensitization of HNSCC cells | Vanderdys et al., 2018 | |
| Liver cancer | Preclinical efficacy associated with induction of protective autophagy and apoptosis in HCC models | Luo et al., 2012 |
| Preclinical efficacy in Phb1-KO mouse models of HCC by destabilizing LKB1 and Akt | Barbier-Torres et al., 2015 | |
| Synergistic effects with autophagy inhibitors in cell lines and mouse models of HCC | Chen et al., 2015 | |
| Lung cancer | Antitumor effects in KrasG12D-driven lung cancer models via inhibition of NF-κB and mTOR pathways | Li et al., 2014a |
| Preclinical efficacy and synergistic antitumor effects with platinum in lung adenocarcinoma models | Li et al., 2014b | |
| Synergistic effects with the PARP inhibitor olaparib in NSCLC cell lines via inhibiting BRCA1 recruitment to DNA damage sites | Guo et al., 2017 | |
| Antitumor effects in paclitaxel-resistant human lung adenocarcinoma cells with no synergism with paclitaxel | Xu et al., 2018b | |
| Lymphoma | Preclinical efficacy in DLBCL via NF-κB pathway inhibition and DNA re-replication | Milhollen et al., 2010 |
| Antitumor effects in MCL cells via stabilization of Noxa | Dengler et al., 2014 | |
| Antitumor effects in lymphoma cell lines associated with apoptosis and senescence | Wang et al., 2015 | |
| Preclinical efficacy in MCL models and additive/synergistic antitumor effects with conventional therapies | Czuczman et al., 2016 | |
| Phase 1 clinical trial showing tolerability and pharmacodynamic effects in relapsed/refractory lymphoma | Shah et al., 2016 | |
| Sensitization of DLBCL cells to the death receptor agonists TRAIL and FasL by enhancing death receptor signaling | Paiva et al., 2017 | |
| Melanoma | A genome-wide siRNA screen identified the p21-dependent intra–S-phase checkpoint as a key mediator of pevonedistat cytotoxicity in melanoma cells independent of CDT1 stabilization | Blank et al., 2013 |
| Preclinical efficacy in melanoma models via DNA re-replication and senescence and synergistic effects with the BRAF kinase inhibitor vemurafenib | Benamar et al., 2016 | |
| Phase 1 clinical trial showing tolerability and durable stable disease in a subset of patients | Bhatia et al., 2016 | |
| Preclinical efficacy and antimetastatic effects in UM models via antiangiogenic and anti-CSC effects | Jin et al., 2018 | |
| Preclinical efficacy in models of melanoma and gene expression differences between sensitive and resistant cell lines | Wong et al., 2017 | |
| Mesothelioma | Preclinical efficacy in NF2-mutant mesothelioma models and synergistic effects with mTOR inhibitors | Cooper et al., 2017 |
| Myeloma | Preclinical efficacy and additive effects with conventional drugs in MM models | McMillin et al., 2012 |
| Antitumor effects in MM cells via upregulation of REDD1 and subsequent inhibition of AKT and mTOR signaling | Gu et al., 2014 | |
| Antitumor effects in CKS1B-overexpressing MM cell lines via p21 stabilization | Huang et al., 2015 | |
| Phase 1 clinical trial showing tolerability and pharmacodynamic effects in relapsed/refractory MM | Shah et al., 2016 | |
| Synergistic cytotoxicity with pomalidomide using sequential treatment schedule in MM cells | Liu et al., 2019 | |
| Nasopharyngeal carcinoma | Preclinical efficacy in NPC models associated with stabilization of c-Jun and synergistic effects with radio- and chemotherapy | Xie et al., 2017 |
| Osteosarcoma | Preclinical efficacy in OS models associated with induction of senescence and apoptosis | Zhang et al., 2016 |
| Genetic and chemical inhibitors of Mcl-1 sensitize OS cells to pevonedistat | Zhang et al., 2017 | |
| Ovarian cancer | Synergistic effects with platinum in ovarian cancer cells | Jazaeri et al., 2013 |
| Synergistic effects with cisplatin in ovarian cancer cells and mouse xenograft models | Nawrocki et al., 2013 | |
| Antitumor effects alone and in combination with conventional therapies in EOC cells | Pan et al., 2013 | |
| Synergistic effects with the IAP antagonist T-3256336 in an ovarian cancer cell line | Sumi et al., 2016 | |
| Antagonistic effects with paclitaxel in ovarian cancer cells | Hong et al., 2019 | |
| Pancreatic cancer | Radiosensitization of preclinical models of pancreatic cancer | Wei et al., 2012 |
| Antiangiogenic and antimetastatic effects in pancreatic cancer models | Yao et al., 2014 | |
| Sensitization of preclinical models of PDAC to gemcitabine via accumulation of Noxa and ERBIN | Misra et al., 2017 | |
| Potentiating the antitumor effects of pevonedistat by the Chk1 inhibitor SCH 900776 in preclinical models of pancreatic cancer | Li et al., 2018 | |
| Pediatric cancers | Preclinical efficacy in a subset of pediatric tumors tested in the Pediatric Preclinical Testing Program (PPTP) | Smith et al., 2012 |
| Prostate cancer | Antitumor effects in prostate cancer cells with apoptosis observed only at high concentrations | Rulina et al., 2016 |
| Radiosensitization of hormone-resistant prostate cancer cells via accumulation of WEE1, p21, and p27 | Wang et al., 2016 | |
| Pevonedistat promotes migration of prostate cancer cells via induction of caveolin-1 phosphorylation | Park et al., 2018 | |
| Renal cell carcinoma | Antitumor effects in CCRCC cell lines via induction of DNA damage and suppression of EMT | Tong et al., 2017 |
| Antitumor effects in RCC cell lines via upregulation of Noxa | Wang et al., 2017 | |
| Preclinical efficacy in RCC models associated with the induction of cell cycle arrest, senescence, and apoptosis | Xu et al., 2018a | |
| Solid cancers | Chemical/biochemical characterization and preclinical evaluation in models of CRC and lung cancer | Soucy et al., 2009a |
| Antitumor effects via induction of senescence in CRC, lung, and GBM cell lines | Jia et al., 2011 | |
| Antitumor effects via DNA re-replication in CRC and breast cancer cell lines | Milhollen et al., 2011 | |
| Synergistic effects with DNA interstrand cross-linking agents in CRC and breast cancer cell lines | Kee et al., 2012 | |
| Inhibition of autophagy sensitizes solid cancer cell lines to pevonedistat | Zhao et al., 2012 | |
| Synergistic effects with mitomycin C, cisplatin, cytarabine, UV radiation, SN-38, and gemcitabine | Garcia et al., 2014 | |
| Selective antitumor effects in solid CRC and melanoma cell lines as well as zebrafish embryos in a p53-based cyclotherapy to selectively target p53-mutant cells | Malhab et al., 2016 | |
| Phase 1 clinical trial showing tolerability and pharmacodynamic effects of pevonedistat | Sarantopoulos et al., 2016 | |
| Phase 1b clinical trial showing tolerability in combination with either docetaxel or carboplatin + paclitaxel with sustained clinical responses in the latter combination | Lockhart et al., 2019 | |
| Urothelial carcinoma | Synergistic effects with cisplatin in urothelial cancer cell lines and mouse xenograft models | Ho et al., 2015 |
| Preclinical efficacy in UC models associated with ER stress induction, cell cycle arrest, and apoptosis | Kuo et al., 2015 |
Akt, AKR thymoma protein; ALL, acute lymphoblastic leukemia; ATF4, activating transcription factor 4; Bcl-2, B-cell lymphoma 2; BRCA1, breast cancer type 1 susceptibility protein; CC, cervical carcinoma; CCRCC, clear cell renal cell carcinoma; c-FLIP, cellular FADD-like IL-1β-converting enzyme-inhibitory protein; CHK, checkpoint kinase; CHOP, C/EBP-homologous protein; CKS1B, cyclin-dependent kinases regulatory subunit 1; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CRC, colorectal cancer; CSC, cancer stem cell; DLBCL, diffuse large B-cell lymphoma; DR5, death receptor 5; EMT, epithelial-to-mesenchymal transition; EOC, epithelial ovarian cancer; ERBIN, ES, Ewing sarcoma; ESCC, esophageal squamous cell carcinoma; FasL, tumor necrosis factor receptor superfamily member 6 ligand; FLT3-ITD, Fms-like tyrosine kinase 3-internal tandem duplication; GBM, glioblastoma; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; IAP, inhibitor of apoptosis protein; ICC, intrahepatic cholangiocarcinoma; KO, knockout; KRAS, Kirsten rat sarcoma viral oncogene homolog; LSC, leukemic stem cell; LSD1, lysine-specific demethylase 1A; MCL, mantle cell lymphoma; MEK, MAPK/ERK kinase; miR-155, microRNA-155; NF2, neurofibromatosis type 2; NPC, nasopharyngeal carcinoma; NSCLC, non–small-cell lung cancer; OS, osteosarcoma; PARP, poly (ADP-ribose) polymerase; PDAC, pancreatic ductal adenocarcinoma; PD-L1, programmed death-ligand 1; Phb1, prohibitin 1; RCC, renal cell carcinoma; REDD1, regulated in development and DNA damage responses 1; RRM2, ribonucleoside-diphosphate reductase; siRNA, small interfering RNA; T-ALL, T-cell acute lymphoblastic leukemia; UC, urothelial carcinoma; UM, uveal melanoma.