Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
19 Dec 2023
19 Dec 2023
Historique:
received:
25
08
2023
accepted:
30
11
2023
revised:
23
11
2023
medline:
20
12
2023
pubmed:
20
12
2023
entrez:
19
12
2023
Statut:
aheadofprint
Résumé
CFI-400945 is a selective oral polo-like kinase 4 (PLK4) inhibitor that regulates centriole duplication. PLK4 is aberrantly expressed in patients with acute myeloid leukemia (AML). Preclinical studies indicate that CFI-400945 has potent in vivo efficacy in hematological malignancies and xenograft models, with activity in cells harboring TP53 mutations. In this phase 1 study in very high-risk patients with relapsed/refractory AML and myelodysplastic syndrome (MDS) (NCT03187288), 13 patients were treated with CFI-400945 continuously in dose escalation from 64 mg/day to 128 mg/day. Three of the 9 efficacy evaluable AML patients achieved complete remission (CR). Two of 4 AML patients (50%) with TP53 mutations and complex monosomal karyotype achieved a CR with 1 patient proceeding to allogenic stem cell transplant. A third patient with TP53 mutated AML had a significant reduction in marrow blasts by > 50% with an improvement in neutrophil and platelet counts. Responses were observed after 1 cycle of therapy. Dose-limiting toxicity was enteritis/colitis. A monotherapy and combination therapy study with a newer crystal form of CFI-400945 in patients with AML, MDS and chronic myelomonocytic leukemia (CMML) is ongoing (NCT04730258).
Identifiants
pubmed: 38114624
doi: 10.1038/s41375-023-02110-9
pii: 10.1038/s41375-023-02110-9
doi:
Banques de données
ClinicalTrials.gov
['NCT04730258']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Princess Margaret Cancer Foundation (PMCF)
ID : n/a
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
Références
DiNardo CD, Erba HP, Freeman SD, Wei AH. Acute myeloid leukaemia. Lancet. 2023;401:2073–86.
pubmed: 37068505
doi: 10.1016/S0140-6736(23)00108-3
Dohner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140:1345–77.
pubmed: 35797463
doi: 10.1182/blood.2022016867
Grob T, Al Hinai ASA, Sanders MA, Kavelaars FG, Rijken M, Gradowska PL, et al. Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2022;139:2347–54.
pubmed: 35108372
doi: 10.1182/blood.2021014472
Daver NG, Maiti A, Kadia TM, Vyas P, Majeti R, Wei AH, et al. TP53-mutated myelodysplastic syndrome and acute myeloid leukemia: biology, current therapy, and future directions. Cancer Discov. 2022;12:2516–29.
pubmed: 36218325
pmcid: 9627130
doi: 10.1158/2159-8290.CD-22-0332
Deeg HJ. Optimization of transplant regimens for patients with myelodysplastic syndrome (MDS). Hematology Am Soc Hematol Educ Program. (2005):167–73.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32.
pubmed: 19230772
pmcid: 4086808
doi: 10.1016/S1470-2045(09)70003-8
Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–803.
pubmed: 16532500
doi: 10.1002/cncr.21792
Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–40.
pubmed: 12011120
doi: 10.1200/JCO.2002.04.117
Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24:3895–903.
pubmed: 16921040
doi: 10.1200/JCO.2005.05.4346
Prebet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29:3322–7.
pubmed: 21788559
pmcid: 4859209
doi: 10.1200/JCO.2011.35.8135
Mason JM, Lin DC, Wei X, Che Y, Yao Y, Kiarash R, et al. Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell. 2014;26:163–76.
pubmed: 25043604
doi: 10.1016/j.ccr.2014.05.006
Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 2006;7:96.
pubmed: 16643655
pmcid: 1468408
doi: 10.1186/1471-2164-7-96
van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009.
pubmed: 12490681
doi: 10.1056/NEJMoa021967
Macmillan JC, Hudson JW, Bull S, Dennis JW, Swallow CJ. Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer. Ann Surg Oncol. 2001;8:729–40.
pubmed: 11597015
doi: 10.1007/s10434-001-0729-6
He Y, Wang H, Yan M, Yang X, Shen R, Ni X, et al. High LIN28A and PLK4 co‑expression is associated with poor prognosis in epithelial ovarian cancer. Mol Med Rep. 2018;18:5327–36.
pubmed: 30365085
pmcid: 6236221
Salvatore G, Nappi TC, Salerno P, Jiang Y, Garbi C, Ugolini C, et al. A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. Cancer Res. 2007;67:10148–58.
pubmed: 17981789
doi: 10.1158/0008-5472.CAN-07-1887
Chng WJ, Braggio E, Mulligan G, Bryant B, Remstein E, Valdez R, et al. The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition. Blood. 2008;111:1603–9.
pubmed: 18006703
doi: 10.1182/blood-2007-06-097774
Mu XR, Ma MM, Lu ZY, Liu J, Xue YT, Cao J, et al. Effects of the PLK4 inhibitor Centrinone on the biological behaviors of acute myeloid leukemia cell lines. Front Genet. 2022;13:898474.
pubmed: 36051696
pmcid: 9424683
doi: 10.3389/fgene.2022.898474
Kolosenko I, Goroshchuk O, Vidarsdottir L, Bjorklund AC, Dowdy SF, Palm-Apergi C. RNAi prodrugs decrease elevated mRNA levels of Polo-like kinase 1 in ex vivo cultured primary cells from pediatric acute myeloid leukemia patients. FASEB J. 2021;35:e21476.
pubmed: 33788972
doi: 10.1096/fj.202002454RR
Chen S, Zhong L, Chu X, Wan P, Liu Z, Lu Y, et al. Downregulation of Polo-like kinase 4 induces cell apoptosis and G2/M arrest in acute myeloid leukemia. Pathol Res Pract. 2023;243:154376.
pubmed: 36821942
doi: 10.1016/j.prp.2023.154376
Ayoub E, Marupudi A, Nishida Y, Montoya RH, Mohanty V, Walter W, et al. Polyploidy Is necessary for apoptotic cell death in TP53-mut AML in response to polo-like-kinase 4 (PLK4) inhibition and results in caspase 3 cleavage. Blood. 2022;140:5941–3.
doi: 10.1182/blood-2022-170152
Portelinha A, da Silva Ferreira M, Erazo T, Jiang M, Asgari Z, de Stanchina E, et al. Synthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma. Nat Commun. 2023;14:1522.
pubmed: 36934096
pmcid: 10024740
doi: 10.1038/s41467-023-37216-2
Lohse I, Mason J, Cao PM, Pintilie M, Bray M, Hedley DW. Activity of the novel polo-like kinase 4 inhibitor CFI-400945 in pancreatic cancer patient-derived xenografts. Oncotarget. 2017;8:3064–71.
pubmed: 27902970
doi: 10.18632/oncotarget.13619
Kawakami M, Mustachio LM, Zheng L, Chen Y, Rodriguez-Canales J, Mino B, et al. Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers. Proc Natl Acad Sci USA. 2018;115:1913–8.
pubmed: 29434041
pmcid: 5828621
doi: 10.1073/pnas.1719760115
Sampson PB, Liu Y, Forrest B, Cumming G, Li SW, Patel NK. et al. The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5•’-methoxyspiro[cyclopropane-1,3•’-indolin]-2•’-one (CFI-400945) as a potent, orally active antitumor agent. J Med Chem. 2015;58:147–69.
pubmed: 25723005
doi: 10.1021/jm5005336
Veitch ZW, Cescon DW, Denny T, Yonemoto LM, Fletcher G, Brokx R, et al. Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial. Br J Cancer. 2019;121:318–24.
pubmed: 31303643
pmcid: 6738068
doi: 10.1038/s41416-019-0517-3
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–9.
pubmed: 14673054
doi: 10.1200/JCO.2003.04.036
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–25.
pubmed: 16609072
doi: 10.1182/blood-2005-10-4149
Kawakami M, Mustachio LM, Zheng L, Chen Y, Rodriguez-Canales J, Mino B, et al. Reply to Oegema et al.: CFI-400945 and Polo-like kinase 4 inhibition. Proc Natl Acad Sci USA. 2018;115:E10810–E1.
pubmed: 30377273
pmcid: 6243257
doi: 10.1073/pnas.1813967115
Chan CY, Yuen VW, Chiu DK, Goh CC, Thu KL, Cescon DW, et al. Polo-like kinase 4 inhibitor CFI-400945 suppresses liver cancer through cell cycle perturbation and eliciting antitumor immunity. Hepatology. 2023;77:729–44.
pubmed: 35302667
doi: 10.1002/hep.32461
Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.
pubmed: 27895058
pmcid: 5291965
doi: 10.1182/blood-2016-08-733196
Yan B, Chen Q, Xu J, Li W, Xu B, Qiu Y. Low-frequency TP53 hotspot mutation contributes to chemoresistance through clonal expansion in acute myeloid leukemia. Leukemia. 2020;34:1816–27.
pubmed: 31988438
pmcid: 7597970
doi: 10.1038/s41375-020-0710-7
Li J, Tan M, Li L, Pamarthy D, Lawrence TS, Sun Y. SAK, a new polo-like kinase, is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing. Neoplasia. 2005;7:312–23.
pubmed: 15967108
pmcid: 1501148
doi: 10.1593/neo.04325
Fischer M, Quaas M, Wintsche A, Muller GA, Engeland K. Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein. Nucleic Acids Res. 2014;42:163–80.
pubmed: 24071582
doi: 10.1093/nar/gkt849
Ward A, Hudson JW. p53-Dependent and cell specific epigenetic regulation of the polo-like kinases under oxidative stress. PLoS One. 2014;9:e87918.
pubmed: 24498222
pmcid: 3909268
doi: 10.1371/journal.pone.0087918
West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124:30–9.
pubmed: 24382387
pmcid: 3871231
doi: 10.1172/JCI69738
Ayoub E, Montoya RH, Mohanty V, Walter W, Patsilevas T, Issa GC, et al. Targeting polo-like kinase 4 triggers polyploidy and apoptotic cell death in TP53-mutant acute myeloid leukemia. Blood. 2021;138:1167.
doi: 10.1182/blood-2021-153436
Dang CC, Ng KLN, Lam W, Zeng XY, Zheng LC, Chan KC, et al. Inhibition of Polo-like kinase 4 induced both cell intrinsic and non-cell intrinsic anti-leukemia effects on TP53 -mutated acute myeloid leukemia. Blood. 2022;140:3099.
doi: 10.1182/blood-2022-165205
Holland AJ, Fachinetti D, Zhu Q, Bauer M, Verma IM, Nigg EA, et al. The autoregulated instability of Polo-like kinase 4 limits centrosome duplication to once per cell cycle. Genes Dev. 2012;26:2684–9.
pubmed: 23249732
pmcid: 3533073
doi: 10.1101/gad.207027.112
Holland AJ, Fachinetti D, Da Cruz S, Zhu Q, Vitre B, Lince-Faria M, et al. Polo-like kinase 4 controls centriole duplication but does not directly regulate cytokinesis. Mol Biol Cell. 2012;23:1838–45.
pubmed: 22456511
pmcid: 3350549
doi: 10.1091/mbc.e11-12-1043
Sercin O, Larsimont JC, Karambelas AE, Marthiens V, Moers V, Boeckx B, et al. Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis. Nat Cell Biol. 2016;18:100–10.
pubmed: 26595384
doi: 10.1038/ncb3270
Bernard E, Nannya Y, Hasserjian RP, Devlin SM, Tuechler H, Medina-Martinez JS, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26:1549–56.
pubmed: 32747829
pmcid: 8381722
doi: 10.1038/s41591-020-1008-z
DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383:617–29.
pubmed: 32786187
doi: 10.1056/NEJMoa2012971
Pollyea DA, DiNardo CD, Arellano ML, Pigneux A, Fiedler W, Konopleva M, et al. Impact of Venetoclax and Azacitidine in treatment-naive patients with acute myeloid Leukemia and IDH1/2 mutations. Clin Cancer Res. 2022;28:2753–61.
pubmed: 35046058
pmcid: 9365354
doi: 10.1158/1078-0432.CCR-21-3467
DiNardo CD, Tiong IS, Quaglieri A, MacRaild S, Loghavi S, Brown FC, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020;135:791–803.
pubmed: 31932844
pmcid: 7068032
doi: 10.1182/blood.2019003988
Versluis J, Lindsley RC. Transplant for TP53-mutated MDS and AML: because we can or because we should? Hematology Am Soc Hematol Educ Program. 2022;2022:522–7.
pubmed: 36485102
pmcid: 9820679
doi: 10.1182/hematology.2022000354
Machado NO. Neutropenic enterocolitis: A continuing medical and surgical challenge. N Am J Med Sci. 2010;2:293–300.
pubmed: 22558577
pmcid: 3341635
Kaunitz JD, Akiba Y. Control of intestinal epithelial proliferation and differentiation: the microbiome, enteroendocrine l cells, telocytes, enteric nerves, and GLP, Too. Dig Dis Sci. 2019;64:2709–16.
pubmed: 31435858
pmcid: 7211432
doi: 10.1007/s10620-019-05778-1
Veillette A, Chen J. SIRPalpha-CD47 immune checkpoint blockade in anticancer therapy. Trends Immunol. 2018;39:173–84.
pubmed: 29336991
doi: 10.1016/j.it.2017.12.005
Kwon J, Bakhoum SF. The Cytosolic DNA-sensing cGAS-STING pathway in cancer. Cancer Discov. 2020;10:26–39.
pubmed: 31852718
doi: 10.1158/2159-8290.CD-19-0761
Man CH, Lam W, Dang CC, Zeng XY, Zheng LC, Chan NN, et al. Inhibition of PLK4 remodels histone methylation and activates immune response via cGAS-STING pathway in TP53 mutated AML. Blood. (2023).