Treatment of Higher Risk Myelodysplastic Syndrome Patients Unresponsive to Hypomethylating Agents with ON 01910.Na

Overview

Journal Leuk Res

Date 2011 Sep 20

PMID 21924492

Citations 25

Authors

Mahesh Seetharam

Alice C Fan

Mai Tran

Liwen Xu

John P Renschler

Dean W Felsher

Kunju Sridhar

Francois Wilhelm

Peter L Greenberg

Affiliations

Soon will be listed here.

Abstract

In a Phase I/II clinical trial, 13 higher risk red blood cell-dependent myelodysplastic syndrome (MDS) patients unresponsive to hypomethylating therapy were treated with the multikinase inhibitor ON 01910.Na. Responses occurred in all morphologic, prognostic risk and cytogenetic subgroups, including four patients with marrow complete responses among eight with stable disease, associated with good drug tolerance. In a subset of patients, a novel nanoscale immunoassay showed substantially decreased AKT2 phosphorylation in CD34+ marrow cells from patients responding to therapy but not those who progressed on therapy. These data demonstrate encouraging efficacy and drug tolerance with ON 01910.Na treatment of higher risk MDS patients.

Citing Articles

Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na).

Monfort-Vengut A, de Carcer G Pharmaceutics. 2023; 15(4).

PMID: 37111716 PMC: 10145883. DOI: 10.3390/pharmaceutics15041232.

Synthesis and antitumor effects of novel benzyl naphthyl sulfoxide/sulfone derivatives derived from Rigosertib.

Tang L, Chen T, Yang H, Wen X, Sun Y, Liu S RSC Adv. 2022; 11(59):37462-37471.

PMID: 35496445 PMC: 9043816. DOI: 10.1039/d1ra05226h.

Deciphering the Key Pharmacological Pathways and Targets of Yisui Qinghuang Powder That Acts on Myelodysplastic Syndromes Using a Network Pharmacology-Based Strategy.

Han Z, Song L, Qi K, Ding Y, Wei M, Jia Y Evid Based Complement Alternat Med. 2021; 2020:8877295.

PMID: 33488754 PMC: 7787775. DOI: 10.1155/2020/8877295.

The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?.

Luserna di Rora A, Martinelli G, Simonetti G J Hematol Oncol. 2019; 12(1):123.

PMID: 31771633 PMC: 6880427. DOI: 10.1186/s13045-019-0808-4.

The 'Achilles Heel' of Metabolism in Renal Cell Carcinoma: Glutaminase Inhibition as a Rational Treatment Strategy.

Hoerner C, Chen V, Fan A Kidney Cancer. 2019; 3(1):15-29.

PMID: 30854496 PMC: 6400133. DOI: 10.3233/KCA-180043.

References

Fenaux P, Mufti G, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A . 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(3):223-32. PMC: 4086808. DOI: 10.1016/S1470-2045(09)70003-8. View

Gumireddy K, Reddy M, Cosenza S, Boominathan R, Boomi Nathan R, Baker S . ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell. 2005; 7(3):275-86. DOI: 10.1016/j.ccr.2005.02.009. View

Park S, Chapuis N, Tamburini J, Bardet V, Cornillet-Lefebvre P, Willems L . Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia. Haematologica. 2009; 95(5):819-28. PMC: 2864389. DOI: 10.3324/haematol.2009.013797. View

Perego P, Cossa G, Zuco V, Zunino F . Modulation of cell sensitivity to antitumor agents by targeting survival pathways. Biochem Pharmacol. 2010; 80(10):1459-65. DOI: 10.1016/j.bcp.2010.07.030. View

Jimeno A, Chan A, Cusatis G, Zhang X, Wheelhouse J, Solomon A . Evaluation of the novel mitotic modulator ON 01910.Na in pancreatic cancer and preclinical development of an ex vivo predictive assay. Oncogene. 2008; 28(4):610-8. PMC: 3107737. DOI: 10.1038/onc.2008.424. View

Follo M, Mongiorgi S, Bosi C, Cappellini A, Finelli C, Chiarini F . The Akt/mammalian target of rapamycin signal transduction pathway is activated in high-risk myelodysplastic syndromes and influences cell survival and proliferation. Cancer Res. 2007; 67(9):4287-94. DOI: 10.1158/0008-5472.CAN-06-4409. View

Eckerdt F, Yuan J, Strebhardt K . Polo-like kinases and oncogenesis. Oncogene. 2005; 24(2):267-76. DOI: 10.1038/sj.onc.1208273. View

Chun A, Cosenza S, Taft D, Maniar M . Preclinical pharmacokinetics and in vitro activity of ON 01910.Na, a novel anti-cancer agent. Cancer Chemother Pharmacol. 2009; 65(1):177-86. DOI: 10.1007/s00280-009-1022-9. View

Cheson B, Greenberg P, Bennett J, Lowenberg B, Wijermans P, Nimer S . Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006; 108(2):419-25. DOI: 10.1182/blood-2005-10-4149. View

10.

Kawauchi K, Ogasawara T, Yasuyama M, Otsuka K, Yamada O . The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009; 9(5):550-9. DOI: 10.2174/187152009788451851. View

11.

Prebet T, Gore S, Esterni B, Gardin C, Itzykson R, Thepot S . Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011; 29(24):3322-7. PMC: 4859209. DOI: 10.1200/JCO.2011.35.8135. View

12.

Seetharam M, Fan A, Tran M, Xu L, Renschler J, Felsher D . Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na. Leuk Res. 2011; 36(1):98-103. PMC: 3612532. DOI: 10.1016/j.leukres.2011.08.022. View

13.

Liu X, Erikson R . Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci U S A. 2003; 100(10):5789-94. PMC: 156279. DOI: 10.1073/pnas.1031523100. View

14.

Grandage V, Gale R, Linch D, Khwaja A . PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. Leukemia. 2005; 19(4):586-94. DOI: 10.1038/sj.leu.2403653. View

15.

ONeill R, Bhamidipati A, Bi X, Deb-Basu D, Cahill L, Ferrante J . Isoelectric focusing technology quantifies protein signaling in 25 cells. Proc Natl Acad Sci U S A. 2006; 103(44):16153-8. PMC: 1618307. DOI: 10.1073/pnas.0607973103. View

16.

Sloand E, Pfannes L, Chen G, Shah S, Solomou E, Barrett J . CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins. Blood. 2006; 109(6):2399-405. PMC: 1852203. DOI: 10.1182/blood-2006-01-030643. View

17.

Schoffski P . Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009; 14(6):559-70. DOI: 10.1634/theoncologist.2009-0010. View

18.

Mure H, Matsuzaki K, Kitazato K, Mizobuchi Y, Kuwayama K, Kageji T . Akt2 and Akt3 play a pivotal role in malignant gliomas. Neuro Oncol. 2010; 12(3):221-32. PMC: 2940586. DOI: 10.1093/neuonc/nop026. View

19.

Jimeno A, Li J, Messersmith W, Laheru D, Rudek M, Maniar M . Phase I study of ON 01910.Na, a novel modulator of the Polo-like kinase 1 pathway, in adult patients with solid tumors. J Clin Oncol. 2008; 26(34):5504-10. PMC: 4824307. DOI: 10.1200/JCO.2008.17.9788. View

20.

Martelli A, Nyakern M, Tabellini G, Bortul R, Tazzari P, Evangelisti C . Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia. 2006; 20(6):911-28. DOI: 10.1038/sj.leu.2404245. View