Early phase studies

Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies

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Abstract

The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.

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References

  1. 1

    Xu D, Grishin NV, Chook YM . NESdb: a database of NES-containing CRM1 cargoes. Mol Biol Cell 2012; 23: 3673–3676.

  2. 2

    Brennan CM, Gallouzi I-E, Steitz JA . Protein ligands to HuR modulate its interaction with target mRNAs in vivo. J Cell Biol 2000; 151: 1–14.

  3. 3

    Wen W, Meinkoth JL, Tsien RY, Taylor SS . Identification of a signal for rapid export of proteins from the nucleus. Cell 1995; 82: 463–473.

  4. 4

    Fornerod M, Ohno M, Yoshida M, Mattaj IW . CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 1997; 90: 1051–1060.

  5. 5

    Dong X, Biswas A, Suel KE, Jackson LK, Martinez R, Gu H et al. Structural basis for leucine-rich nuclear export signal recognition by CRM1. Nature 2009; 458: 1136–1141.

  6. 6

    Monecke T, Guttler T, Neumann P, Dickmanns A, Gorlich D, Ficner R . Crystal structure of the nuclear export receptor CRM1 in complex with Snurportin1 and RanGTP. Science 2009; 324: 1087–1091.

  7. 7

    Fung HYJ, Fu S-c, Brautigam CA, Chook YM . Structural determinants of nuclear export signal orientation in binding CRM1. eLife 2015; 4.

  8. 8

    Tai Y-T, Landesman Y, Acharya C, Calle Y, Zhong MY, Cea M et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia 2014; 28: 155–165.

  9. 9

    Van Der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D et al. The karyopherin proteins, Crm1 and Karyopherin Beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer 2009; 124: 1829–1840.

  10. 10

    Tan DSP, Bedard PL, Kuruvilla J, Siu LL, Razak ARA . Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy. Cancer Discov 2014; 4: 527–537.

  11. 11

    Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–266.

  12. 12

    Yoshimura M, Ishizawa J, Ruvolo V, Dilip A, Quintas-Cardama A, McDonnell TJ et al. Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma. Cancer Sci 2014; 105: 795–801.

  13. 13

    Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475: 101–105.

  14. 14

    Lapalombella R, Sun Q, Williams K, Tangeman L, Jha S, Zhong Y et al. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood 2012; 120: 4621–4634.

  15. 15

    Ranganathan P, Yu X, Na C, Santhanam R, Shacham S, Kauffman M et al. Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood 2012; 120: 1765–1773.

  16. 16

    Ranganathan P, Yu X, Santhanam R, Hofstetter J, Walker A, Walsh K et al. Decitabine priming enhances the anti-leukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia. Blood 2015; 125: 2689–2692.

  17. 17

    Kuruvilla J, Gutierrez M, Shah BD, Gabrail NY, de Nully Brown P, Stone RM et al. Preliminary evidence of anti tumor activity of selinexor (KPT-330) in a phase I trial of a first-in-class oral selective inhibitor of nuclear export (SINE) in patients (pts) with relapsed/refractory non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Blood 2013; 122: 90.

  18. 18

    Chen CI, Gutierrez M, de Nully Brown P, Gabrail N, Baz R, Reece DE et al. Anti tumor activity of selinexor (KPT-330), a first-in-class oral selective inhibitor of nuclear export (SINE) XPO1/CRM1 antagonist in patients (pts) with relapsed/refractory multiple myeloma (MM) Or Waldenstrom’s macroglobulinemia (WM). Blood 2013; 122: 1942–1942.

  19. 19

    Savona M, Garzon R, de Nully Brown P, Yee K, Lancet JE, Gutierrez M et al. Phase I trial of selinexor (KPT-330), a first-in-class oral selective inhibitor of nuclear export (SINE) in patients (pts) with advanced acute myelogenous leukemia (AML). Blood 2013; 122: 1440–1440.

  20. 20

    Chook YM, Blobel G . Structure of the nuclear transport complex karyopherin-beta2-Ran x GppNHp. Nature 1999; 399: 230–237.

  21. 21

    Sun Q, Carrasco YP, Hu Y, Guo X, Mirzaei H, Macmillan J et al. Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. Proc Natl Acad Sci USA 2013; 110: 1303–1308.

  22. 22

    Koyama M, Matsuura Y . An allosteric mechanism to displace nuclear export cargo from CRM1 and RanGTP by RanBP1. EMBO J 2010; 29: 2002–2013.

  23. 23

    Etchin J, Sun Q, Kentsis A, Farmer A, Zhang ZC, Sanda T et al. Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. Leukemia 2013; 27: 66–74.

  24. 24

    Haines JD, Herbin O, de la Hera B, Vidaurre OG, Moy GA, Sun Q et al. Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination. Nat Neurosci 2015; 18: 511–520.

  25. 25

    Bichi R, Shinton SA, Martin ES, Koval A, Calin GA, Cesari R et al. Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proc Natl Acad Sci USA 2002; 99: 6955–6960.

  26. 26

    Zhong Y, El-Gamal D, Dubovsky JA, Beckwith KA, Harrington BK, Williams KE et al. Selinexor suppresses downstream effectors of B-cell activation, proliferation and migration in chronic lymphocytic leukemia cells. Leukemia 2014; 28: 1158–1163.

  27. 27

    Johnson AJ, Lucas DM, Muthusamy N, Smith LL, Edwards RB, De Lay MD et al. Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. Blood 2006; 108: 1334–1338.

  28. 28

    Hing ZA, Mantel R, Beckwith KA, Guinn D, Williams E, Smith LL et al. Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. Blood 2015; 125: 3128–3132.

  29. 29

    Newlands ES, Rustin GJ, Brampton MH . Phase I trial of elactocin. Br J Cancer 1996; 74: 648–649.

  30. 30

    Mutka SC, Yang WQ, Dong SD, Ward SL, Craig Da, Timmermans PBMWM et al. Identification of nuclear export inhibitors with potent anticancer activity in vivo. Cancer Res 2009; 69: 510–517.

  31. 31

    Etchin J, Berezovskaya A, Conway AS, Galinsky IA, Stone RM, Baloglu et al. KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells. Leukemia 2016; ; e-pub ahead of print 23 May 2016; doi:10.1038/leu.2016.145.

  32. 32

    Turner JG, Dawson J, Sullivan DM . Nuclear export of proteins and drug resistance in cancer. Biochem Pharmacol 2012; 83: 1021–1032.

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Acknowledgements

We thank the patients who provided blood for the above-mentioned studies. We also thank Dr John B MacMillan, PhD, for thoughtful contributions to this manuscript. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. This work is funded by Cancer Prevention Research Institute of Texas (CPRIT) Grants RP120352 and RP150053 (to YMC), R01 GM069909 (to YMC), the University of Texas Southwestern Endowed Scholars Program (to YMC), Welch Foundation Grant I-1532 (to YMC), Leukemia and Lymphoma Society Scholar Award (to YMC), Croucher Foundation Scholarship (to HYJF), the Leukemia and Lymphoma Society in the form of a translational grant (to JCB and RL), K12 CA133250 (to JCB), R01CA192928 (to RL and JCB), R01CA188269 (to RG and JCB), F30CA196082 (to ZAH), the Department of Defense DOD W81XWH-14-01-0190 (to RL), the Leukemia and Lymphoma Society Special Fellow award (LLS 60046395 to PR) and the Leukemia and Lymphoma Society Scholar Award (LLS 20020030 to RG). This work was also supported by P30 CA016058.

Author contributions

ZAH, PR, HYJF, JCB, YMC, RG and RL designed the experiments, analyzed the data, wrote the paper and reviewed and approved the final version. EB designed KPT-8602. EB, SM, DE, KW, JAW, JS, XY, VMG, XM, QS, TC, DML, SS, MGK and AML planned and contributed to components of the experimental work presented (chemistry, biology, clinical or animal studies or statistical analysis of data), reviewed and modified versions of the paper and approved the final version.

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Correspondence to R Lapalombella.

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Competing interests

EB, SS and MGK are employees of Karyopharm Therapeutics Inc. and have financial interests in this company. YMC is a consultant for Karyopharm Therapeutics Inc. The other authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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