Volasertib Preclinical Activity in High-risk Hepatoblastoma

Overview

Journal Oncotarget

Specialty Oncology

Date 2019 Nov 20

PMID 31741706

Citations 13

Authors

Dina Kats

Cora A Ricker

Noah E Berlow

Benedicte Noblet

Delphine Nicolle

Katell Mevel

Sophie Branchereau

Jean-Gabriel Judde

Cody D Stiverson

Christina L Stiverson

Matthew N Svalina

Teagan Settelmeyer

Kevin Matlock

Melvin Lathara

Charlotte Mussini

James I Geller

Christopher Noakes

Ido Sloma

Narendra Bharathy

Stefano Cairo

Charles Keller

Affiliations

Soon will be listed here.

Abstract

Relapsed and metastatic hepatoblastoma represents an unmet clinical need with limited chemotherapy treatment options. In a chemical screen, we identified volasertib as an agent with activity, inhibiting hepatoblastoma cell growth while sparing normal hepatocytes. Volasertib targets PLK1 and prevents the progression of mitosis, resulting in eventual cell death. PLK1 is overexpressed in hepatoblastoma biopsies relative to normal liver tissue. As a potential therapeutic strategy, we tested the combination of volasertib and the relapse-related hepatoblastoma chemotherapeutic irinotecan. We found both and efficacy of this combination, which may merit further preclinical investigation and exploration for a clinical trial concept.

Citing Articles

Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids.

Kluiver T, Lu Y, Schubert S, Kraaier L, Ringnalda F, Lijnzaad P Nat Commun. 2024; 15(1):8576.

PMID: 39567475 PMC: 11579375. DOI: 10.1038/s41467-024-52757-w.

Modelling the impact of liver regeneration on hepatoblastoma patient-derived-xenograft tumor growth.

Cornet M, Brulle-Soumare L, Bisio V, Deas O, Mussini C, Guettier C Pediatr Res. 2024; 96(3):668-677.

PMID: 38263451 DOI: 10.1038/s41390-024-03020-x.

EZH2 is a key component of hepatoblastoma tumor cell growth.

Glaser K, Schepers E, Zwolshen H, Lake C, Timchenko N, Karns R Pediatr Blood Cancer. 2023; 71(2):e30774.

PMID: 37990130 PMC: 10842061. DOI: 10.1002/pbc.30774.

Genome-wide mapping of cancer dependency genes and genetic modifiers of chemotherapy in high-risk hepatoblastoma.

Fang J, Singh S, Cheng C, Natarajan S, Sheppard H, Abu-Zaid A Nat Commun. 2023; 14(1):4003.

PMID: 37414763 PMC: 10326052. DOI: 10.1038/s41467-023-39717-6.

expression is elevated in hepatoblastoma and correlates with inferior patient survival.

Nousiainen R, Eloranta K, Isoaho N, Cairo S, Wilson D, Heikinheimo M Front Genet. 2023; 14:1170940.

PMID: 37377594 PMC: 10291054. DOI: 10.3389/fgene.2023.1170940.

References

Armeanu-Ebinger S, Hoh A, Wenz J, Fuchs J . Targeting EpCAM (CD326) for immunotherapy in hepatoblastoma. Oncoimmunology. 2013; 2(1):e22620. PMC: 3583930. DOI: 10.4161/onci.22620. View

Liu X . Targeting Polo-Like Kinases: A Promising Therapeutic Approach for Cancer Treatment. Transl Oncol. 2015; 8(3):185-95. PMC: 4486469. DOI: 10.1016/j.tranon.2015.03.010. View

Kobayashi Y, Yamauchi T, Kiyoi H, Sakura T, Hata T, Ando K . Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with acute myeloid leukemia. Cancer Sci. 2015; 106(11):1590-5. PMC: 4714695. DOI: 10.1111/cas.12814. View

Nicolle D, Fabre M, Simon-Coma M, Gorse A, Kappler R, Nonell L . Patient-derived mouse xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management. Hepatology. 2016; 64(4):1121-35. DOI: 10.1002/hep.28621. View

Yan Z, Zhu Z, Qian Z, Hu G, Wang H, Liu W . Pharmacokinetic characteristics of vincristine sulfate liposomes in patients with advanced solid tumors. Acta Pharmacol Sin. 2012; 33(6):852-8. PMC: 4010381. DOI: 10.1038/aps.2012.44. View

Tomicic M, Kaina B . Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors. Biochim Biophys Acta. 2012; 1835(1):11-27. DOI: 10.1016/j.bbcan.2012.09.002. View

Pommier Y . Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006; 6(10):789-802. DOI: 10.1038/nrc1977. View

Ranganathan S, Ningappa M, Ashokkumar C, Higgs B, Min J, Sun Q . Loss of EGFR-ASAP1 signaling in metastatic and unresectable hepatoblastoma. Sci Rep. 2016; 6:38347. PMC: 5133573. DOI: 10.1038/srep38347. View

Khaderi S, Guiteau J, Cotton R, OMahony C, Rana A, Goss J . Role of liver transplantation in the management of hepatoblastoma in the pediatric population. World J Transplant. 2014; 4(4):294-8. PMC: 4274598. DOI: 10.5500/wjt.v4.i4.294. View

10.

Jin J, Jin J, Woodfield S, Patel R, Jin N, Shi Y . Targeting LRH‑1 in hepatoblastoma cell lines causes decreased proliferation. Oncol Rep. 2018; 41(1):143-153. PMC: 6278492. DOI: 10.3892/or.2018.6793. View

11.

Cairo S, Armengol C, De Reynies A, Wei Y, Thomas E, Renard C . Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell. 2008; 14(6):471-84. DOI: 10.1016/j.ccr.2008.11.002. View

12.

Lopez-Terrada D, Cheung S, Finegold M, Knowles B . Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol. 2009; 40(10):1512-5. DOI: 10.1016/j.humpath.2009.07.003. View

13.

Hu K, Lee C, Qiu D, Fotovati A, Davies A, Abu-Ali S . Small interfering RNA library screen of human kinases and phosphatases identifies polo-like kinase 1 as a promising new target for the treatment of pediatric rhabdomyosarcomas. Mol Cancer Ther. 2009; 8(11):3024-35. PMC: 2783569. DOI: 10.1158/1535-7163.MCT-09-0365. View

14.

McCarthy D, Chen Y, Smyth G . Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012; 40(10):4288-97. PMC: 3378882. DOI: 10.1093/nar/gks042. View

15.

Lin C, Su W, Yen C, Hsu C, Su W, Yeh K . A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies. Br J Cancer. 2014; 110(10):2434-40. PMC: 4021529. DOI: 10.1038/bjc.2014.195. View

16.

Garnier A, Ilmer M, Kappler R, Berger M . Therapeutic Innovations for Targeting Hepatoblastoma. Anticancer Res. 2016; 36(11):5577-5592. DOI: 10.21873/anticanres.11143. View

17.

Hao Z, Kota V . Volasertib for AML: clinical use and patient consideration. Onco Targets Ther. 2015; 8:1761-71. PMC: 4514349. DOI: 10.2147/OTT.S60762. View

18.

Awada A, Dumez H, Aftimos P, Costermans J, Bartholomeus S, Forceville K . Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity. Invest New Drugs. 2015; 33(3):611-20. PMC: 4435638. DOI: 10.1007/s10637-015-0223-9. View

19.

Lipshultz S, Miller T, Scully R, Lipsitz S, Rifai N, Silverman L . Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes. J Clin Oncol. 2012; 30(10):1042-9. PMC: 3341148. DOI: 10.1200/JCO.2010.30.3404. View

20.

Carceller A, Blanchard H, Champagne J, St-Vil D, Bensoussan A . Surgical resection and chemotherapy improve survival rate for patients with hepatoblastoma. J Pediatr Surg. 2001; 36(5):755-9. DOI: 10.1053/jpsu.2001.22953. View