AMG 900, a potent inhibitor of aurora kinases causes pharmacodynamic changes in p-Histone H3 immunoreactivity in human tumor xenografts and proliferating mouse tissues

Journal of Translational Medicine

Marc Payton²  Greg Friberg¹  Robert Loberg¹  Robert Radinsky²  Richard Kendall²  Stephen Zoog¹  Jennifer M Hawkins³  Grace Chung²  Raffi Manoukian¹  Connie Ma¹  Tammy L Bush²  Gloria Juan¹ 

[1] Departments of Oncology Biomarkers and Early Development, Thousand Oaks 91320, CA, USA;Departments of Oncology Research, Thousand Oaks 91320, CA, USA;Department of Pathology, Amgen Inc, One Amgen Center Drive, Thousand Oaks 91320, CA, USA

关键词: Tumor biopsies;    Cytometry;    Pharmacodynamics;    Mitosis;    Histone H3;   

Others  :  1147355
DOI  :  10.1186/s12967-014-0307-x

 received in 2014-09-11, accepted in 2014-10-22,  发布年份 2014

【 摘 要 】

Background

The Aurora family of serine-threonine kinases are essential regulators of cell division in mammalian cells. Aurora-A and ¿B expression and kinase activity is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis. AMG 900 is a highly potent and selective pan-aurora kinase inhibitor that has entered clinical evaluation in adult patients with advanced cancers. In mice, oral administration of AMG 900 blocks the phosphorylation of histone H3 on serine-10 (p-Histone H3), a proximal substrate of aurora-B and inhibits the growth of multiple human tumor xenografts, including multidrug-resistant models.

Methods

In order to establish a preclinical pharmacokinetic-pharmacodynamic (PK-PD) relationship for AMG 900 that could be translated to the clinic, we used flow cytometry and laser scanning cytometry detection platforms to assess the effects on p-Histone H3 inhibition in terms of sensitivity, precision, and specificity, in human tumor xenografts in conjunction with mouse skin and bone marrow tissues. Mice with established COLO 205 tumors were administered AMG 900 at 3.75, 7.5, and 15 mg/kg and assessed after 3 hours.

Results

Significant suppression of p-Histone H3 in mouse skin was only observed at 15 mg/kg (p <0.0001), whereas in mouse bone marrow and in tumor a dose-dependent inhibition was achieved at all three doses (p ?0.00015). These studies demonstrate that AMG 900 inhibits p-Histone H3 in tumors and surrogate tissues (although tissues such as skin may be less sensitive for assessing PD effects). To further extend our work, we evaluated the feasibility of measuring p-Histone H3 using fine-needle aspirate (FNA) tumor xenograft biopsies. Treatment with AMG 900 significantly inhibited p-Histone H3 (>99% inhibition, p <0.0001) in COLO 205 tumors. Lastly, we illustrate this LSC-based approach can detect p-Histone H3 positive cells using mock FNAs from primary human breast tumor tissues.

Conclusion

Phosphorylation of histone H3 is a useful biomarker to determine the pharmacodynamics (PD) activity of AMG 900. FNA biopsies may be a viable approach for assessing AMG 900 PD effects in the clinic.

【 授权许可】

   
2014 Juan et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Warner SL, Bearss DJ, Han H, Von Hoff DD: Targeting aurora-2 kinase in cancer. Mol Cancer Ther 2003, 2:589-595.
• [2]Gizatullin F, Yao Y, Kung V, Harding MW, Loda M, Shapiro GI: The aurora kinase inhibitor VX-680 induces endoreduplication and apoptosis preferentially in cells with compromised p53-dependent postmitiotic checkpoint function. Cancer Res 2006, 66:7668-7677.
• [3]Carmena M, Earnshaw WC: The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 2003, 4:842-854.
• [4]Jackson JR, Patrick DR, Dar MM, Huang PS: Targeting anti-mitotic therapies: can we improve on tubulin agents? Nat Rev Cancer 2007, 7:107-117.
• [5]Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A, Su M, Golec JMC, Miller KM: VX-680, a potent and selective small-molecule inhibitor of the aurora kinases, suppresses tumor growth in vivo. Nat Med 2004, 10:262-267.
• [6]Carpinelli P, Ceruti R, Giorgini ML, Cappella P, Gianellini L, Croci V, Degrassi A, Texido G, Rocchetti M, Vianello P, Rusconi L, Storici P, Zugnoni P, Arrigoni C, Soncini C, Alli C, Patton V, Marsiglio A, Ballinari D, Pesenti E, Fancelli D, Moll J: PHA-739358, a potent inhibitor of aurora kinases with a selective target inhibition profile relevant to cancer. Mol Cancer Ther 2007, 6:3158-3168.
• [7]Wilkinson RW, Odedra R, Heaton SP, Wedge SR, Keen NJ, Crafter C, Foster JR, Brady MC, Bigley A, Brown E, Byth KF, Barrass NC, Mundt KE, Foote KM, Heron NM, Jung FH, Mortlock AA, Boyle FT, Green S: AZD-1152, a selective inhibitor of aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 2007, 13:3682-3688.
• [8]Payton M, Bush TL, Chung G, Ziegler B, Eden P, McElroy P, Ross S, Cee VJ, Deak HL, Hodous BL, Nguyen HN, Olivieri PR, Romero K, Schenkel LB, Bak A, Stanton M, Dussault I, Patel VF, Geuns-Meyer S, Radinsky R, Kendall R: Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res 2010, 70:9846-9854.
• [9]Ajiro K, Nishimoto T: Specific site of histone H3 phosphorylation related to the maintenance of premature chromosome condensation. Evidence for catalytically induced interchange of the subunits. J Biol Chem 1985, 260:15379-15381.
• [10]Giet R, Glover DM: Drosophila aurora B kinase is required for histone H3 phosphorylation and condensing recruitment during chromosome condensation and to organize the central spindle during cytokinesis. J Cell Biol 2001, 152:669-682.
• [11]Juan G, Traganos F, James WM, Ray JM, Roberge M, Sauve DM, Anderson H, Darzynkiewicz Z: Histone H3 phosphorylation and expression of cyclins A and B1 measured in individual cells during their progression through G2 and mitosis. Cytometry 1998, 32:1-8.
• [12]Kulesza P, Eltoum IA: Endoscopic ultrasound-guided fine-needle aspiration: sampling, pitfalls, and quality management. Clin Gastroenterol Hepatol 2007, 5:1248-1254.
• [13]Schwock J, Ho JC, Luther E, Hedley DW, Geddie WR: Measurement of signaling pathway activities in solid tumor fine-needle biopsies by slide-based cytometry. Diagn Mol Pathol 2007, 16:130-140.
• [14]Zoog SJ, Ma C, Kaplan-Lefko PJ, Hawkins J, Moriguchi J, Zhou L, Pan Y, Hsu C-P, Friberg G, Herbst R, Hill J, Juan G: Measurement of Conatumumab-induced apoptotic activity in tumors by fine needle aspirate sampling. Cytometry A 2010, 77A:849-860.
• [15]Huang L, Zheng M, Zhou Q-M, Zhang M-Y, Jia W-H, Yun J-P, Wang H-Y: Identification of a gene-expression signature for predicting lymph node metastasis in patients with early stage cervical carcinoma. Cancer 2011, 117:3363-3373.
• [16]Myers J: A review of automated slide strainers for IHC and ISH. Med Lab Obs 2008, January:41-44.
• [17]Hegyi K, Mehes G: Mitotic failures in cancer: Aurora B kinase and its potential role in the development of aneuploidy. Pathol Oncol Res (Review) 2012, 18:761-769.
• [18]Henriksen M, Miller B, Newmark J, Al-Kofahi Y, Holden E: Laser scanning cytometry and its applications: a pioneering technology in the field of quantitative imaging cytometry. Methods Cell Biol 2011, 102:161-205.
• [19]Huang L, Be X, Berry L, Moore E, Janosky B, Wells M, Pan W-J, Zhao Z, Lin M-H J: In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases. Xenobiotica 2011, 41:400-408.
• [20]Boeddinghaus I, Johnson SR: Serial biopsies/fine-needle aspirates and their assessment. Methods Mol Med 2006, 120:29-41.
• [21]Saleh H, Masood S: Value of ancillary studies in fine-needle aspiration biopsy. Diagn Cytopathol 1995, 13:310-315.
• [22]Brotherick I, Shenton BK, Lennard TW: Are fine-needle breast aspirates representative of the underlying solid tumour? A comparison of receptor levels, ploidy and the influence of cytokeratin gates. Br J Cancer 1995, 72:732-737.
• [23]Nizzoli R, Bozzetti C, Naldi N, Guazzi A, Gabrielli M, Michiara M, Camisa R, Barilli A, Cocconi G: Comparison of the results of immunocytochemical assays for biologic variables on preoperative fine-needle aspirates and on surgical specimens of primary breast carcinomas. Cancer 2000, 90:61-66.
• [24]Zabaglo L, Ormerod MG, Dowsett M: Measurement of markers for breast cancer in a model system using laser scanning cytometry. Cytometry 2000, 41:166-171.
• [25]Zabaglo L, Ormerod MG, Dowsett M: Measurement of proliferation marker Ki67 in breast tumour FNAs using laser scanning cytometry in comparison to conventional immunocytochemistry. Cytometry B Clin Cytom 2003, 56:55-61.
• [26]Keen N, Taylor S: Aurora-kinase inhibitors as anti-cancer agents. Nat Rev Cancer 2004, 4:927-936.
• [27]Perez Fidalgo JA, Roda D, Rosello S, Rodriguez-Braun E, Cervantes A: Aurora kinase inhibitors: a new class of drugs targeting the regulatory mitotic system. Clin Transl Oncol 2009, 11:787-798.
• [28]Carvajal RD, Tse A, Schwartz GK: Aurora kinases: new targets for cancer therapy. Clin Cancer Res 2006, 12:6869-6875.
• [29]Hilton JF, Shapiro GI: Aurora kinase inhibitors as an anticancer strategy. J Clin Onc 2014, 32:57-59.
• [30]Luo J, Solimini NL, Elledge SJ: Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 2009, 136:823-837.
• [31]Cohen RB, Jones SF, Arrarwal C, von Mehren M, Cheng J, Spigel DR, Greco FA, Mariani M, Rocchetti M, Ceruti R, Comis S, Laffranchi B, Moll J, Burris HA: A phase I dose-escalation study of Danusertib (PHA-737358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors. Clin Cancer Res 2009, 1:OF1-OF8.
• [32]Chakravarty A, Shinde V, Tabernero J, Cervantes A, Cohen RB, Dees EC, Burris H, Infante JR, Macarulla T, Elez E, Andreu J, Rodriguez-Braun E, Rosello S, von Mehren M, Meropol NJ, Langer CJ, ONeal B, Bowman D, Zhang M, Danaee H, Faron-Yowe L, Gray G, Liu H, Pappas J, Silverman L, Simpson C, Stringer B, Tirrell S, Veiby OP, Venkatakrishnan K, et al.: Phase I assessment of new mechanism-based pharmacodynamic biomarkers for MLN8054, a small-molecule inhibitor of aurora A kinase. Cancer Res 2010, 71:675-685.
• [33]Gadea BB, Ruderman JV: Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts. Mol Biol Cell 2005, 16:1305-1318.
• [34]Steeghs N, Eskens F, Gelderblom H, Verweij J, Nortier JWR, Ouwerkerk J, van Noort C, Mariani M, Spinelli R, Carpinelli P, Laffranchi B, de Jonge JA: Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors. J Clin Oncol 2009, 27:5094-5101.
• [35]Herbst R, Kurzrock R, Hong D, Valdivieso M, Hsu C-P, Goyal L, Juan G, Hwang Y, Wong S, Hill J, Friberg G, LoRusso P: A first-in-human study of conatumumab in adult patients with advanced solid tumors. Clin Cancer Res 2010, 16:5883-5891.
• [36]Huang X, Kurose A, Tanaka T, Traganos F, Dai W, Darzynkiewicz Z: Sequential Phosphorylation of Ser-10 on Histone H3 and Ser-139 on Histone H2AX and ATM Activation during premature chromosome condensation: relationship to cell-cycle phase and apoptosis. Cytometry A 2006, 69A:222-229.
• [37]Juan G, Traganos F, Darzynkiewicz Z: Histone H3 Phosphorylation in human monocytes and during HL-60 cell differentiation. Exp Cell Res 1999, 246:212-220.