Overcoming platinum resistance in ovarian cancer by targeting pregnancy-associated plasma protein-A


Autoři: Diogo Torres aff001;  Xiaonan Hou aff002;  Laurie Bale aff003;  Ethan P. Heinzen aff004;  Matthew J. Maurer aff004;  Valentina Zanfagnin aff002;  Ann L. Oberg aff004;  Cheryl Conover aff003;  S. John Weroha aff002
Působiště autorů: Department of Obstetrics and Gynecology, Division of Gynecologic Surgery, Mayo Clinic, Rochester, MN, United States aff001;  Department of Oncology, Division of Medical Oncology, Mayo Clinic, Rochester, MN, United States aff002;  Division of Endocrinology, Mayo Clinic, Rochester, MN, United States aff003;  Department of Health Science Research, Division of Biomedical Statistics and Informatics, Rochester, MN, United States aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224564

Souhrn

Objectives

Inhibition of pregnancy-associated plasma protein-A (PAPP-A), an upstream activator of the insulin-like growth factor (IGF) pathway, is known to augment sensitivity to platinum-based chemotherapy. This study further tests the efficacy of PAPP-A inhibition with a monoclonal antibody inhibitor (mAb-PA) in ovarian cancer (OC) platinum-resistant patient-derived xenograft (PDX) models.

Methods

PAPP-A expression was quantitated in platinum-resistant PDX models by ELISA. A subset with High (n = 5) and Low (n = 2) expression were revived in female SCID/beige mice for studies with either saline, carboplatin/paclitaxel (CP) + mAb-PA, or CP + IgG2a. The primary endpoint was tumor area by ultrasound on day 28 relative to baseline. Conversion to platinum-sensitive was defined by average tumor regression below baseline. Statistical analyses included linear mixed effects modeling and Kaplan Meier curves. Response to therapy was correlated with changes in the ratio of phosphorylated/total AKT and ERK 1/2 using Wes analysis.

Results

The addition of mAb-PA to CP induced tumor regression below baseline in one High PAPP-A PDX model; another three models exhibited notable growth inhibition relative to CP + IgG2a. None of the Low PAPP-A PDX models regressed below baseline. The PDX model with the greatest magnitude of tumor regression from baseline after combination therapy was maintained on single agent mAb-PA or IgG2a, but no benefit was observed. Decreased phosphorylation of ERK1/2 correlated with conversion to platinum-sensitive.

Conclusions

The addition of mAb-PA to CP overcame platinum-resistance in one of five High PAPP-A PDX models; three other models demonstrated improved platinum-response. This supports further clinical development of this novel therapeutic.

Klíčová slova:

Biomarkers – Cancer chemotherapy – Cancer treatment – Enzyme-linked immunoassays – Monoclonal antibodies – Ovarian cancer – Platinum – Combination chemotherapy


Zdroje

1. Kehoe S, Nankivell M. Primary chemotherapy versus primary surgery for ovarian cancer—Authors' reply. Lancet. 2015;386(10009):2143. Epub 2015/12/08. doi: 10.1016/S0140-6736(15)01052-1 26638963.

2. Markman M, Hall J, Spitz D, Weiner S, Carson L, Van Le L, et al. Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol. 2002;20(9):2365–9. Epub 2002/05/01. doi: 10.1200/JCO.2002.09.130 11981009.

3. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15. Epub 2011/07/02. doi: 10.1038/nature10166 21720365; PubMed Central PMCID: PMC3163504.

4. Kalli KR, Conover CA. The insulin-like growth factor/insulin system in epithelial ovarian cancer. Front Biosci. 2003;8:d714–22. Epub 2003/04/18. 12700030.

5. Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK, et al. Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol. 1999;13(5):787–96. Epub 1999/05/13. doi: 10.1210/mend.13.5.0274 10319328.

6. Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, et al. Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Mol Cell Biol. 1999;19(10):7203–15. Epub 1999/09/22. doi: 10.1128/mcb.19.10.7203 10490655; PubMed Central PMCID: PMC84713.

7. Yamauchi K, Pessin JE. Insulin receptor substrate-1 (IRS1) and Shc compete for a limited pool of Grb2 in mediating insulin downstream signaling. J Biol Chem. 1994;269(49):31107–14. Epub 1994/12/09. 7983051.

8. Iams WT, Lovly CM. Molecular Pathways: Clinical Applications and Future Direction of Insulin-like Growth Factor-1 Receptor Pathway Blockade. Clin Cancer Res. 2015;21(19):4270–7. Epub 2015/10/03. doi: 10.1158/1078-0432.CCR-14-2518 26429980; PubMed Central PMCID: PMC4593065.

9. Juergens H, Daw NC, Geoerger B, Ferrari S, Villarroel M, Aerts I, et al. Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol. 2011;29(34):4534–40. Epub 2011/10/26. doi: 10.1200/JCO.2010.33.0670 22025154; PubMed Central PMCID: PMC3236653.

10. Olmos D, Postel-Vinay S, Molife LR, Okuno SH, Schuetze SM, Paccagnella ML, et al. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol. 2010;11(2):129–35. Epub 2009/12/29. doi: 10.1016/S1470-2045(09)70354-7 20036194; PubMed Central PMCID: PMC2941877.

11. Pappo AS, Patel SR, Crowley J, Reinke DK, Kuenkele KP, Chawla SP, et al. R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. J Clin Oncol. 2011;29(34):4541–7. Epub 2011/10/26. doi: 10.1200/JCO.2010.34.0000 22025149; PubMed Central PMCID: PMC3236654.

12. Schoffski P, Adkins D, Blay JY, Gil T, Elias AD, Rutkowski P, et al. An open-label, phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours. Eur J Cancer. 2013;49(15):3219–28. Epub 2013/07/10. doi: 10.1016/j.ejca.2013.06.010 23835252.

13. Haluska P, Menefee M, Plimack ER, Rosenberg J, Northfelt D, LaVallee T, et al. Phase I dose-escalation study of MEDI-573, a bispecific, antiligand monoclonal antibody against IGFI and IGFII, in patients with advanced solid tumors. Clin Cancer Res. 2014;20(18):4747–57. Epub 2014/07/16. doi: 10.1158/1078-0432.CCR-14-0114 25024259; PubMed Central PMCID: PMC4377301.

14. Puzanov I, Lindsay CR, Goff L, Sosman J, Gilbert J, Berlin J, et al. A phase I study of continuous oral dosing of OSI-906, a dual inhibitor of insulin-like growth factor-1 and insulin receptors, in patients with advanced solid tumors. Clin Cancer Res. 2015;21(4):701–11. Epub 2014/09/13. doi: 10.1158/1078-0432.CCR-14-0303 25212606.

15. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995;16(1):3–34. Epub 1995/02/01. doi: 10.1210/edrv-16-1-3 7758431.

16. Conover CA. Key questions and answers about pregnancy-associated plasma protein-A. Trends Endocrinol Metab. 2012;23(5):242–9. Epub 2012/04/03. doi: 10.1016/j.tem.2012.02.008 22463950; PubMed Central PMCID: PMC3348390.

17. Mikkelsen JH, Resch ZT, Kalra B, Savjani G, Kumar A, Conover CA, et al. Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity. Oncotarget. 2014;5(4):1014–25. Epub 2014/02/28. doi: 10.18632/oncotarget.1629 24572990; PubMed Central PMCID: PMC4011579.

18. King ER, Zu Z, Tsang YT, Deavers MT, Malpica A, Mok SC, et al. The insulin-like growth factor 1 pathway is a potential therapeutic target for low-grade serous ovarian carcinoma. Gynecol Oncol. 2011;123(1):13–8. Epub 2011/07/06. doi: 10.1016/j.ygyno.2011.06.016 21726895; PubMed Central PMCID: PMC3171566.

19. Boldt HB, Conover CA. Overexpression of pregnancy-associated plasma protein-A in ovarian cancer cells promotes tumor growth in vivo. Endocrinology. 2011;152(4):1470–8. Epub 2011/02/10. doi: 10.1210/en.2010-1095 21303951.

20. Domcke S, Sinha R, Levine DA, Sander C, Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013;4:2126. doi: 10.1038/ncomms3126 23839242; PubMed Central PMCID: PMC3715866.

21. AlHilli MM, Becker MA, Weroha SJ, Flatten KS, Hurley RM, Harrell MI, et al. In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma. Gynecol Oncol. 2016;143(2):379–88. Epub 2016/10/25. doi: 10.1016/j.ygyno.2016.08.328 27614696; PubMed Central PMCID: PMC5370566.

22. Glaser G, Weroha SJ, Becker MA, Hou X, Enderica-Gonzalez S, Harrington SC, et al. Conventional chemotherapy and oncogenic pathway targeting in ovarian carcinosarcoma using a patient-derived tumorgraft. PLoS One. 2015;10(5):e0126867. Epub 2015/05/12. doi: 10.1371/journal.pone.0126867 25962155; PubMed Central PMCID: PMC4427104.

23. Weroha SJ, Becker MA, Enderica-Gonzalez S, Harrington SC, Oberg AL, Maurer MJ, et al. Tumorgrafts as in vivo surrogates for women with ovarian cancer. Clin Cancer Res. 2014;20(5):1288–97. Epub 2014/01/09. doi: 10.1158/1078-0432.CCR-13-2611 24398046; PubMed Central PMCID: PMC3947430.

24. Becker MA, Haluska P Jr., Bale LK, Oxvig C, Conover CA. A novel neutralizing antibody targeting pregnancy-associated plasma protein-a inhibits ovarian cancer growth and ascites accumulation in patient mouse tumorgrafts. Mol Cancer Ther. 2015;14(4):973–81. Epub 2015/02/20. doi: 10.1158/1535-7163.MCT-14-0880 25695953; PubMed Central PMCID: PMC4394033.

25. Mikkelsen JH, Gyrup C, Kristensen P, Overgaard MT, Poulsen CB, Laursen LS, et al. Inhibition of the proteolytic activity of pregnancy-associated plasma protein-A by targeting substrate exosite binding. J Biol Chem. 2008;283(24):16772–80. Epub 2008/04/25. doi: 10.1074/jbc.M802429200 18434323.

26. Butler KA, Hou X, Becker MA, Zanfagnin V, Enderica-Gonzalez S, Visscher D, et al. Prevention of Human Lymphoproliferative Tumor Formation in Ovarian Cancer Patient-Derived Xenografts. Neoplasia. 2017;19(8):628–36. doi: 10.1016/j.neo.2017.04.007 28658648; PubMed Central PMCID: PMC5487305.

27. Staflin K, Jarnum S, Hua J, Honeth G, Kannisto P, Lindvall M. Combretastatin A-1 phosphate potentiates the antitumor activity of carboplatin and paclitaxel in a severe combined immunodeficiency disease (SCID) mouse model of human ovarian carcinoma. Int J Gynecol Cancer. 2006;16(4):1557–64. doi: 10.1111/j.1525-1438.2006.00627.x 16884365.

28. Heitjan DF, Manni A, Santen RJ. Statistical analysis of in vivo tumor growth experiments. Cancer Res. 1993;53(24):6042–50. Epub 1993/12/15. 8261420.

29. Littell RC, Milliken, G. A., Stroup, W. W., Wolfinger, R. R. SAS system, for mixed models. I ed2002.

30. Oberg AL, Mahoney DW. Linear mixed effects models. Methods Mol Biol. 2007;404:213–34. Epub 2008/05/03. doi: 10.1007/978-1-59745-530-5_11 18450052.

31. Oberg AL MDAWLmem. Linear mixed effects models. In: Topics in Biostatistics.

32. Meehan TF, Conte N, Goldstein T, Inghirami G, Murakami MA, Brabetz S, et al. PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models. Cancer Res. 2017;77(21):e62–e6. doi: 10.1158/0008-5472.CAN-17-0582 29092942; PubMed Central PMCID: PMC5738926.

33. Wang Y, Hailey J, Williams D, Wang Y, Lipari P, Malkowski M, et al. Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody. Mol Cancer Ther. 2005;4(8):1214–21. Epub 2005/08/12. doi: 10.1158/1535-7163.MCT-05-0048 16093437.

34. Beltran PJ, Calzone FJ, Mitchell P, Chung YA, Cajulis E, Moody G, et al. Ganitumab (AMG 479) inhibits IGF-II-dependent ovarian cancer growth and potentiates platinum-based chemotherapy. Clin Cancer Res. 2014;20(11):2947–58. Epub 2014/04/15. doi: 10.1158/1078-0432.CCR-13-3448 24727326; PubMed Central PMCID: PMC4138720.

35. Resnicoff M, Ambrose D, Coppola D, Rubin R. Insulin-like growth factor-1 and its receptor mediate the autocrine proliferation of human ovarian carcinoma cell lines. Lab Invest. 1993;69(6):756–60. Epub 1993/12/01. 8264238.

36. Konecny GE, Haluska P, Janicke F, Sehouli J, Beckmann MW, Feisel G, et al. A phase II, multicenter, randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with carboplatin/paclitaxel as front-line therapy for optimally debulked primary ovarian cancer: The TRIO14 trial. Journal of Clinical Oncology. 2014;32(15_suppl):5529-. doi: 10.1200/jco.2014.32.15_suppl.5529

37. Aletti GD, Dowdy SC, Gostout BS, Jones MB, Stanhope CR, Wilson TO, et al. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet Gynecol. 2006;107(1):77–85. Epub 2006/01/06. doi: 10.1097/01.AOG.0000192407.04428.bb 16394043.


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