Skip to main content

Advertisement

SpringerLink
Log in

A pilot study for the early assessment of the effects of BMS-754807 plus gefitinib in an H292 tumor model by [18F]fluorothymidine-positron emission tomography

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

BMS-754807 is an inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor that also represses aurora kinase. Cancers that express high levels of IGF-1/IGF-1R are sensitive to BMS-754807; however, it shows limited efficacy in non-small cell lung cancer (NSCLC) in which IGF-1R-driven signals may not be dominant factors in cell proliferation. In this study, we investigated whether a combination of BMS-754807 and gefitinib would be synergistic in H292 NSCLC and whether [18F]fluorothymidine ([18F]FLT)-positron emission tomography (PET) could predict the effects. We found that BMS-754807 synergized with gefitinib in reducing cell viability (combination index = 0.38) and Akt phosphorylation, and increasing the subG1 fraction in H292 cells. BMS-754807 alone and in combination with gefitinib increased the cells in G2M phase and polyploid cells and decreased the phosphorylation of IGF-1R and histone H3. The inhibition of tumor growth by gefitinib was increased by BMS-754807 (%T/C, 17.5 % vs. 58.0 % for gefitinib alone and combined treatment, respectively), although BMS-754807 alone had little effect. The standardized uptake value by [18F]FLT-PET were increased in vehicle-treated mice by 73 %, minimally changed in gefitinib- or BMS-754807-treated mice, whereas decreased in co-treated mice by −48.8 % between day 0 and day 3. The combination therapy with BMS-754807 and gefitinib might be a more effective anticancer strategy than BMS-754807 alone in tumors that are less IGF-1R-dependent and that [18F]FLT-PET can be used to assess early therapeutic responses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ono M, Kuwano M (2006) Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res 12:7242–7251

    Article  PubMed  CAS  Google Scholar 

  2. Rosell R, Viteri S, Molina MA, Benlloch S, Taron M (2010) Epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in advanced nonsmall-cell lung cancer. Curr Opin Oncol 22:112–120

    Article  PubMed  CAS  Google Scholar 

  3. Ray M, Salgia R, Vokes EE (2009) The role of EGFR inhibition in the treatment of non-small cell lung cancer. Oncologist 14:1116–1130

    Article  PubMed  CAS  Google Scholar 

  4. Cohen MH, Johnson JR, Chattopadhyay S, Tang S, Justice R, Sridhara R, Pazdur R (2010) Approval summary: erlotinib maintenance therapy of advanced/metastatic non-small cell lung cancer (NSCLC). Oncologist 15:1344–1351

    Article  PubMed  CAS  Google Scholar 

  5. Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee H (2007) Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res 13:2795–2803

    Article  PubMed  CAS  Google Scholar 

  6. Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoel MJ, Fartoux L, Venot C, Bladt F, Housset C, Rosmorduc O (2009) Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res 15:5445–5456

    Article  PubMed  CAS  Google Scholar 

  7. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73

    Article  PubMed  Google Scholar 

  8. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043

    Article  PubMed  CAS  Google Scholar 

  9. Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928

    Article  PubMed  CAS  Google Scholar 

  10. Wittman MD, Carboni JM, Yang Z, Lee FY, Antman M, Attar R, Balimane P et al (2009) Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1, 2, 4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. J Med Chem 52:7360–7363

    Article  PubMed  CAS  Google Scholar 

  11. Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, Hillerman S et al (2009) BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther 8:3341–3349

    Article  PubMed  CAS  Google Scholar 

  12. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  13. Twombly R (2006) Criticism of tumor response criteria raises trial design questions. J Natl Cancer Inst 98:232–234

    Article  PubMed  Google Scholar 

  14. Goffin J, Baral S, Tu D, Nomikos D, Seymour L (2005) Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res 11:5928–5934

    Article  PubMed  Google Scholar 

  15. Canellos GP (1988) Residual mass in lymphoma may not be residual disease. J Clin Oncol 6:931–933

    PubMed  CAS  Google Scholar 

  16. Colozza M, Azambuja E, Cardoso F, Sotiriou C, Larsimont D, Piccart MJ (2005) Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now? Ann Oncol 16:1723–1739

    Article  PubMed  CAS  Google Scholar 

  17. Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, Obradovich JE, Muzik O, Mangner TJ (1998) Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 4:1334–1336

    Article  PubMed  CAS  Google Scholar 

  18. Lee SJ, Kim SY, Chung JH, Oh SJ, Ryu JS, Hong YS, Kim TW, Moon DH (2010) Induction of thymidine kinase 1 after 5-fluorouracil as a mechanism for 3′-deoxy-3′-[18F]fluorothymidine flare. Biochem Pharmacol 80:1528–1536

    Article  PubMed  CAS  Google Scholar 

  19. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  PubMed  CAS  Google Scholar 

  20. Teicher BA, Andrews PA (2004) Anticancer drug development Gide: preclinical screening, clinical trials, and approval. Humana Press, New Jersey

    Book  Google Scholar 

  21. Sohn HJ, Yang YJ, Ryu JS, Oh SJ, Im KC, Moon DH, Lee DH, Suh C, Lee JS, Kim SW (2008) [18F]Fluorothymidine positron emission tomography before and 7 days after gefitinib treatment predicts response in patients with advanced adenocarcinoma of the lung. Clin Cancer Res 14:7423–7429

    Article  PubMed  CAS  Google Scholar 

  22. Lee SJ, Oh SJ, Chi DY, Kil HS, Kim EN, Ryu JS, Moon DH (2007) Simple and highly efficient synthesis of 3′-deoxy-3′-[18F]fluorothymidine using nucleophilic fluorination catalyzed by protic solvent. Eur J Nucl Med Mol Imaging 34:1406–1409

    Article  PubMed  CAS  Google Scholar 

  23. Moulder SL, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF, Arteaga CL (2001) Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 61:8887–8895

    PubMed  CAS  Google Scholar 

  24. MacCallum DE, Hall PA (1999) Biochemical characterization of pKi67 with the identification of a mitotic-specific form associated with hyperphosphorylation and altered DNA binding. Exp Cell Res 252:186–198

    Article  PubMed  CAS  Google Scholar 

  25. Steiner P, Joynes C, Bassi R, Wang S, Tonra JR, Hadari YR, Hicklin DJ (2007) Tumor growth inhibition with cetuximab and chemotherapy in non-small cell lung cancer xenografts expressing wild-type and mutated epidermal growth factor receptor. Clin Cancer Res 13:1540–1551

    Article  PubMed  CAS  Google Scholar 

  26. Janmaat ML, Rodriguez JA, Gallegos-Ruiz M, Kruyt FA, Giaccone G (2006) Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells. Int J Cancer 118:209–214

    Article  PubMed  CAS  Google Scholar 

  27. Iwasa T, Okamoto I, Suzuki M, Hatashita E, Yamada Y, Fukuoka M, Ono K, Nakagawa K (2009) Inhibition of insulin-like growth factor 1 receptor by CP-751,871 radiosensitizes non-small cell lung cancer cells. Clin Cancer Res 15:5117–5125

    Article  PubMed  CAS  Google Scholar 

  28. Huang F, Hurlburt W, Greer A, Reeves KA, Hillerman S, Chang H, Fargnoli J, Graf Finckenstein F, Gottardis MM, Carboni JM (2010) Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model. Cancer Res 70:7221–7231

    Article  PubMed  CAS  Google Scholar 

  29. Huang T, Civelek AC, Li J, Jiang H, Ng CK, Postel GC, Shen B, Li XF (2012) Tumor microenvironment-dependent 18F-FDG, 18F-Fluorothymidine, and 18F-Misonidazole Uptake: A Pilot study in mouse models of human non-small cell lung cancer. J Nucl Med 53:1262–1268

    Article  PubMed  CAS  Google Scholar 

  30. Kee N, Sivalingam S, Boonstra R, Wojtowicz JM (2002) The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis. J Neurosci Methods 115:97–105

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant from the Asan Institute for Life Science (No. 2009–430) and Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education, Science and Technology(2010-0025392). We thank for Bristol-Myers Squibb and AstraZeneca for the kind provision of BMS-754807 and gefitinib, respectively.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute for Innovative Cancer Research, Asan Institute for Life Science, Asan Medical Center, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Seung Jin Lee, Haeng Jung Lee, Seog Young Kim, Seung Jun Oh, Jin Sook Ryu & Dae Hyuk Moon

  2. Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Seung Jin Lee, Eun Jung Kim, Haeng Jung Lee, Seog Young Kim, Seung Jun Oh, Jin Sook Ryu, Dae Hyuk Moon, Jin-Hee Ahn & Sang-We Kim

  3. Departments of Nuclear Medicine, University of Ulsan College of Medicine, Asan Medical Center, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Seung Jun Oh, Jin Sook Ryu & Dae Hyuk Moon

  4. Division of Oncology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Jin-Hee Ahn & Sang-We Kim

  5. Division of Oncology, Department of Internal Medicine, Asan Medical Center, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Jin-Hee Ahn & Sang-We Kim

Authors
  1. Seung Jin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eun Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haeng Jung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seog Young Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seung Jun Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin Sook Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dae Hyuk Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jin-Hee Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sang-We Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jin-Hee Ahn or Sang-We Kim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, S.J., Kim, E.J., Lee, H.J. et al. A pilot study for the early assessment of the effects of BMS-754807 plus gefitinib in an H292 tumor model by [18F]fluorothymidine-positron emission tomography. Invest New Drugs 31, 506–515 (2013). https://doi.org/10.1007/s10637-012-9874-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-012-9874-y

Keywords

Search

Navigation