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Target molecule expression profiles in metastatic renal cell carcinoma: Development of individual targeted therapy

  • Original Article
  • Cell Biology
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

The aim of this study is to analyze the level of target molecule expression in metastatic renal cell carcinoma (RCC) to determine whether there is a correlation between molecular marker expression and clinical response. Ten patients with metastatic RCC, who received receptor tyrosine kinase (RTK) targeted therapy after cytoreductive or radical nephrectomy, were included. The expression of target molecules relating to the RTK, mammalian target of rapamycin, hypoxia inducible factor, mitogen activated protein kinase, and adenosine monophosphate-activated protein kinase pathways were analyzed using real-time polymerase chain reaction and immunohistochemistry. We correlated the level of target molecule expression with clinical response, including efficacy and adverse events experience during RTK targeted therapy. All patients showed similar histological subtype and grade on pathological examination; however, the expression of RCC target molecules was very different among the patients. The expression of molecules related to the RTK pathway in RCC tissue as well as relative expression of molecules in RCC tissue compared to normal kidney tissue, were higher in patients who showed a good response to RTK targeted therapy compared to those that showed a poor response. Target molecule expression in normal kidney tissue was higher in patients who experienced high-grade adverse events than in patients who experienced low-grade events. Target molecule expression in metastatic RCC correlates with targeted therapy clinical response including efficacy and adverse events. Personalized target molecule expression profiles could be used to predict clinical response to different targeted therapies, thus helping optimization of targeted therapies for patients with metastatic RCC.

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References

  1. Di Lorenzo G, Autorino R, Sternberg CN. Metastatic renal cell carcinoma: recent advances in the targeted therapy era. Eur Urol 2009;56:959–971.

    Article  PubMed  Google Scholar 

  2. Hutson TE. Targeted therapies for the treatment of metastatic renal cell carcinoma: clinical evidence. Oncologist 2011;16 Suppl 2:14–22.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584–3590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Park JW, Kerbel RS, Kelloff GJ, Barrett JC, Chabner BA, Parkinson DR, et al. Rationale for biomarkers and surrogate end points in mechanism-driven oncology drug development. Clin Cancer Res 2004;10:3885–3896.

    Article  CAS  PubMed  Google Scholar 

  5. Taneja SS. Re: molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns. J Urol 2011;185:1224.

    Google Scholar 

  6. Brannon AR, Reddy A, Seiler M, Arreola A, Moore DT, Pruthi RS, et al. Molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns. Genes Cancer 2010;1:152–163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Garcia-Donas J, Leandro-García LJ, Del Alba AG, Morente M, Alemany I, Esteban E, et al. Prospective study assessing hypoxia-related proteins as markers for the outcome of treatment with sunitinib in advanced clear-cell renal cell carcinoma. Ann Oncol 2013;24:2409–2414.

    Article  CAS  PubMed  Google Scholar 

  8. Kusuda Y, Miyake H, Behnsawy HM, Fukuhara T, Inoue TA, Fujisawa M. Prognostic prediction in patients with metastatic renal cell carcinoma treated with sorafenib based on expression levels of potential molecular markers in radical nephrectomy specimens. Urol Oncol 2013;31:42–50.

    Article  CAS  PubMed  Google Scholar 

  9. Terakawa T, Miyake H, Kusuda Y, Fujisawa M. Expression level of vascular endothelial growth factor receptor-2 in radical nephrectomy specimens as a prognostic predictor in patients with metastatic renal cell carcinoma treated with sunitinib. Urol Oncol 2013;31:493–498.

    Article  CAS  PubMed  Google Scholar 

  10. Siraj MA, Pichon C, Radu A, Ghinea N. Endothelial follicle stimulating hormone receptor in primary kidney cancer correlates with subsequent response to sunitinib. J Cell Mol Med 2012;16:2010–2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009;27:5794–5799.

    Article  CAS  PubMed  Google Scholar 

  12. Liou LS, Shi T, Duan ZH, Sadhukhan P, Der SD, Novick AA, et al. Microarray gene expression profiling and analysis in renal cell carcinoma. BMC Urol 2004 22;4:9.

    Article  Google Scholar 

  13. Cowey CL, Hutson TE. Molecularly targeted agents for renal cell carcinoma: the next generation. Clin Adv Hematol Oncol. 2010;8:357–360, 361-364.

    PubMed  Google Scholar 

  14. Potti A, George DJ. Tyrosine kinase inhibitors in renal cell carcinoma. Clin Cancer Res 2004;10(18 Pt 2):6371S-6376S.

  15. Motzer RJ, Bukowski RM. Targeted therapy for metastatic renal cell carcinoma. J Clin Oncol 2006;24:5601–5608.

    Article  CAS  PubMed  Google Scholar 

  16. Levy AP, Levy NS, Wegner S, Goldberg MA. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 1995;270:13333–13340.

    Article  CAS  PubMed  Google Scholar 

  17. Berger DP, Herbstritt L, Dengler WA, Marmé D, Mertelsmann R, Fiebig HH. Vascular endothelial growth factor (VEGF) mRNA expression in human tumor models of different histologies. Ann Oncol 1995;6:817–825.

    CAS  PubMed  Google Scholar 

  18. Ferrara N. Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int 1999;56:794–814.

    Article  CAS  PubMed  Google Scholar 

  19. Tomisawa M, Tokunaga T, Oshika Y, Tsuchida T, Fukushima Y, Sato H, et al. Expression pattern of vascular endothelial growth factor isoform is closely correlated with tumour stage and vascularisation in renal cell carcinoma. Eur J Cancer 1999;35:133–137.

    Article  CAS  PubMed  Google Scholar 

  20. Takahashi A, Sasaki H, Kim SJ, Tobisu K, Kakizoe T, Tsukamoto T, et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res 1994;54:4233–4237.

    CAS  PubMed  Google Scholar 

  21. Farooqi AA, Waseem S, Riaz AM, Dilawar BA, Mukhtar S, Minhaj S, et al. PDGF: the nuts and bolts of signalling toolbox. Tumour Biol 2011;32:1057–1070.

    Article  CAS  PubMed  Google Scholar 

  22. Song SH, Jeong IG, You D, Hong JH, Hong B, Song C, et al. VEGF/VEGFR2 and PDGF-B/PDGFR-β expression in non-metastatic renal cell carcinoma: a retrospective study in 1,091 consecutive patients. Int J Clin Exp Pathol 2014;7:7681–7689.

    PubMed  PubMed Central  Google Scholar 

  23. Schutz FA, Je Y, Richards CJ, Choueiri TK. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol 2012;30:871-817.

  24. Sivendran S, Liu Z, Portas LJ, Yu M, Hahn N, Sonpavde G, et al. Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: a meta-analysis. Cancer Treat Rev 2012;38:919–925.

    Article  CAS  PubMed  Google Scholar 

  25. Schmidinger M, Zielinski CC. Novel agents for renal cell carcinoma require novel selection paradigms to optimise first-line therapy. Cancer Treat Rev 2009;35:289–296.

    Article  CAS  PubMed  Google Scholar 

  26. Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446–1452.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gadgeel SM, Cote ML, Schwartz AG, Matherly LH, Wozniak A, Bepler G. Parameters for individualizing systemic therapy in non-small cell lung cancer. Drug Resist Updat 2010;13:196–204.

    Article  CAS  PubMed  Google Scholar 

  28. Peña C, Lathia C, Shan M, Escudier B, Bukowski RM. Biomarkers predicting outcome in patients with advanced renal cell carcinoma: results from sorafenib phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. Clin Cancer Res 2010;16:4853–4863.

    Article  PubMed  Google Scholar 

  29. Choueiri TK, Regan MM, Rosenberg JE, Oh WK, Clement J, Amato AM, et al. Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear-cell renal cell carcinoma receiving vascular endothelial growth factor-targeted therapy. BJU Int 2010;106:772–778.

    Article  CAS  PubMed  Google Scholar 

  30. Perez-Gracia JL, Prior C, Guillén-Grima F, Segura V, Gonzalez A, Panizo A, et al. Identification of TNF-alpha and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array. Br J Cancer 2009;101:1876–1883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Barrios CH, Hernandez-Barajas D, Brown MP, Lee SH, Fein L, Liu JH, et al. Phase IItrial of continuous once-daily dosing of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma. Cancer 2012;118:1252–1259.

    Article  CAS  PubMed  Google Scholar 

  32. Koyama S, Yu H, Dalgarno DC, Shin TB, Zydowsky LD, Schreiber SL. Structure of the PI3K SH3 domain and analysis of the SH3 family. Cell 1993;72:945–952.

    Article  CAS  PubMed  Google Scholar 

  33. Wei H, Ke HL, Lin J, Shete S, Wood CG, Hildebrandt MA. MicroRNA target site polymorphisms in the VHL-HIF1a pathway predict renal cell carcinoma risk. Mol Carcinog 2014;53:1–7.

    Article  CAS  PubMed  Google Scholar 

  34. Stillebroer AB, Mulders PF, Boerman OC, Oyen WJ, Oosterwijk E. Carbonic anhydrase IX in renal cell carcinoma: implications for prognosis, diagnosis, and therapy. Eur Urol 2010;58:75–83.

    Article  CAS  PubMed  Google Scholar 

  35. Razorenova OV, Finger EC, Colavitti R, Chernikova SB, Boiko AD, Chan CK, et al. VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKC{delta}-driven migration. Proc Natl Acad Sci U S A 2011;108:1931–1936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee JH, Kim EJ, Kim DK, Lee JM, Park SB, Lee IK, et al. Hypoxia induces PDK4 gene expression through induction of the orphan nuclear receptor ERR?. PLoS One 2012;7:e46324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim J, Jonasch E, Alexander A, Short JD, Cai S, Wen S, et al. Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Clin Cancer Res 2009;15:81–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 2008;11:32–50.

    Article  CAS  PubMed  Google Scholar 

  39. Podar K, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 2005;105:1383–1395.

    Article  CAS  PubMed  Google Scholar 

  40. Keith B, Johnson RS, Simon MC. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 2011;12:9–22.

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Urology, Kyungpook National University School of Medicine, Daegu, Korea

    Jun Nyung Lee, Yun-Sok Ha, Hyun Tae Kim, Tae-Hwan Kim, Eun Sang Yoo, Bup Wan Kim & Tae Gyun Kwon

  2. Biomedical Research Institute, Kyungpook National University Hospital, Daegu, Korea

    So Young Chun

  3. Department of Pathology, Kyungpook National University Scholol of Medicine, Daegu, Korea

    Kyung Hee Choi & Ghil Suk Yoon

  4. Department of Urology, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, Korea

    Tae-Hwan Kim & Tae Gyun Kwon

Authors
  1. Jun Nyung Lee
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  2. So Young Chun
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  3. Yun-Sok Ha
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Correspondence to Tae-Hwan Kim or Tae Gyun Kwon.

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These authors contributed equally to this work.

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Lee, J.N., Chun, S.Y., Ha, YS. et al. Target molecule expression profiles in metastatic renal cell carcinoma: Development of individual targeted therapy. Tissue Eng Regen Med 13, 416–427 (2016). https://doi.org/10.1007/s13770-016-9088-z

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  • DOI: https://doi.org/10.1007/s13770-016-9088-z

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