Skip to main content
SpringerLink
Log in
Book cover

Patient-Derived Mouse Models of Cancer pp 245–250Cite as

Synergy of Patient-Derived Orthotopic Xenografts (PDOX) Models and Molecular Profiling for Optimal Therapy

  • Chapter
  • First Online:

  • 661 Accesses

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

Abstract

The patient-derived orthotopic xenograft (PDOX) model provides the opportunity for testing novel as well as standard agents on primary and metastatic tumors. The present chapter reviews the efficacy of molecular-targeting drugs on PDOX models of Ewing’s sarcoma and melanoma with defining mutations. The results indicate molecular profiling is not sufficient to predict tumor drug sensitivity in the PDOX model and that both molecular profiling and PDOX drug testing can be used very powerfully together for effective, precise individualized therapy.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Fu X, Guadagni F, Hoffman RM. A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically from histologically intact patient specimens. Proc Natl Acad Sci U S A. 1992;89:5645–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hiroshima Y, Zhao M, Maawy A, Zhang Y, Katz MH, Fleming JB, Uehara F, Miwa S, Yano S, Momiyama M, Suetsugu A, Chishima T, Tanaka K, Bouvet M, Endo I, Hoffman RM. Efficacy of Salmonella typhimurium A1-R versus chemotherapy on a pancreatic cancer patient-derived orthotopic xenograft (PDOX). J Cell Biochem. 2014;115:1254–61.

    Article  CAS  PubMed  Google Scholar 

  3. Hiroshima Y, Maawy A, Zhang Y, Murakami T, Momiyama M, Mori R, Matsuyama R, Katz MH, Fleming JB, Chishima T, Tanaka K, Ichikawa Y, Endo I, Hoffman RM, Bouvet M. Metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model is inhibited by neoadjuvant chemotherapy in combination with fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore. PLoS One. 2014;9:e114310.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hiroshima Y, Zhang Y, Murakami T, Maawy AA, Miwa S, Yamamoto M, Yano S, Sato S, Momiyama M, Mori R, Matsuyama R, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Zhao M, Hoffman RM. Efficacy of tumor-targeting Salmonella typhimurium A1-R in combination with anti-angiogenesis therapy on a pancreatic cancer patient-derived orthotopic xenograph (PDOX) and cell line mouse models. Oncotarget. 2014;5:12346–57.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hiroshima Y, Maawy AA, Katz MH, Fleming JB, Bouvet M, Endo I, Hoffman RM. Selective efficacy of zoledronic acid on metastasis in a patient-derived orthotopic xenograph (PDOX) nude-mouse model of human pancreatic cancer. J Surg Oncol. 2015;111:311–5.

    Article  CAS  PubMed  Google Scholar 

  6. Fu X, Le P, Hoffman RM. A metastatic-orthotopic transplant nude-mouse model of human patient breast cancer. Anticancer Res. 1993;13:901–4.

    CAS  PubMed  Google Scholar 

  7. Fu X, Hoffman RM. Human ovarian carcinoma metastatic models constructed in nude mice by orthotopic transplantation of histologically-intact patient specimens. Anticancer Res. 1993;13:283–6.

    CAS  PubMed  Google Scholar 

  8. Wang X, Fu X, Hoffman RM. A new patient-like metastatic model of human lung cancer constructed orthotopically with intact tissue via thoracotomy in immunodeficient mice. Int J Cancer. 1992;51:992–5.

    Article  CAS  PubMed  Google Scholar 

  9. Hiroshima Y, Zhang Y, Zhang M, Maawy A, Mii S, Yamamoto M, Uehara F, Miwa S, Yano S, Murakami T, Momiyama M, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Murata T, Endo I, Hoffman RM. Establishment of a patient-derived orthotopic xenograph (PDOX) model of HER-2-positive cervical cancer expressing the clinical metastatic pattern. PLoS One. 2015;10:e0117417.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Murakami T, Murata T, Kawaguchi K, Kiyuna T, Igarashi K, Hwang HK, Hiroshima Y, Hozumi C, Komatsu S, Kikuchi T, Lwin TM, Delong JC, Miyake K, Zhang Y, Tanaka K, Bouvet M, Endo I, Hoffman RM. Cervical cancer patient-derived orthotopic xenograft (PDOX) is sensitive to cisplatinum and resistant to nab-paclitaxel. Anticancer Res. 2017;37:61–6.

    Google Scholar 

  11. Hiroshima Y, Maawy A, Zhang Y, Zhang N, Murakami T, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM. Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy. Oncotarget. 2016;7(44):71696–702.

    Google Scholar 

  12. Fu X, Besterman JM, Monosov A, Hoffman RM. Models of human metastatic colon cancer in nude mice orthotopically constructed by using histologically intact patient specimens. Proc Natl Acad Sci U S A. 1991;88:9345–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Metildi CA, Kaushal S, Luiken GA, Talamini MA, Hoffman RM, Bouvet M. Fluorescently-labeled chimeric anti-CEA antibody improves detection and resection of human colon cancer in a patient-derived orthotopic xenograft (PDOX) nude mouse model. J Surg Oncol. 2014;109:451–8.

    Article  CAS  PubMed  Google Scholar 

  14. Hiroshima Y, Maawy A, Metildi CA, Zhang Y, Uehara F, Miwa S, Yano S, Sato S, Murakami T, Momiyama M, Chishima T, Tanaka K, Bouvet M, Endo I, Hoffman RM. Successful fluorescence-guided surgery on human colon cancer patient-derived orthotopic xenograft mouse models using a fluorophore-conjugated anti-CEA antibody and a portable imaging system. J Laparoendosc Adv Surg Tech A. 2014;24:241–7.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Furukawa T, Kubota T, Watanabe M, Kitajima M, Fu X, Hoffman RM. Orthotopic transplantation of histologically intact clinical specimens of stomach cancer to nude mice: correlation of metastatic sites in mouse and individual patient donors. Int J Cancer. 1993;53:608–12.

    Article  CAS  PubMed  Google Scholar 

  16. Astoul P, Wang X, Colt HG, Boutin C, Hoffman RM. A patient-like human malignant pleural mesothelioma nude-mouse model. Oncol Rep. 1996;3:483–7.

    CAS  PubMed  Google Scholar 

  17. Murakami T, DeLong J, Eilber FC, Zhao M, Zhang Y, Zhang N, Singh A, Russell T, Deng S, Reynoso J, Quan C, Hiroshima Y, Matsuyama R, Chishima T, Tanaka K, Bouvet M, Chawla S, Endo I, Hoffman RM. Tumor-targeting Salmonella typhimurium A1-R in combination with doxorubicin eradicate soft tissue sarcoma in a patient-derived orthotopic xenograft PDOX model. Oncotarget. 2016;7:12783–90.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hiroshima Y, Zhang Y, Zhang N, Uehara F, Maawy A, Murakami T, Mii S, Yamamoto M, Miwa S, Yano S, Momiyama M, Mori R, Matsuyama R, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM. Patient-derived orthotopic xenograft (PDOX) nude mouse model of soft-tissue sarcoma more closely mimics the patient behavior in contrast to the subcutaneous ectopic model. Anticancer Res. 2015;35:697–701.

    PubMed  Google Scholar 

  19. Hiroshima Y, Zhao M, Zhang Y, Zhang N, Maawy A, Murakami T, Mii S, Uehara F, Yamamoto M, Miwa S, Yano S, Momiyama M, Mori R, Matsuyama R, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM. Tumor-targeting Salmonella typhimurium A1-R arrests a chemo-resistant patient soft-tissue sarcoma in nude mice. PLoS One. 2015;10:e0134324.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kiyuna T, Murakami T, Tome Y, Kawaguchi K, Igarashi K, Zhang Y, Zhao M, Li Y, Bouvet M, Kanaya F, Singh A, Dry S, Eilber FC, Hoffman RM. High efficacy of tumor-targeting Salmonella typhimurium A1-R on a doxorubicin- and dactolisib-resistant follicular dendritic-cell sarcoma in a patient-derived orthotopic xenograft nude mouse model. Oncotarget. 2016;7:33046–54.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Konecny GE, Winterhoff B, Kolarova T, Qi J, Manivong K, Dering J, Yang G, Chalukya M, Wang HJ, Anderson L, Kalli KR, Finn RS, Ginther C, Jones S, Velculescu VE, Riehle D, Cliby WA, Randolph S, Koehler M, Hartmann LC, Slamon DJ. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res. 2011;17:1591–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cen L, Carlson BL, Schroeder MA, Ostrem JL, Kitange GJ, Mladek AC, Fink SR, Decker PA, Wu W, Kim JS, Waldman T, Jenkins RB, Sarkaria JN. p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro-Oncology. 2012;14:870–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. von Witzleben A, Goerttler LT, Marienfeld R, Barth H, Lechel A, Mellert K, Böhm M, Kornmann M, Mayer-Steinacker R, von Baer A, Schultheiss M, Flanagan AM, Möller P, Brüderlein S, Barth TF. Preclinical characterization of novel chordoma cell systems and their targeting by pharmacological inhibitors of the CDK4/6 cell-cycle pathway. Cancer Res. 2015;75:3823–31.

    Article  Google Scholar 

  24. Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, Landa J, Qin LX, Rathbone DD, Condy MM, Ustoyev Y, Crago AM, Singer S, Schwartz GK. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31:2024–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Murakami T, Singh AS, Kiyuna T, Dry SM, Li Y, James AW, Igarashi K, Kawaguchi K, DeLong JC, Zhang Y, Hiroshima Y, Russell T, Eckardt MA, Yanagawa J, Federman N, Matsuyama R, Chishima T, Tanaka K, Bouvet M, Endo I, Eilber FC, Hoffman RM. Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget. 2016;7:47556–64.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, Buck E, Foreman K, Landfair D, O’Connor M, Pirritt C, Sun Y, Yao Y, Arnold LD, Gibson NW, Ji QS. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem. 2009;1:1153–71.

    Article  CAS  PubMed  Google Scholar 

  27. Garofalo C, Manara MC, Nicoletti G, Marino MT, Lollini PL, Astolfi A, Pandini G, Lopez-Guerrero JA, Schaefer KL, Belfiore A, Picci P, Scotlandi K. Efficacy of and resistance to anti-IGF-1R therapies in Ewing’s sarcoma is dependent on insulin receptor signaling. Oncogene. 2011;30:2730–40.

    Article  CAS  PubMed  Google Scholar 

  28. Kuijjer ML, Peterse EF, van den Akker BE, Briaire-de Bruijn IH, Serra M, Meza-Zepeda LA, Myklebost O, Hassan AB, Hogendoorn PC, Cleton-Jansen AM. IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma. BMC Cancer. 2013;13:245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shing DC, McMullan DJ, Roberts P, Smith K, Chin SF, Nicholson J, Tillman RM, Ramani P, Cullinane C, Coleman N. FUS/ERG gene fusions in Ewing’s tumors. Cancer Res. 2003;63:4568–76.

    CAS  PubMed  Google Scholar 

  30. Chen S, Deniz K, Sung YS, Zhang L, Dry S, Antonescu CR. Ewing sarcoma with ERG gene rearrangements: a molecular study focusing on the prevalence of FUS-ERG and common pitfalls in detecting EWSR1-ERG fusions by FISH. Genes Chromosomes Cancer. 2016;55:340–9.

    Article  CAS  PubMed  Google Scholar 

  31. Kawaguchi K, Murakami T, Chmielowski B, Igarashi K, Kiyuna T, Unno M, Nelson SD, Russell TA, Dry SM, Li Y, Eilber FC, Hoffman RM. Vemurafenib-resistant BRAF-V600E mutated melanoma is regressed by MEK targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model. Oncotarget. 2016;7(44):71737–43.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA, 92111, USA

    Robert M. Hoffman, Takashi Murakami & Kei Kawaguchi

  2. Department of Surgery, University of California, San Diego, CA, USA

    Robert M. Hoffman, Takashi Murakami & Kei Kawaguchi

  3. Division of Hematology-Oncology, University of California, Los Angeles, CA, USA

    Arun S. Singh

  4. Division of Surgical Oncology, University of California, Los Angeles, CA, USA

    Fritz C. Eilber

Authors
  1. Robert M. Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takashi Murakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kei Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arun S. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fritz C. Eilber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert M. Hoffman .

Editor information

Editors and Affiliations

  1. University of California and AntiCancer Inc., San Diego, California, USA

    Robert M. Hoffman

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Hoffman, R.M., Murakami, T., Kawaguchi, K., Singh, A.S., Eilber, F.C. (2017). Synergy of Patient-Derived Orthotopic Xenografts (PDOX) Models and Molecular Profiling for Optimal Therapy. In: Hoffman, R. (eds) Patient-Derived Mouse Models of Cancer . Molecular and Translational Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-57424-0_18

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-57424-0_18

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-57423-3

  • Online ISBN: 978-3-319-57424-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation