Abstract
Experimental oncology research and preclinical drug development both substantially require specific, clinically relevant in vitro and in vivo tumor models. The increasing knowledge about the heterogeneity of cancer requested a substantial restructuring of the test systems for the different stages of development. To be able to cope with the complexity of the disease, larger panels of patient-derived tumor models have to be implemented and extensively characterized. Together with individual genetically engineered tumor models and supported by core functions for expression profiling and data analysis, an integrated discovery process has been generated for predictive and personalized drug development.
Improved “humanized” mouse models should help to overcome current limitations given by xenogeneic barrier between humans and mice. Establishment of a functional human immune system and a corresponding human microenvironment in laboratory animals will strongly support further research.
Drug discovery, systems biology, and translational research are moving closer together to address all the new hallmarks of cancer, increase the success rate of drug development, and increase the predictive value of preclinical models.
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References
Alcantar-Orozco EM, Gornall H, Baldan V, Hawkins RE, Gilham DE (2013) Potential limitations of the NSG humanized mouse as a model system to optimize engineered human T cell therapy for cancer. Hum Gene Ther Methods 24(5):310–320
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26(10):1626–1634
Amendt C, Staub E, Friese-Hamim M, Störkel S, Stroh C (2014) Association of EGFR expression level and cetuximab activity in patient-derived xenograft models of human non-small cell lung cancer. Clin Cancer Res 20(17):4478–4487
Angevin E, Glukhova L, Pavon C, Chassevent A, Terrier-Lacombe MJ, Goguel AF, Bougaran J, Ardouin P, Court BH, Perrin JL, Vallancien G, Triebel F, Escudier B (1999) Human renal cell carcinoma xenografts in SCID mice: tumorigenicity correlates with a poor clinical prognosis. Lab Invest 79:879–888
Bankert RB, Egilmez NK, Hess S (2001) Human-SCID mouse chimeric models for the evaluation of anti-cancer therapies. Trends Immunol 22:386–393
Bankert RB, Balu-Iyer SV, Odunsi K, Shultz LD, Kelleher RJ, Barnas JL (2011) Humanized mouse models of ovarian cancer recapitulates patient solid tumor progression, ascites formation, and metastasis. PLoS One 6:e24420
Becker M, Nitsche A, Neumann C, Aumann J, Junghahn I, Fichtner I (2002) Sensitive PCR method for the detection and real-time quantification of human cells in xenotransplantation systems. Br J Cancer 87(11):1328–1335
Becker M, Sommer A, Krätzschmar JR, Seidel H, Pohlenz HD, Fichtner I (2004) Distinct gene expression patterns in a tamoxifen-sensitive human mammary carcinoma xenograft and its tamoxifen-resistant subline MaCa 3366/TAM. Mol Cancer Ther 4:151–168
Behrens D, Hallas C, Anders D, Hoffmann J, Fichtner I (2014) In vivo models of pancreatic cancer for translational medicine. Eur J Cancer 50(Supplement 5):S1–S247
Bosma MJ, Carroll AM (1991) The SCID mouse mutant: definition, characterization, and potential uses. Annu Rev Immunol 9:323–335
Brischwein K, Schlereth B, Guller B, Steiger C, Wolf A, Lutterbuese R, Offner S, Locher M, Urbig T, Raum T, Kleindienst P, Wimberger P, Kimmig R, Fichtner I, Kufer P, Hofmeister R, da Silva AJ, Baeuerle PA (2006) MT110: a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors. Mol Immunol 43:1129–1143
Cao S, Durrani FA, Tóth K, Rustum YM (2014) Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models. Br J Cancer 110(7):1733–1743
Carter TC, Dunn LC, Falconer DS (1952) Standardized nomenclature for inbred strains of mice: prepared by the committee on standardized nomenclature for inbred strains of mice. Cancer Res 12:602–613
Chiarugi P, Paoli P, Cirri P (2014) Tumor microenvironment and metabolism in prostate cancer. Semin Oncol 41(2):267–280
Cook RS, Jacobsen KM, Wofford AM, DeRyckere D, Stanford J, Prieto AL, Redente E, Sandahl M, Hunter DM, Strunk KE, Graham DK, Earp HS 3rd (2013) MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis. J Clin Invest 123(8):3231–3242
Cree IA, Glaysher S, Harvey AL (2010) Efficacy of anti-cancer agents in cell lines versus human primary tumour tissue. Curr Opin Pharmacol 10(4):375–379
daChuna A, Michelin MA, Murta EF (2014) Pattern of response of dendritic cells in the tumor microenvironment and breast cancer. World J Clin Oncol 5(3):495–502
Decaudin D (2011) Primary human tumor xenografted models (“tumorgrafts”) for good management of patients with cancer. Anticancer Drugs 22:827–841
Dechantsreiter MA, Planker E, Matha B, Lohof E, Holzemann G, Jonczyk A (1999) N-methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists. J Med Chem 42:3033–3040
Dreier T, Baeuerle PA, Fichtner I, Grün M, Schlereth B, Lorenczewski G, Kufer P, Lutterbüse R, Riethmüller G, Gjorstrup P, Bargou RC (2003) T cell costimulus-independent and very efficacious inhibition of tumor growth in mice bearing subcutaneous or leukemic human B cell lymphoma xenografts by a CD19-/CD3- bispecific single-chain antibody construct. J Immunol 170:4397–4402
Duechler M, Peczek L, Szubert M, Suzin J (2014) Influence of hypoxia inducible factors on the immune microenvironment in ovarian cancer. Anticancer Res 34(6):2811–2819
Fang H, DeClerk YA (2013) Targeting the tumor microenvironment: from understanding pathways to effective clinical trails. Cancer Res 73(16):4965–4977
Fichtner I, Becker M, Zeisig R, Sommer A (2004) In vivo models for endocrine-dependent breast carcinomas: special considerations of clinical relevance. Eur J Cancer 40:845–851
Fichtner I, Rolff J, Soong R, Hoffmann J, Hammer S, Sommer A, Becker M, Merk J (2008) Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers. Clin Cancer Res 14(20):6456–6468
Fu S, Wang J, Sun W, Xu Y, Zhou X, Cheng W (2014) Preclinical humanized mouse model with ectopic ovarian tissues. Exp Ther Med 8(3):742–746
Furman WL, Stewart CF, Poquette CA, Pratt CB, Santana VM, Zamboni WC, Bowman LC, Ma MK, Hoffer FA, Meyer WH, Pappo AS, Walter AW, Houghton PJ (1999) Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17:1815–1824
Futakuchi M, Singh RK (2013) Animal model for mammary tumor growth in the bone microenvironment. Breast Cancer 20(3):195–203
Garber K (2009) From human to mouse and back: ‘tumorgraft’ models surge in popularity. J Natl Cancer Inst 101:6–8
Garralda E, Paz K, López-Casas PP, Jones S, Katz A, Kann LM, López-Rios F, Sarno F, Al-Shahrour F, Vasquez D, Bruckheimer E, Angiuoli SV, Calles A, Diaz LA, Velculescu VE, Valencia A, Sidransky D, Hidalgo M (2014) Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment. Clin Cancer Res 20(9):2476–2484
Garrido-Laguna I, Uson M, Rajeshkumar NV, Tan AC, de Oliveira E, Karikari C (2011) Tumor engraftment in nude mice and enrichment in stroma-related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer. Clin Cancer Res 17:5793–5800
Goubran HA, Kotb RR, Stakiw J, Emara ME, Burnouf T (2014) Regulation of tumor growth and metastasis: the role of tumor microenvironment. Cancer Growth Metastasis 7:9–18
Haddad TC, Yee D (2008) Of mice and (wo)men: is this any way to test a new drug? J Clin Oncol 26:830–832
Hammer S, Sommer A, Fichtner I, Becker M, Rolff J, Merk J, Klar U, Hoffmann J (2010) Comparative profiling of the novel epothilone, Sagopilone, in xenografts derived from primary non-small cell lung cancer. Clin Cancer Res 16:1452–1465
Henderson D, Ogilvie LA, Hoyle N, Keilholz U, Lange B, Lehrach H, OncoTrack Consortium (2014) Personalized medicine approaches for colon cancer driven by genomics and systems biology: OncoTrack. Biotechnol J 9(9)
Hersey P, Sosman J, O’Day S, Richards J, Bedikian A, Gonzalez R (2010) A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or − dacarbazine in patients with stage IV metastatic melanoma. Cancer 116:1526–1534
Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Mælandsmo GM, Roman-Roman S, Seoane J, Trusolino L, Villanueva A (2014) Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov 4(9):998–1013
Hoffmann J, Fichtner I, Lemm M, Lienau P, Hess-Stumpp H, Rotgeri A, Hofmann B, Klar U (2009) Sagopilone crosses the blood–brain barrier in vivo to inhibit brain tumor growth and metastases. Neuro Oncol 11(2):158–166
Hoffmann J, Orthmann A, Hoffmann A, Reiner R, Fichtner I (2014) Establishment and validation of models for metastasis developed from patient xenogragrafts (PDX). In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research, 2014 Apr 5–9. AACR, San Diego. Abstract 4953
Hylander BL, Punt N, Tang H, Hillmann J, Vaughan M, Bshara W (2013) Origin of the vasculature supporting growth of primary patient tumor xenografts. J Transl Med 11:110
Kelloff GJ, Sigman CC (2012) Cancer biomarkers: selecting the right drug for the right patient. Nat Rev Drug Discov 11:201–214
Lee H (2014) Genetically engineered mouse models for drug development and preclinical trials. Biomol Ther (Seoul) 22(4):267–274
Lee TK, Na KS, Kim J, Jeong HJ (2014) Establishment of animal models with orthotopic hepatocellular carcinoma. Nucl Med Mol Imaging 48(3):173–179
Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995
Malaney P, Nicosia SV, Davé V (2014) One mouse, one patient paradigm: new avatars of personalized cancer therapy. Cancer Lett 344(1):1–12
McCullough DJ, Nguyen LM, Siemann DW, Behnke BJ (2013) Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model. J Appl Physiol 115(12):1846–1854
Monsma DJ, Monks NR, Cherba DM, Dylewski D, Eugster E, Jahn H, Srikanth S, Scott SB, Richardson PJ, Everts RE, Ishkin A, Nikolsky Y, Resau JH, Sigler R, Nickoloff BJ, Webb CP (2012) Genomic characterization of explant tumorgraft models derived from fresh patient tumor tissue. J Transl Med 10:125
Morton CL, Houghton PJ (2007) Establishment of human tumor xenografts in immunodeficient mice. Nat Protoc 2(2):247–250
Nevins JR, Huang ES, Dressman H, Pittman J, Huang AT, West M (2003) Towards integrated clinico-genomic models for personalized medicine: combining gene expression signatures and clinical factors in breast cancer outcomes prediction. Hum Mol Genet 12(Spec No 2):R153–R157
Nwabo Kamdje AH, Muller JM, Lukong KE (2014) Signaling pathways in breast cancer: therapeutic targeting of the microenvironment. Cell Signal. doi:10.1016/j.cellsig.2014.07.034
O’Day S, Pavlick A, Loquai C, Lawson D, Gutzmer R, Richards J (2011) A randomised, phase II study of intetumumab, an anti-alphav-integrin mAb, alone and with dacarbazine in stage IV melanoma. Br J Cancer 105:346–352
Park SI, Kim SJ, McCauley LK, Gallick GE (2010) Pre-clinical mouse models of human prostate cancer and their utility in drug discovery. Curr Protoc Pharmacol Chapter 14:Unit 14.15. doi:10.1002/0471141755.ph1415s5
Paulsson J, Ehnman M, Ostman A (2014) PDGF receptors in tumor biology: prognostic and predictive potential. Future Oncol 10(9):1695–1708
Pechanska P, Becker M, Mayr T (2013) Mutation status of KRAS, BRAF, PIK3CA and expression level of AREG and EREG identify responders to cetuximab in a large panel of patient derived colorectal carcinoma xenografts of all four UICC stages. J Cancer Ther. doi:10.4236/jct.2013
Perez-Soler R, Kemp B, Wu QP, Mao L, Gomez J, Zeleniuch-Jacquotte A, Yee H, Lee JS, Jagirdar J, Ling YH (2006) Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude mice. Clin Cancer Res 6:4932–4938
Peterson JK, Houghton PJ (2004) Integrating pharmacology and in vivo cancer models in preclinical and clinical drug development. Eur J Cancer 40:837–844
Rappaport A, Johnson L (2014) Genetically engineered knock-in and conditional knock-in mouse models of cancer. Cold Spring Harb Protoc 2:2014(9)
Reisfeld RA (2013) The tumor microenvironment: a target for combination therapy of breast cancer. Crit Rev Oncog 18(1–2):115–133
Rivera M, Keil M, Boehnke K, Lange M, Schumacher D, Schäfer R, Regenbrecht CRA, Henderson D, Keilholz U, Kuehn A, El-Heliebi A, Hohensee T, Haybäck J, Reinhard C, Velasco JA, Lehrach H, Garin-Chesa P, Beran G, Hoffmann J (2014) Generation of drug response data from 57 new patient-derived colon cancer xenografts and 3D cell cultures for systematic correlation with tumor biology within the OncoTrack* project. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research, 2014 Apr 5–9. AACR, San Diego, CA. Abstract 2978
Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV, Teichmann LL, Saito Y, Marches F, Halene S, Palucka AK, Manz MG, Flavell RA (2014) Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol 32(4):364–372
Rossi ML, Rehman AA, Gondi CS (2014) Therapeutic options for the management of pancreatic cancer. World J Gastroenterol 20(32):11142–11159
Rubio-Viqueira B, Jimeno A, Cusatis G, Zhang X, Iacobuzio-Donahue C, Karikari C (2006) An in vivo platform for translational drug development in pancreatic cancer. Clin Cancer Res 12:4652–4661
Schlereth B, Fichtner I, Lorenczewski G, Kleindienst P, Brischwein K, da Silva A, Kufer P, Lutterbuese R, Junghahn I, Kasimir-Bauer S, Wimberger P, Kimmig R, Baeuerle PA (2005) Eradication of tumors from a human colon cancer cell line and from ovarian cancer metastases in immunodeficient mice by a single-chain Ep-CAM-/CD3-bispecific antibody construct. Cancer Res 65:2882–2889
Schmieder R, Hoffmann J, Becker M, Bhargava A, Müller T, Kahmann N, Ellinghaus P, Adams R, Rosenthal A, Thierauch KH, Scholz A, Wilhelm SM, Zopf D (2014) Regorafenib (BAY 73–4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. Int J Cancer 135(6):1487–1496
Scott CL, Becker MA, Haluska P, Samimi G (2013) Patient-derived xenograft models to improve targeted therapy in epithelial ovarian cancer treatment. Front Oncol 3(295):1–8
Sebastiani V, Ricci F, Rubio-Viqueira B, Kulesza P, Yeo CJ, Hidalgo M (2006) Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res 12:2492–2497
Sharpless NE, Depinho RA (2006) The mighty mouse: genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 5:741–754
Shull JD (2007) The rat oncogenome: comparative genetics and genomics of rat models of mammary carcinogenesis. Breast Dis 28:69–86
Siolas D, Hannon GJ (2013) Patient-derived tumor xenografts: transforming clinical samples into mouse models. Cancer Res 73:5315–5319
Slamon D, Pegram M (2001) Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol 28(1 Suppl 3):13–19
Smith HW, Muller WJ (2013) Transgenic mouse models – a seminal breakthrough in oncogene research. Cold Spring Harb Protoc 12:1099–1108
Sommer A, Hoffmann J, Lichtner RB, Schneider MR, Parczyk K (2003) Studies on the development of resistance to the pure antiestrogen Faslodex in three human breast cancer cell lines. J Steroid Biochem Mol Biol 85(1):33–47
Stromnes IM, Schmitt TM, Chapuis AG, Hingorani SR, Greenberg PD (2014) Re-adapting T cells for cancer therapy: from mouse models to clinical trials. Immunol Rev 257(1):145–164
Strube A, Hoffmann J, Stepina E, Hauff P, Klar U, Käkönen SM (2009) Sagopilone inhibits breast cancer bone metastasis and bone destruction due to simultaneous inhibition of both tumor growth and bone resorption. Clin Cancer Res 15(11):3751–3759
Thibaudeau L, Taubenberger AV, Holzapfel BM, Quent VM, Fuehrmann T, Hesami P, Brown TD, Dalton PD, Power CA, Hollier BG, Hutmacher DW (2014) A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone. Dis Model Mech 7(2):299–309
Tran PH, Tran TT, Lee BJ (2014) Biodistribution and pharmacokinetics in rats and antitumor effect in various types of tumor-bearing mice of novel self-assembled gelatin-oleic acid nanoparticles containing paclitaxel. J Biomed Nanotechnol 10(1):154–165
Tschida BR, Largaespada DA, Keng VW (2014) Mouse models of cancer: sleeping beauty transposons for insertional mutagenesis screens and reverse genetic studies. Semin Cell Dev Biol 27:86–95
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691–1703
Wang T, Liu G, Wang R (2014) The intercellular metabolic interplay between tumor and immune cells. Front Immunol 5:358
Wege AK, Schmidt M, Ueberham E, Ponnath M, Ortmann O, Brockhoff G, Lehmann J (2014) Co-transplantation of human hematopoietic stem cells and human breast cancer cells in NSG mice: a novel approach to generate tumor cell specific human antibodies. MAbs 6(4):968–977
Wenzel J, Zeisig R, Haider W, Habedank S, Fichtner I (2010) Inhibition of pulmonary metastasis in a human MT3 breast cancer xenograft model by dual liposomes preventing intravasal fibrin clot formation. Breast Cancer Res Treat 121(1):13–22
Zhang L, Cao DY, Wang J, Xiang B, Dun JN, Fang Y, Xue GQ (2013) PEG-coated irinotecan cationic liposomes improve the therapeutic efficacy of breast cancer in animals. Eur Rev Med Pharmacol Sci 17(24):3347–3361
Zhou Q, Facciponte J, Jin M, Shen Q, Lin Q (2014) Humanized NOD-SCID IL2rg−/− mice as a preclinical model for cancer research and its potential use for individualized cancer therapies. Cancer Lett 344(1):13–19
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Behrens, D., Rolff, J., Hoffmann, J. (2015). Predictive In Vivo Models for Oncology. In: Nielsch, U., Fuhrmann, U., Jaroch, S. (eds) New Approaches to Drug Discovery. Handbook of Experimental Pharmacology, vol 232. Springer, Cham. https://doi.org/10.1007/164_2015_29
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