Skip to main content

Advertisement

SpringerLink
Log in

Preclinical strategies to define predictive biomarkers for therapeutically relevant cancer subtypes

  • Review Paper
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Defining key driver mutations in cancer, the resulting aberrations in molecular mechanisms and the subsequent phenotype underpins the development and implementation of novel personalized medicine strategies. The literature is replete with biomarkers of prognosis and therapeutic responsiveness identified in single cohorts of patients that have not been independently validated and as a consequence, not developed. Integrating companion biomarker discovery with therapeutic development at the preclinical stage creates the opportunity to identify candidate biomarkers early, which would significantly facilitate both biomarker and therapeutic development. Advances in “-omic” technologies have led to large-scale efforts in characterizing and cataloguing the full range of aberrations in cancer. These include the International Cancer Genome Consortium and The Cancer Genome Atlas, which aim to comprehensively catalogue the range of genomic aberrations for large numbers of cancers for a progressively increasing range of cancer types and subtypes. The technical challenges associated with achieving these goals in some instances have required the generation of primary xenografts and cell lines. These extensively characterized model systems will provide an unprecedented resource for the discovery of biomarkers of therapeutic responsiveness for established therapies, and the development of companion biomarkers linked with preclinical novel therapeutic development in the future.

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

Similar content being viewed by others

References

  • Beerenwinkel N, Antal T, Dingli D, Traulsen A, Kinzler KW, Velculescu VE, Vogelstein B, Nowak MA (2007) Genetic progression and the waiting time to cancer. PLoS Comput Biol 3:e225

    Article  PubMed  Google Scholar 

  • Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27:663–671

    Article  PubMed  CAS  Google Scholar 

  • Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C, Kladny J, Gorski B, Lubinski J, Narod SA (2009) Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 115:359–363

    Article  PubMed  CAS  Google Scholar 

  • Carol H, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Maris JM, Keir ST, Watkins A, Smith MA, Lock RB (2010) Initial testing of topotecan by the pediatric preclinical testing program. Pediatr Blood Cancer 54:707–715

    PubMed  Google Scholar 

  • Collins FS, Barker AD (2007) Mapping the cancer genome. Pinpointing the genes involved in cancer will help chart a new course across the complex landscape of human malignancies. Sci Am 296:50–57

    Article  PubMed  CAS  Google Scholar 

  • Coombes KR, Wang J, Baggerly KA (2007) Microarrays: retracing steps. Nat Med 13:1276–1277 (author reply 1277–1278)

  • Croce CM (2008) Oncogenes and cancer. N Engl J Med 358:502–511

    Article  PubMed  CAS  Google Scholar 

  • Dagher R, Cohen M, Williams G, Rothmann M, Gobburu J, Robbie G, Rahman A, Chen G, Staten A, Griebel D, Pazdur R (2002) Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 8:3034–3038

    PubMed  CAS  Google Scholar 

  • Dickson D (1999) Wellcome funds cancer database. Nature 401:729

    Article  PubMed  CAS  Google Scholar 

  • Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001a) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042

    Article  PubMed  CAS  Google Scholar 

  • Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001b) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y et al (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266:120–122

    Article  PubMed  CAS  Google Scholar 

  • Heinrich MC, Blanke CD, Druker BJ, Corless CL (2002) Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol 20:1692–1703

    Article  PubMed  CAS  Google Scholar 

  • Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892–5899

    Article  PubMed  CAS  Google Scholar 

  • ICGC Consortium (2010) International network of cancer genome projects. Nature 464:993–998

    Article  Google Scholar 

  • Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, Ueyama Y, Koyanagi Y, Sugamura K, Tsuji K, Heike T, Nakahata T (2002) NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 100:3175–3182

    Article  PubMed  CAS  Google Scholar 

  • Jimeno A, Rubio-Viqueira B, Amador ML, Oppenheimer D, Bouraoud N, Kulesza P, Sebastiani V, Maitra A, Hidalgo M (2005) Epidermal growth factor receptor dynamics influences response to epidermal growth factor receptor targeted agents. Cancer Res 65:3003–3010

    PubMed  CAS  Google Scholar 

  • Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S, Kalyandrug S, Christian M, Arbuck S, Hollingshead M, Sausville EA (2001) Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 84:1424–1431

    Article  PubMed  CAS  Google Scholar 

  • Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP (2009) Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324:217

    Article  PubMed  CAS  Google Scholar 

  • Kang MH, Kang YH, Szymanska B, Wilczynska-Kalak U, Sheard MA, Harned TM, Lock RB, Reynolds CP (2007) Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood 110:2057–2066

    Article  PubMed  CAS  Google Scholar 

  • Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542–2551

    Article  PubMed  Google Scholar 

  • Katz MH, Takimoto S, Spivack D, Moossa AR, Hoffman RM, Bouvet M (2004) An imageable highly metastatic orthotopic red fluorescent protein model of pancreatic cancer. Clin Exp Metastasis 21:7–12

    Article  PubMed  CAS  Google Scholar 

  • Kim MP, Evans DB, Wang H, Abbruzzese JL, Fleming JB, Gallick GE (2009) Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice. Nat Protoc 4:1670–1680

    Article  PubMed  CAS  Google Scholar 

  • Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, Taber DA, Karrison T, Dachman A, Stadler WM, Vokes EE (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23:8033–8040

    Article  PubMed  CAS  Google Scholar 

  • Larbouret C, Robert B, Bascoul-Mollevi C, Penault-Llorca F, Ho-Pun-Cheung A, Morisseau S, Navarro-Teulon I, Mach JP, Pelegrin A, Azria D (2010) Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts. Ann Oncol 21:98–103

    Article  PubMed  CAS  Google Scholar 

  • Lee EM, Bachmann PS, Lock RB (2007a) Xenograft models for the preclinical evaluation of new therapies in acute leukemia. Leuk Lymphoma 48:659–668

    Article  PubMed  Google Scholar 

  • Lee JK, Havaleshko DM, Cho H, Weinstein JN, Kaldjian EP, Karpovich J, Grimshaw A, Theodorescu D (2007b) A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery. Proc Natl Acad Sci USA 104:13086–13091

    Article  PubMed  CAS  Google Scholar 

  • Lee CK, Lord SJ, Coates AS, Simes RJ (2009) Molecular biomarkers to individualise treatment: assessing the evidence. Med J Aust 190:631–636

    PubMed  Google Scholar 

  • Marra G, Boland CR (1995) Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 87:1114–1125

    Article  PubMed  CAS  Google Scholar 

  • Marshall E (2004) Getting the noise out of gene arrays. Science 306:630–631

    Article  PubMed  CAS  Google Scholar 

  • Messersmith WA, Rajeshkumar NV, Tan AC, Wang XF, Diesl V, Choe SE, Follettie M, Coughlin C, Boschelli F, Garcia-Garcia E, Lopez-Rios F, Jimeno A, Hidalgo M (2009) Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts. Mol Cancer Ther 8:1484–1493

    Article  PubMed  CAS  Google Scholar 

  • Moldovan GL, D’Andrea AD (2009) How the Fanconi anemia pathway guards the genome. Annu Rev Genet 43:223–249

    Article  PubMed  CAS  Google Scholar 

  • Mullenders J, von der Saal W, van Dongen MM, Reiff U, van Willigen R, Beijersbergen RL, Tiefenthaler G, Klein C, Bernards R (2009) Candidate biomarkers of response to an experimental cancer drug identified through a large-scale RNA interference genetic screen. Clin Cancer Res 15:5811–5819

    Article  PubMed  CAS  Google Scholar 

  • Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Ruckert F, Grutzmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–1461

    Article  PubMed  CAS  Google Scholar 

  • Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826

    Article  PubMed  CAS  Google Scholar 

  • Pajic M, Iyer JK, Kersbergen A, van der Burg E, Nygren AO, Jonkers J, Borst P, Rottenberg S (2009) Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer. Cancer Res 69:6396–6404

    Article  PubMed  CAS  Google Scholar 

  • Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101:13306–13311

    Article  PubMed  CAS  Google Scholar 

  • Pitts TM, Tan AC, Kulikowski GN, Tentler JJ, Brown AM, Flanigan SA, Leong S, Coldren CD, Hirsch FR, Varella-Garcia M, Korch C, Eckhardt SG (2010) Development of an integrated genomic classifier for a novel agent in colorectal cancer: approach to individualized therapy in early development. Clin Cancer Res 16:3193–3204

    Article  PubMed  CAS  Google Scholar 

  • Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598

    Article  PubMed  CAS  Google Scholar 

  • Rottenberg S, Nygren AO, Pajic M, van Leeuwen FW, van der Heijden I, van de Wetering K, Liu X, de Visser KE, Gilhuijs KG, van Tellingen O, Schouten JP, Jonkers J, Borst P (2007) Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl Acad Sci USA 104:12117–12122

    Article  PubMed  CAS  Google Scholar 

  • Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O’Connor MJ, Martin NM, Borst P, Jonkers J (2008) High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci USA 105:17079–17084

    Article  PubMed  CAS  Google Scholar 

  • Rubio-Viqueira B, Jimeno A, Cusatis G, Zhang X, Iacobuzio-Donahue C, Karikari C, Shi C, Danenberg K, Danenberg PV, Kuramochi H, Tanaka K, Singh S, Salimi-Moosavi H, Bouraoud N, Amador ML, Altiok S, Kulesza P, Yeo C, Messersmith W, Eshleman J, Hruban RH, Maitra A, Hidalgo M (2006) An in vivo platform for translational drug development in pancreatic cancer. Clin Cancer Res 12:4652–4661

    Article  PubMed  CAS  Google Scholar 

  • Singh M, Lima A, Molina R, Hamilton P, Clermont AC, Devasthali V, Thompson JD, Cheng JH, Bou Reslan H, Ho CC, Cao TC, Lee CV, Nannini MA, Fuh G, Carano RA, Koeppen H, Yu RX, Forrest WF, Plowman GD, Johnson L (2010) Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat Biotechnol 28:585–593

    Article  PubMed  CAS  Google Scholar 

  • Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  • Staunton JE, Slonim DK, Coller HA, Tamayo P, Angelo MJ, Park J, Scherf U, Lee JK, Reinhold WO, Weinstein JN, Mesirov JP, Lander ES, Golub TR (2001) Chemosensitivity prediction by transcriptional profiling. Proc Natl Acad Sci USA 98:10787–10792

    Article  PubMed  CAS  Google Scholar 

  • Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234

    Article  PubMed  CAS  Google Scholar 

  • Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354:2531–2541

    Article  PubMed  CAS  Google Scholar 

  • TCGA Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

    Article  Google Scholar 

  • van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009

    Article  PubMed  Google Scholar 

  • Van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536

    Article  Google Scholar 

  • Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726

    Article  PubMed  CAS  Google Scholar 

  • Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792

    Article  PubMed  CAS  Google Scholar 

  • Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, Pals G, Errami A, Gluckman E, Llera J, Wang W, Livingston DM, Joenje H, de Winter JP (2007) Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 39:159–161

    Article  PubMed  CAS  Google Scholar 

  • Zamboni WC, Stewart CF, Thompson J, Santana VM, Cheshire PJ, Richmond LB, Luo X, Poquette C, Houghton JA, Houghton PJ (1998) Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts. J Natl Cancer Inst 90:505–511

    Article  PubMed  CAS  Google Scholar 

  • Zander SA, Kersbergen A, van der Burg E, de Water N, van Tellingen O, Gunnarsdottir S, Jaspers JE, Pajic M, Nygren AO, Jonkers J, Borst P, Rottenberg S (2010) Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res 70:1700–1710

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Prof Liz Musgrove and Dr Tim Molloy for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia

    Marina Pajic, Christopher J. Scarlett, David K. Chang, Robert L. Sutherland & Andrew V. Biankin

Authors
  1. Marina Pajic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher J. Scarlett
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David K. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert L. Sutherland
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew V. Biankin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew V. Biankin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pajic, M., Scarlett, C.J., Chang, D.K. et al. Preclinical strategies to define predictive biomarkers for therapeutically relevant cancer subtypes. Hum Genet 130, 93–101 (2011). https://doi.org/10.1007/s00439-011-0990-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-011-0990-0

Keywords

Search

Navigation