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models established in immune-compromised mice. It interpret studies. Collectively, these new developments
is well documented and accepted that immune system emphasize the importance of employing PDX models in
is an important part of tumor stroma and signifi cantly key areas of oncology drug discovery and development.
contributes to tumor initiation, progression, metastasis
and therapeutic response. [84,85] The introduction of mice References
with partially or completely humanized immune systems 1. DiMasi JA, Reichert JM, Feldman L, Malins A. Clinical
can potentially ameliorate this issue, but signifi cant approval success rates for investigational cancer drugs.
technical challenges still exist. [86,87] Clin Pharmacol Ther 2013;94:329-35.
2. Kola I, Landis J. Can the pharmaceutical industry reduce
Second, although technical advances have gradually attrition rates? Nat Rev Drug Discov 2004;3:711-5.
improved the tumor take, different tumor types, and 3. Rosfjord E, Lucas J, Li G, Gerber HP. Advances in
different subtypes within the same tumor type, have patient-derived tumor xenografts: From target identifi cation
varying rates of success. This has led to imbalanced to predicting clinical response rates in oncology.
representation of tumor types/subtypes that is more Biochem Pharmacol 2014;91:135-43.
determined by take rate rather than clinical incidence 4. Hanahan D, Weinberg RA. Hallmarks of cancer: The next
rate. Although PDX models can avoid artifi cial selection generation. Cell 2011;144:646-74.
in extended culture on plastic, the in vivo selection 5. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell
process exists as soon as the tumors are implanted. For 2000;100:57-70.
example, high-grade, fast proliferating tumors tend to be 6. Hoelder S, Clarke PA, Workman P. Discovery of small
cancer
drugs:
challenges
Successes,
and
molecule
easier to establish as PDX models than low-grade, slowly opportunities. Mol Oncol 2012;6:155-76.
growing but progressive tumors. [88,89] 7. Gibbs JB. Mechanism-based target identifi cation and drug
Additionally, compared to cell lines, PDX models are discovery in cancer research. Science 2000;287:1969-73.
diffi cult to manipulate genetically. Most PDX models 8. Carter P, Smith L, Ryan M. Identifi cation and validation
are established from and passaged as tumor fragments, of cell surface antigens for antibody targeting in oncology.
Endocr Relat Cancer 2004;11:659-87.
and conventional transfection or transduction are not 9. Wang IM, Stone DJ, Nickle D, Loboda A, Puig O, Roberts C.
effi cient to genetically modify the tumors or introduce Systems biology approach for new target and biomarker
detection markers (such as luciferase or fl uorescent identifi cation. Curr Top Microbiol Immunol 2013;363:169-99.
proteins). Therefore, PDX tumors are rarely established 10. Rius M, Lyko F. Epigenetic cancer therapy: Rationales, targets
as orthotopic models, unless there is a surrogate and drugs. Oncogene 2012;31:4257-65.
biomarker that be readily used to measure tumor burden 11. Jerby L, Ruppin E. Predicting drug targets and biomarkers of
noninvasively. [90] cancer via genome-scale metabolic modeling. Clin Cancer Res
2012;18:5572-84.
Conclusion 12. Boven E, Winograd B, Berger DP, Dumont MP, Braakhuis BJ,
Fodstad O, Langdon S, Fiebig HH. Phase II preclinical
Although hardly a new concept, PDX models have drug screening in human tumor xenografts: A fi rst European
gained much attention and premium status in the past multicenter collaborative study. Cancer Res 1992;52:5940-7.
few years as they are becoming increasingly available 13. Voskoglou-Nomikos T, Pater JL, Seymour L. Clinical
and affordable, and are believed to offer a superior predictive value of the in vitro cell line, human xenograft, and
predictive value over conventional cell line xenograft mouse allograft preclinical cancer models. Clin Cancer Res
models. Ample data indicated that PDX models maintain 2003;9:4227-39.
heterogeneity and tumor initiation ability, as well as 14. Tentler JJ, Tan AC, Weekes CD, Jimeno A, Leong S, Pitts TM,
Arcaroli JJ, Messersmith WA, Eckhardt SG. Patient-derived
molecular and genetic characteristics refl ective of human tumour xenografts as models for oncology drug development.
tumors. Emerging data indicated an improved predictive Nat Rev Clin Oncol 2012;9:338-50.
value of the PDX models; however, it is still early to 15. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C,
conclude whether the advantage in translatability is Bignell G, Davies H, Teague J, Butler A, Stevens C,
applicable to large sample size and to various therapeutic Edkins S, O’Meara S, Vastrik I, Schmidt EE, Avis T,
mechanisms and modalities. The mouse clinical trial Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J,
has the potential to accelerate and de-risk human Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R,
Hills K, Hinton J, Jenkinson A, Jones D, Menzies A,
clinical trials and hopefully reduce clinical attrition rates Mironenko T, Perry J, Raine K, Richardson D, Shepherd R,
for novel compounds, and to prioritize therapies by Small A, Tofts C, Varian J, Webb T, West S, Widaa S,
allowing parallel testing of multiple treatment schemes Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG,
for an individual patient. However, there are still much Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A,
to be done to address technical challenges to make Greaves MF, Green AR, Campbell P, Birney E, Easton DF,
this approach feasible and affordable and to convince Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST,
Leung SY, Wooster R, Futreal PA, Stratton MR. Patterns
the medical and insurance community of the value of somatic mutation in human cancer genomes. Nature
this approach can offer. At the same time, one cannot 2007;446:153-8.
overlook the limitations of PDX models and should take 16. Stratton MR, Campbell PJ, Futreal PA. The cancer genome.
into consideration of their shortcomings when design and Nature 2009;458:719-24.

12 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 1 ¦ April 15, 2015 ¦