Creating a free account will enable you to subscribe to our daily and weekly email newsletters, as well as customize your reading experience to show only the categories most relevant to you.
Signing up only take a few minutes, so why not give it a try and see what you've been missing out on.
If you really want to understand why a particular human cancer resists treatment, you have to be able to study that tumor - really study it - in a way that just isn't possible in humans. Cancer biologists have been developing a new approach to this challenge, by transplanting human cancers directly from patients to mice whose crippled immune systems will allow those human tissues to grow. According to research published in the Cell Press publication Cell Reports, this new approach permits analysis of human cancer in unprecedented detail. The new work shows that those transplanted cancers, known as PDX (for patient-derived xenografts), are very good genomic replicas of the original at every level of analysis.
Overall, the PDX approach promises to speed the development of new drugs along with doctors' ability to make more precise choices about how those drugs are used to treat patients, the researchers say.
"The development of precision pharmacology is clearly the current focus in PDX research," said Matthew Ellis of Washington University in St Louis. "Human testing is hugely expensive, and often the response rates for the patients on experimental drugs are low because the biology of each patient is not well defined. Panels of clinically and genomically annotated PDX can therefore be very valuable for studying drug action and developing predictive biomarkers. Extensive pre- and post-drug sampling can be conducted to study drug effects and drug resistance in a way that would be impossible in the clinical setting."
In the new study, Ellis and his team transplanted drug-resistant human breast cancers into mice and then made very detailed comparisons of those transplanted tumors versus the originals.
The researchers' deep whole-genome analyses showed a high degree of genomic fidelity. In other words, the complex human tumor tissues in the mice looked very much like those in the people they originally came from. While some new mutations did arise after transplantation, those genetic changes rarely had functional significance.
The researchers were surprised to discover that the original and PDX cancers were similar at the cellular level as well. Cancer cells carrying mutations that were relatively rare in the patient were also maintained at lower frequencies in the mice. Likewise, more dominant clones in the original tumor tended to stay dominant in the mice. This suggests that the frequency of genetically distinct tumor cells is in an equilibrium that survives transplantation into mice for reasons that aren't yet clear.
An analysis of multiple estrogen receptor-positive PDX from patients with endocrine therapy-resistant disease shows just how this approach can yield tumor-specific explanations for therapy resistance. Resistant tumors were associated with different kinds of alterations to the estrogen receptor gene ESR1, the researchers found, producing different responses to endocrine therapy.
"The prevalence of ESR1 mutations and gene arrangements in the luminal PDX was a deep surprise to me as I thought these events were rare," Ellis said. "There had been very sporadic reports of ESR1 point mutations in clinical samples over the years, but to find them at high prevalence in the PDX and therefore in a setting where the link to endocrine therapy resistance can be directly studied was, for me, a critical breakthrough in our understanding of this critical problem."
Shunqiang Li, Dong Shen, Jieya Shao, Robert Crowder, Wenbin Liu, Aleix Prat, Xiaping He, Shuying Liu, Jeremy Hoog, Charles Lu, Li Ding, Obi L. Griffith, Christopher Miller, Dave Larson, Robert S. Fulton, Michelle Harrison, Tom Mooney, Joshua F. McMichael, Jingqin Luo, Yu Tao, Rodrigo Goncalves, Christopher Schlosberg, Jeffrey F. Hiken, Laila Saied, Cesar Sanchez, Therese Giuntoli, Caroline Bumb, Crystal Cooper, Robert T. Kitchens, Austin Lin, Chanpheng Phommaly, Sherri R. Davies, Jin Zhang, Megha Shyam Kavuri, Donna McEachern, Yi Yu Dong, Cynthia Ma, Timothy Pluard, Michael Naughton, Ron Bose, Rama Suresh, Reida McDowell, Loren Michel, Rebecca Aft, William Gillanders, Katherine DeSchryver, Richard K. Wilson, Shaomeng Wang, Gordon B. Mills, Ana Gonzalez-Angulo, John R. Edwards, Christopher Maher, Charles M. Perou, Elaine R. Mardis, Matthew J. Ellis. 10.1016/j.celrep.2013.08.022
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our Breast Cancer category page for the latest news on this subject.
Please use one of the following formats to cite this article in your essay, paper or report:
Press, Cell. "Tackling drug-resistant cancers using a genome-forward approach." Medical News Today. MediLexicon, Intl., 23 Sep. 2013. Web.
12 Dec. 2013. <http://www.medicalnewstoday.com/releases/266380>
Press, C. (2013, September 23). "Tackling drug-resistant cancers using a genome-forward approach." Medical News Today. Retrieved from
Please note: If no author information is provided, the source is cited instead.
If you write about specific medications, operations, or procedures please do not name healthcare professionals by name.
For any corrections of factual information, or to contact the our editorial team, please use our feedback form. Please send any medical news or health news press releases to:
Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.
This page was printed from: http://www.medicalnewstoday.com/releases/266380.php
Visit www.medicalnewstoday.com for medical news and health news headlines posted throughout the day, every day.
© 2004-2013 All rights reserved. MNT (logo) is the registered trade mark of MediLexicon International Limited.