Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Design “Evolutionary Trap” to Thwart Drug Resistance

13.02.2015

Cancer is a notoriously evasive disease. It can adopt multiple identities, accumulating mutations or even gaining or losing whole chromosomes to create genetic variants of itself that are resistant to whatever drug is thrown its way.

This ability to evolve to changing conditions and new therapies can turn cancer care into a game of whack-a-mole, as clinicians hit cancer cells with one treatment after another only to have new drug resistant forms pop up.


Rong Li Lab, Stowers Institute for Medical Research

Graphical abstract

Now, using theoretical and experimental approaches, researchers at the Stowers Institute for Medical Research have developed a two-pronged strategy that uses an evolving cell population’s adaptive nature against it.

First, the method was designed to steer the cell population into one evolutionary path, shutting off the other openings where it might rear its ugly head. Once the cells are trapped in this way, the method then positions its hammer over the single remaining target, knocking out the cell population for good.

The new approach, which the researchers call an “evolutionary trap,” was reported February 12, 2015 in Cell. The strategy may potentially be applied not just to cancer treatment but also to other clinical scenarios where drug resistance is a problem, such as fungal infections.

“We know evolution is the creative force that shapes living organisms,” says Stowers Investigator Rong Li, Ph.D., who led the study. “But too often we think about organisms as machines, like they are built by a blueprint and are never going to change. In fact, when we are dealing with cancers or pathogenic organisms we are faced with systems that continuously adapt and change so that they are moving targets. We need to develop treatments that stop them from evolving altogether.”

Li has long been interested in how cells evolve, and she has spent years investigating the types of genetic variants that quickly emerge when cells are stressed. Recently, she found that the first and most effective change that evolving cells undergo is to gain or lose a chromosome, a condition known as aneuploidy. By basically scrambling the dosage of the genes carried on these chromosomes, cells can take on new characteristics needed to survive under changing conditions.

Li wondered if it was possible to turn cancer’s rapidly evolving nature into a weakness.

“The idea of an evolutionary trap involves training the population so that it has reduced adaptability” says Li. “You take a heterogeneous population of cells and treat it with a drug so that only one specific type of genetic variant will survive. The entire population may be good at growing under that condition, but its homogeneity becomes its Achilles heel. Then you target that by throwing in a second drug to drastically switch the conditions.”

Guangbo Chen, a recently graduated Ph.D. student in Li’s lab, tested this approach in a proof-of-principle study. First, he constructed a yeast population that mimics the diversity observed in fungal pathogens or human cancers. He treated the budding yeast with high concentrations of radicicol, a natural antibiotic and antifungal that kills all forms of the yeast except those that have gained an extra copy of chromosome XV. Chen then searched for pharmaceuticals that were effective against this chromosome XV gain, landing on a drug called hygromycin B. He found that treating the yeast with a combination of both the drugs effectively wiped out all of the cultures.

The researchers then wanted to see if this evolutionary trap strategy could improve treatment in situations where antifungals have failed. The human pathogen Candida albicans becomes resistant to the common antifungal drug fluconazole by acquiring an extra arm of chromosome 5. Chen and his colleagues screened over a thousand FDA-approved drugs for those effective against this chromosomal abnormality in a sample of Candida albicans isolated from a patient with fluconazole resistance. They showed that the drug pyrvinium pamoate, which is used to treat pediatric pinworm infections, suppressed the growth of the fungus when combined with fluconazole.

“Many diseases that evolve drug resistance involve cell populations with different chromosome copy numbers. Here we have shown that aneuploidy can be used as a drug target,” says Chen, who is lead author of the study.

Chen and Li have also proposed the design of an evolutionary trap against glioblastoma, the most common and deadliest primary brain tumor in adults. Nearly all glioblastoma tumors carry an extra arm or entire copy of chromosome 7, and specific anti-cancer drugs called EGFR inhibitors are likely to further select for this type of aneuploidy. This additional genetic material has also been detected in lung cancers that have developed resistance to specific anti-cancer drugs like gefitinib and erlotinib. By analyzing a large brain tumor dataset containing both chromosome copy number and drug sensitivity information, the researchers found a drug called irinotecan, already approved for use in colon cancer, which may be toxic to cancer cells with chromosome 7 gain.

“Hopefully our study is just the beginning,” says Li. “There is a vast amount of data that we can mine for other drug pairs with the potential to form evolutionary traps on cancer. I am particularly interested in looking deeper into whether we can apply this strategy to clinical treatment, and plan to collaborate with clinicians to figure out ways we can test this approach.”

Other contributors from the Stowers Institute include Wahid A. Mulla, Andrei Kucharavy, Hung-Ji Tsai, Ph.D., Boris Rubinstein, Ph.D., Juliana Conkright, Ph.D., Scott McCrosky, William D. Bradford, Lauren Weems, Jeff S. Haug, and Chris W. Seidel, Ph.D.

The work was funded by the Stowers Institute for Medical Research and a grant from the National Institutes of Health (National Institute of General Medicine Sciences award R01GM059964). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Lay Summary of Findings

Cancers and human pathogens rapidly evolve and adapt to their surrounding environment -- accumulating genetic changes and even gaining or losing entire chromosomes -- to develop drug resistance. In the current issue of the scientific journal Cell, Stowers Institute scientists report a new strategy to combat drug resistance by hijacking the evolutionary process. Stowers Investigator Rong Li, Ph.D., who led the study, explains that this “evolutionary trap” uses one drug to steer a population of cells down a single evolutionary path, and then a second drug to target the trapped population. In the study, Li and her colleagues explored the feasibility of the approach against a fungal pathogen and predicted its possible efficacy toward certain human cancers.

About the Stowers Institute for Medical Research

The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife, Virginia, opened the Institute in 2000. Since then, the Institute has spent over 900 million dollars in pursuit of its mission.

Currently, the Institute is home to almost 550 researchers and support personnel; over 20 independent research programs; and more than a dozen technology-development and core facilities.

Contact Information
Kim Bland
Head, Science Communications
816-926-4015
ksb@stowers.org

Kim Bland | newswise
Further information:
http://www.stowers.org

Further reports about: Design Evolutionary Medical Stowers Institute drug resistance fluconazole fungal

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>