Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists reprogram cancer cells with low doses of epigenetic drugs

23.03.2012
Experimenting with cells in culture, researchers at the Johns Hopkins Kimmel Cancer Center have breathed possible new life into two drugs once considered too toxic for human cancer treatment.

The drugs, azacitidine (AZA) and decitabine (DAC), are epigenetic-targeted drugs and work to correct cancer-causing alterations that modify DNA.

The researchers said the drugs also were found to take aim at a small but dangerous subpopulation of self-renewing cells, sometimes referred to as cancer stem cells, which evade most cancer drugs and cause recurrence and spread.

In a report published in the March 20, 2012, issue of Cancer Cell, the Johns Hopkins team said their study provides evidence that low doses of the drugs tested on cell cultures cause antitumor responses in breast, lung, and colon cancers.

Conventional chemotherapy agents work by indiscriminately poisoning and killing rapidly-dividing cells, including cancer cells, by damaging cellular machinery and DNA. "In contrast, low doses of AZA and DAC may re-activate genes that stop cancer growth without causing immediate cell-killing or DNA damage," says Stephen Baylin, M.D., Ludwig Professor of Oncology and deputy director of the Johns Hopkins Kimmel Cancer Center.

Many cancer experts had abandoned AZA and DAC for the treatment of common cancers, according to the researchers, because they are toxic to normal cells at standard high doses, and there was little research showing how they might work for cancer in general. Baylin and his colleague Cynthia Zahnow, Ph.D., decided to take another look at the drugs after low doses of the drugs showed a benefit in patients with a pre-leukemic disorder called myelodysplastic syndrome (MDS). Johns Hopkins investigators also showed benefit of low doses of the drugs in tests with a small number of advanced lung cancer patients. "This is contrary to the way we usually do things in cancer research," says Baylin, noting that "typically, we start in the laboratory and progress to clinical trials. In this case, we saw results in clinical trials that made us go back to the laboratory to figure out how to move the therapy forward."

For the research, Baylin and Zahnow's team worked with leukemia, breast, and other cancer cell lines and human tumor samples using the lowest possible doses that were effective against the cancers. In all, the investigators studied six leukemia cell lines, seven leukemia patient samples, three breast cancer cell lines, seven breast tumor samples (including four samples of tumors that had spread to the lung), one lung cancer tumor sample, and one colon cancer tumor sample. The team treated cell lines and tumor cells with low-dose AZA and DAC in culture for three days and allowed the drug-treated cells to rest for a week. Treated cells and tumor samples were then transplanted into mice where the researchers observed continued antitumor responses for up to 20 weeks. This extended response was in line with observations in some MDS patients who continued to have anticancer effects long after stopping the drug.

The low-dose therapy reversed cancer cell gene pathways, including those controlling cell cycle, cell repair, cell maturation, cell differentiation, immune cell interaction, and cell death. Effects varied among individual tumor cells, but the scientists generally saw that cancer cells reverted to a more normal state and eventually died. These results were caused, in part, by alteration of the epigenetic, or chemical environment, of DNA. Epigenetic activities turn on certain genes and block others, says Zahnow, assistant professor of oncology and the Evelyn Grolman Glick Scholar at Johns Hopkins.

The research team also tested AZA and DAC's effect on a type of metastatic breast cancer cell thought to drive cancer growth and resist standard therapies. Metastatic cells are difficult to study in standard laboratory tumor models, because they tend to break away from the original tumor and float around in blood and lymph fluids. The Johns Hopkins team re-created the metastatic stem cells' environment, allowing them to grow as floating spheres. "These cells were growing well as spheres in suspension, but when we treated the cells with AZA, both the size and number of spheres were dramatically reduced," says Zahnow.

The precise mechanism of how the drugs work is the focus of ongoing studies by Baylin and his team. "Our findings match evidence from recent clinical trials suggesting that the drugs shrink tumors more slowly over time as they repair altered mechanisms in cells and genes return to normal function and the cells may eventually die," says Baylin.

The results of clinical trials in lung cancer, led by Johns Hopkins' Charles Rudin, M.D., and published late last year in Cancer Discovery, also indicate that the drugs make tumors more responsive to standard anticancer drug treatment. This means, they say, that the drugs could become part of a combined treatment approach rather than a stand-alone therapy and as part of personalized approaches in patients whose cancers fit specific epigenetic and genetic profiles.

Low doses of both drugs are approved by the U.S. Food and Drug Administration for the treatment of MDS and chronic myelomonocytic leukemia (CMML). Clinical trials in breast and lung cancer have begun in patients with advanced disease, and trials in colon cancer are planned.

In addition to Baylin and Zahnow, other investigators participating in this study include Hsing-Chen Tsai, Huili Li, Leander Van Neste, Yi Cai, Carine Robert, Feyruz V. Rassool, James J. Shin, Kirsten M. Harbom, Robert Beaty, Emmanouil Pappou, James Harris, Ray-Whay Chiu Yen, Nita Ahuja, Malcolm V. Brock, Vered Stearns, David Feller-Kopman, Lonny B. Yarmus, Yi-Chun Lin, Alana L. Welm, Jean-Pierre Issa, Il Minn, William Matsui, Yoon-Young Jang, and Saul J. Sharkis.

The research was funded by a SPORE grant for lung cancer from the National Institutes of Health, the Hodson Trust Foundation, Entertainment Industry Foundation, Lee Jeans, Samuel Waxman Cancer Research Foundation, Department of Defense Breast Cancer Research Program, Huntsman Cancer Foundation, and the Cindy Rosencrans Fund for Triple Negative Breast Cancer Research. All of the studies have been accelerated by funding from the Stand Up to Cancer (SU2C) project in partnership with the American Association of Cancer Research (AACR).

On the Web:

Clinical trial of epigenetics therapy published in Cancer Discovery:
http://www.hopkinsmedicine.org/news/media/releases/combination_epigenetic_therapy_clinical_trial_results_
What is epigenetics?
http://www.hopkinsmedicine.org/kimmel_cancer_center/research_clinical_trials/research/su2c/what_is_epigenetics.html
SU2C Epigenetics Dream Team:
http://youtu.be/KgXBrxvlUeA
Stephen Baylin, M.D., explains epigenetics:
http://youtu.be/UW3f2XAxjdM

Vanessa Wasta | EurekAlert!
Further information:
http://www.jhmi.edu

More articles from Life Sciences:

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

nachricht When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short
23.03.2017 | Institut für Pflanzenbiochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Steep rise of the Bernese Alps

24.03.2017 | Earth Sciences

How cheetahs stay fit and healthy

24.03.2017 | Life Sciences

When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short

23.03.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>