Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New screening tool could speed development of ovarian cancer drugs

10.02.2015

University of Chicago Medicine researchers have built a model system that uses multiple cell types from patients to rapidly test compounds that could block the early steps in ovarian cancer metastasis. Their three-dimensional cell-culture system, adapted for high-throughput screening, has enabled them to identify small molecules that can inhibit adhesion and invasion, preventing ovarian cancers from spreading to nearby tissues.

The study, published online February 5, 2015, in the journal Nature Communications, is the first to describe a high-throughput screening drug-discovery platform for ovarian cancer that mimics the structural organization and function of human tissue. The model reconstructs the surfaces of the omentum and the peritoneum, membranes that line the abdominal cavity, which are the most frequent sites of ovarian cancer metastasis.


This is a multi-layered 3-D 'organotypic' platform for quantitative high-throughput screening to identify new therapeutics for ovarian cancer. Fibroblasts are red. Mesothelial cells are blue. Ovarian cancer cells are green. The square image is the XY-planes (up-down, right-left). The images on the sides are Z-planes (depth).

Credit: Lengyel laboratory, University of Chicago

"Visualizing how cancer cells interact with a tumor microenvironment that accurately reflects the complex biology of ovarian cancer should help us understand the mechanisms underlying metastatic progression as well as identify new therapeutics that can inhibit this process," said clinical gynecologic oncologist Ernst Lengyel, MD, PhD, senior author of the study and a professor of obstetrics and gynecology at the University of Chicago.

This is a long overdue step forward for ovarian cancer therapy. The current treatment for metastatic ovarian cancer is surgery and chemotherapy, which has a low five-year survival rate. Although recently approved therapies can increase progression-free survival by a few months, "we think this novel screening system has the potential to uncover new, more effective medications that could be targeted more specifically at a patient's cancer," Lengyel said.

Each year about 21,290 women in the United States will be diagnosed with ovarian cancer and about 14,180 women will die from the disease. Ovarian cancer is aggressive and is rarely detected at an early stage. Tumors that form in the ovary or fallopian tube typically travel through the peritoneal fluid to the surfaces of other abdominal organs. Metastatic tumors are usually confined to the abdominal cavity and initially cause few symptoms.

To assemble their model, the researchers collected non-cancerous omental tissue from patients undergoing abdominal surgery. In the laboratory, they isolated and cultured mesothelial cells and fibroblasts, two of the predominant cell types found in omental tissue. Then they combined these cells with extracellular matrix proteins to generate a multi-layered cell-culture model.

The authors were able to miniaturize their model for use in high-throughput screening (HTS), a drug discovery process that can quickly determine the biological or biochemical activity of thousands of compounds. Because HTS has traditionally been performed on an unrealistic platform--monolayers of cancer cells cultured on plastic surfaces--many drugs that seemed promising in initial screens proved ineffective in clinical testing.

So the researchers developed a new system that better reflects human biology and is specific to ovarian cancer. Instead of growing cancer cells on plastic, they inserted a multi-layered omental tissue culture model into each well of a 384-well or 1536-well HTS platform.

Next, ovarian cancer cells, expressing a fluorescent marker to distinguish them from the other cells, were added. Then the wells were exposed to a library of small-molecule compounds. The numbers of ovarian cancer cells that adhered to and invaded the HTS model were counted, and the inhibitory potential of each compound evaluated.

In a primary screen, the researchers identified 17 compounds that inhibited cancer cell adhesion and invasion by at least 75 percent. Six of these compounds were active in a dose-response relationship in three distinct ovarian cancer cell lines. Four compounds significantly inhibited key ovarian cancer cell functions in the early steps of metastasis at low doses.

The research team confirmed those results by testing the four compounds at a low dose in mice injected with ovarian cancer cells. Remarkably, all four compounds inhibited metastasis. Two compounds more than doubled survival. In a follow-up study, one of the compounds--beta-escin, isolated from the seed of the Chinese horse chestnut--inhibited tumor growth and metastasis by 97 percent.

"This study was based on our initial tests of 2,420 compounds," said first author Hilary Kenny, PhD, a research associate (assistant professor) in obstetrics and gynecology at the University of Chicago. "Our model has since been used to test more than 68,000 compounds. This could exceed 100,000 by the end of this year. We are learning to identify compounds with similar structures and functions that may be important for inhibiting key steps in metastasis."

This project emerged as a result of the patient-oriented approach taken by the researchers and clinicians. It is "an important step towards personalized medicine, as described in the new precision medicine initiative proposed by President Obama," Kenny said. "In the future, organotypic models that reflect the unique biology of individual patients could be used in screening. Therefore, personalized high-throughput screening platforms could enable the identification of effective therapeutics for each patient. This is exactly how personalized medicine is supposed to work."

###

The study was funded by Bears Care, the charitable beneficiary of the Chicago Bears Football Club; the National Institutes of Health; the National Cancer Institute; and the National Institute of Neurological Disorders and Stroke. Additional authors were Erin A. White, Chun-Yi Chiang, Anirban K. Mitra, Yilin Zhang, Marion Curtis, Elizabeth M. Schryver and Sam Bettis from the University of Chicago; and Ajit Jadhav, Matthew B. Boxer, Madhu Lal-Nag, Min Shen, Zhuyin Li, and Marc Ferrer from the NIH's National Center for Advancing Translational Sciences.

John Easton | EurekAlert!

More articles from Health and Medicine:

nachricht How cancer metastasis happens: Researchers reveal a key mechanism
19.01.2018 | Weill Cornell Medicine

nachricht Researchers identify new way to unmask melanoma cells to the immune system
17.01.2018 | Duke University Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Thanks for the memory: NIST takes a deep look at memristors

22.01.2018 | Materials Sciences

Radioactivity from oil and gas wastewater persists in Pennsylvania stream sediments

22.01.2018 | Earth Sciences

Saarland University bioinformaticians compute gene sequences inherited from each parent

22.01.2018 | Life Sciences

VideoLinks Wissenschaft & Forschung
Overview of more VideoLinks >>>