Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Mount Sinai researchers develop a multi-target approach to treating tumors

Pioneering use of fruit flies to identify a drug that targets cancer

Researchers from Mount Sinai School of Medicine developed a cancer model built in the fruit fly Drosophila, then used it to create a whole new approach to the discovery of cancer treatments.

The result is an investigational compound AD80 that precisely targets multiple cancer genes. Tested in mouse models, the drug proved far more effective and less toxic than standard cancer drugs, which generally focus on a single target. This is the first time that whole-animal screening has been used in a rational, step-wise approach to polypharmacology. The study appears online in the journal Nature.

Conventional drug design embraces the "one gene, one drug, one disease" philosophy. Polypharmacology focuses on multi-target drugs and has emerged as a new paradigm in drug discovery. The hope is that AD80—showing unparalleled effectiveness in fly and mouse models—will be tested in Phase I clinical trials.

"We've come up with one drug that hits multiple targets through 'rational polypharmacology,' and our approach represents a new concept we believe will have great success in suppressing tumors," said Ross L. Cagan, Ph.D., Professor and Associate Dean at Mount Sinai School of Medicine, and senior author on the study. "Scientists are beginning to recognize that single-target drugs can be problematic. I believe that, within the next five years, we'll see more drugs entering clinical trials that use rational polypharmacology as the basis of drug discovery."

The study represented an unusual collaboration between fly geneticists and medicinal chemists. Typically, scientists use human tumor cell lines to screen for single target anti-cancer drugs. In this project, Dr. Cagan, along with co-authors Tirtha Das, Ph.D, from Mount Sinai and their collaborators Arvin Dar, PhD and Kevan Shokat, Ph.D. from the University of California, San Francisco, used their fly cancer models to screen a large chemical library for novel drug leads that shrunk the tumors. They then combined classical fly genetic tools with chemical modeling to develop second-generation drugs to better hit specific targets.

"Many successful drugs now in the marketplace have, by chance, wound up hitting several tumor targets, which is probably why they work," said Dr. Cagan. "The intention of our research was to hit multiple targets purposefully. By using fruit fly genetics we identified, step-by-step, the targets we needed. To my knowledge, this has never been done before. It's also a cost effective model and my prediction is there is going to be more emphasis on whole animal polypharmacology approaches in cancer drug research in the future."

For the study, investigators started out with Ret, the kinase that drives the growth of medullary thyroid tumors in people whose Ret has a cancer-activating mutation; a subset of lung cancer patients also have activated Ret. Researchers engineered a cancer form of Ret into fruit flies. The flies grew tumors wherever Ret was expressed. The investigators then tested dozens of drugs with the goal of curing the tumor.

One challenge is that Ret has many normal cellular roles and shutting it down everywhere in the body would lead to toxicity, a major problem with cancer drugs. "Our goal did not include the assumption that Ret needed to be shut down," said Dr. Cagan. "We wanted to see what worked on the tumors, and then figure out why it worked."

Researchers determined that their lead drug, AD57, suppressed several cancer signals emanating from Ret. These signals include some of the best-known cancer proteins such as Raf, Src, and Tor. Ret itself was not entirely shut down, which suggested to scientists that a patient would experience fewer side effects. The researchers then set out to improve AD57. They manipulated genes in the presence of the original drug hit, a process that had never been done before. As a result, they found that if they lowered the amount of Raf signaling in the presence of AD57, the drug would work even better.

Raf therefore was found to act as a desirable "target." Reducing Tor made AD57 more toxic, so researchers christened Tor an "anti-target," a new concept in drug discovery. Armed with an ideal target/anti-target profile, the Shokat laboratory then developed a derivative of AD57 called AD80.

"When we fed AD80 to the fruit flies, it was like a super drug," said Cagan. "It was remarkable how much AD80 you could give these flies and they didn't mind. This drug wiped the tumors out in a way AD57 or any other drug did not."

Tested in mice models with the same cancer, AD80 performed 500 times better on human cell lines, and far better in mice with very low toxicity, than a cancer drug that the FDA had recently approved for the same cancer type." That drug, vandetanib, is an orphan drug for patients with late-stage medullary thyroid cancer who are not eligible for surgery. Vandetanib was validated in similar fly models from the Cagan laboratory some years earlier.

"We hope that our research will influence the debate between those who favor pursuing drugs that address single vs. multiple tumor targets," said Cagan, who believes the rational polypharmacology model's success in identifying AD80 will prompt scientists and drug companies to pursue broader approaches to attack tumors.

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of the leading medical schools in the United States. The Medical School is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.

The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2011, U.S. News & World Report ranked The Mount Sinai Hospital 16th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Of the top 20 hospitals in the United States, Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.

Find Mount Sinai on:
Twitter @mountsinainyc

Mount Sinai Press Office | EurekAlert!
Further information:

More articles from Health and Medicine:

nachricht Resolving the mystery of preeclampsia
21.10.2016 | Universitätsklinikum Magdeburg

nachricht New potential cancer treatment using microwaves to target deep tumors
12.10.2016 | University of Texas at Arlington

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: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

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

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>