Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New drug strategy attacks resistant leukemia and lymphoma

30.05.2012
Scientists build a synthetic peptide that overcomes cancer cells’ survival defenses

Scientists at the Dana-Farber/Children's Hospital Cancer Center have developed an anti-cancer peptide that overcomes the stubborn resistance to chemotherapy and radiation often encountered in certain blood cancers when the disease recurs following initial treatment.

The strategy could pave the way for much needed new therapies to treat relapsed and refractory blood cancers, which are difficult to cure because their cells deploy strong protein "deflector shields" to neutralize the cell death signals that chemotherapy agents used against them initially, say the researchers.

The prototype compound, called a "stapled BIM BH3 peptide," is designed to disable the cancer's defenses by hitting a family of protein targets that regulate cell death.

In proof-of-concept studies in mice with transplanted, drug-resistant leukemia tumors, the compound alone suppressed cancer growth, and when paired with other drugs, showed synergistic anti-cancer activity, say researchers led by Loren Walensky, MD, PhD, of Dana-Farber/Children's Hospital Cancer Center.

Their paper has been posted online by the Journal of Clinical Investigation and will appear in the journal's June issue. Walensky is the senior author and James LaBelle, MD, PhD, is the first author.

A cell's "fate" – when and whether it lives or dies – depends on a tug-of-war between pro-death and anti-death forces within the cell that serve as a check-and-balance system to maintain orderly growth. The system is regulated by the BCL-2 family of proteins, which contains both pro-death and pro-survival members.

When cells are no longer needed or are damaged beyond repair, the body activates pro-death BCL-2 proteins to shut down mitochondria – the power plants of the cell– resulting in an orchestrated cellular destruction known as apoptosis, or programmed cell death.

Many cell-killing cancer treatments work by triggering these "executioner proteins" to cause tumor cells to commit suicide in this fashion. But cancer cells can escape their death sentence – and even become immortal – by hyperactivating the survival arm of the family; these proteins intercept the executioner proteins and block their lethal mission.

"When cancers recur, they activate not just one type of survival protein, but many," explains Walensky, whose laboratory has extensively studied the cell-death system and makes compounds to manipulate it for research and therapeutic purposes.

"It's as if relapsed cancers 'learned' from their initial exposure to chemotherapy such that when they come back, they put up a variety of formidable barriers to apoptosis," he adds. "To reactivate cell death in refractory hematologic cancers, we need new pharmacologic strategies that broadly target these obstacles and substantially lower the apoptotic threshold."

When cancers specifically rely on one or two survival proteins, treating them with selective BCL-2 inhibitors can be very effective at eliminating the cancer cells' survival advantage. But relapsed cancers often evade such agents by deploying a battery of alternate survival proteins, so what's needed, Walensky says, are "next-generation" compounds that can block a wider range of survival proteins without jeopardizing normal tissues.

In the current research, the scientists built a chemically-reinforced peptide containing the death-activating BH3 domain of an especially potent killer protein, BIM, which is able to tightly bind with and neutralize all of the BCL-2 family survival proteins. This 'stapled' peptide, which incorporates the natural structure and properties of BIM BH3, not only disables the survival proteins, but also directly activates pro-death BCL-2 family proteins in cancer cells, making them self-destruct. Importantly, non-cancerous cells and tissues were relatively unaffected by the treatment.

"The diversity of BCL-2 family survival proteins blunts the anti-tumor activity of essentially all cancer treatments to some degree," Walensky points out. "By using Nature's solution to broad targeting of the BCL-2 pathway with a stapled BIM BH3 peptide, our goal is to eliminate cancer's protective force field and enable the arsenal of cancer treatments to do their job."

The research was supported in part by grants from the National Institutes of Health (grants 1K08CA151450, 5P01CA92625 and 5R01CA050239) and the Leukemia and Lymphoma Society.

In addition to Walensky and LaBelle, the papers other authors are Samuel Katz, MD, PhD, Brigham and Women's Hospital; Gregory Bird, PhD, Evripidis Gavathiotis, PhD, and Andrew Kung, MD, PhD, Dana-Farber/Children's Hospital Cancer Center; Michelle Stewart, Chelsea Lawrence, Jill Fisher, Marina Godes, and Kenneth Pitter, Dana-Farber.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Children's Hospital Boston as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.

Bill Schaller | EurekAlert!
Further information:
http://www.dana-farber.org

Further reports about: BH3 BIM Bcl-2 Cancer blood cancer cancer cells cancer treatments cell death health services proteins

More articles from Life Sciences:

nachricht Gold nanoclusters: new frontier for developing medication for treatment of Alzheimer's disease
17.02.2020 | Science China Press

nachricht Catalyst deposition on fragile chips
17.02.2020 | Ruhr-University Bochum

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Freiburg researcher investigate the origins of surface texture

Most natural and artificial surfaces are rough: metals and even glasses that appear smooth to the naked eye can look like jagged mountain ranges under the microscope. There is currently no uniform theory about the origin of this roughness despite it being observed on all scales, from the atomic to the tectonic. Scientists suspect that the rough surface is formed by irreversible plastic deformation that occurs in many processes of mechanical machining of components such as milling.

Prof. Dr. Lars Pastewka from the Simulation group at the Department of Microsystems Engineering at the University of Freiburg and his team have simulated such...

Im Focus: Skyrmions like it hot: Spin structures are controllable even at high temperatures

Investigation of the temperature dependence of the skyrmion Hall effect reveals further insights into possible new data storage devices

The joint research project of Johannes Gutenberg University Mainz (JGU) and the Massachusetts Institute of Technology (MIT) that had previously demonstrated...

Im Focus: Making the internet more energy efficient through systemic optimization

Researchers at Chalmers University of Technology, Sweden, recently completed a 5-year research project looking at how to make fibre optic communications systems more energy efficient. Among their proposals are smart, error-correcting data chip circuits, which they refined to be 10 times less energy consumptive. The project has yielded several scientific articles, in publications including Nature Communications.

Streaming films and music, scrolling through social media, and using cloud-based storage services are everyday activities now.

Im Focus: New synthesis methods enhance 3D chemical space for drug discovery

After helping develop a new approach for organic synthesis -- carbon-hydrogen functionalization -- scientists at Emory University are now showing how this approach may apply to drug discovery. Nature Catalysis published their most recent work -- a streamlined process for making a three-dimensional scaffold of keen interest to the pharmaceutical industry.

"Our tools open up whole new chemical space for potential drug targets," says Huw Davies, Emory professor of organic chemistry and senior author of the paper.

Im Focus: Quantum fluctuations sustain the record superconductor

Superconductivity approaching room temperature may be possible in hydrogen-rich compounds at much lower pressures than previously expected

Reaching room-temperature superconductivity is one of the biggest dreams in physics. Its discovery would bring a technological revolution by providing...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

70th Lindau Nobel Laureate Meeting: Around 70 Laureates set to meet with young scientists from approx. 100 countries

12.02.2020 | Event News

11th Advanced Battery Power Conference, March 24-25, 2020 in Münster/Germany

16.01.2020 | Event News

Laser Colloquium Hydrogen LKH2: fast and reliable fuel cell manufacturing

15.01.2020 | Event News

 
Latest News

Gold nanoclusters: new frontier for developing medication for treatment of Alzheimer's disease

17.02.2020 | Life Sciences

Artificial intelligence is becoming sustainable!

17.02.2020 | Information Technology

Catalyst deposition on fragile chips

17.02.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>