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!
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.
The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
20.07.2018 | Power and Electrical Engineering
20.07.2018 | Information Technology
20.07.2018 | Materials Sciences