New combination therapy developed for multiple myeloma

This is Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Cancer Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. Credit: VCU Massey Cancer Center

Each year, more than 25,000 Americans are diagnosed with multiple myeloma, a form of blood cancer that often develops resistance to therapies. However, researchers at Virginia Commonwealth University Massey Cancer Center are reporting promising results from laboratory experiments testing a new combination therapy that could potentially overcome the resistance hurdle.

While several drugs are effective against multiple myeloma, including the proteasome inhibitor bortezomib, multiple myeloma cells are often able to survive by increasing the production of a protein known as Mcl-1. Mcl-1 regulates a number of processes that promote cell survival and has been implicated in resistance to anti-myeloma drugs that were initially effective. However, a team of researchers led by Xin-Yan Pei, M.D., Ph.D., and Steven Grant, M.D., recently published the findings of a study in the journal PLoS ONE demonstrating that a novel drug combination both reduces Mcl-1 expression and disrupts its interactions with other proteins to effectively kill multiple myeloma cells. The therapy combines a type of drug known as a Chk1 inhibitor with another called a MEK inhibitor. Chk1 inhibitors prevent cells from arresting in stages of the cell cycle that facilitate the repair of DNA damage, while MEK inhibitors prevent cells from activating a variety of proteins that regulate DNA repair processes while promoting the accumulation of pro-death proteins.

"This research builds on our previous studies that showed exposing multiple myeloma and leukemia cells to Chk1 inhibitors activated a protective response through the Ras/MEK/ERK signaling pathway," says Pei, instructor in the Department of Internal Medicine at the VCU School of Medicine. "By combining a Chk1 inhibitor with a MEK inhibitor, we have developed one of only a limited number of strategies shown to circumvent therapeutic resistance caused by high expressions of Mcl-1."

In laboratory experiments, the scientists enforced overexpression of Mcl-1 in human multiple myeloma cells. They found that this caused the cells to become highly resistant to bortezomib, but it failed to protect them from the Chk1/MEK inhibitor regimen. 

Additionally, the combination therapy was able to completely overcome resistance due to microenvironmental factors associated with increased expression of Mcl-1. A cell's microenvironment consists of surrounding cells and the fluids in which they reside, and the communication between cancer cells and their surrounding cells can significantly impact resistance. Mcl-1 plays a key role in this communication by facilitating events that promote cancer cell survival.

"Not only was the combination therapy effective against multiple myeloma cells, it notably did not harm normal bone marrow cells, raising the possibility of therapeutic selectivity," says Grant, the study's lead investigator and Shirley Carter Olsson and Sture Gordon Olsson Chair in Cancer Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. "We are hopeful that this research will lead to better therapies for multiple myeloma, and help make current therapies more effective by overcoming resistance caused by Mcl-1."

The researchers have started initial discussions with clinical investigators and drug manufacturers with hopes of developing a clinical trial testing a combination of Chk1 and MEK inhibitors in patients with refractory multiple myeloma. It is too early to estimate when the trial will open.

Source: Virginia Commonwealth University

Targeting fatty acids may be treatment strategy for arthritis, leukemia

The bone marrow of mice with normal ether lipid production (top) contains more white blood cells than are found in the bone marrow of mice with ether lipid deficiency (bottom).
Credit: Washington University School of Medicine

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, potentially opening up new avenues for treating these diverse diseases, according to new research at Washington University School of Medicine in St. Louis.

Working with genetically engineered mice, the researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of specialized white blood cells called neutrophils. Neutrophils are the most abundant type of white blood cell and a hallmark of inflammation, which is a key component of rheumatoid arthritis. Abnormally high levels of neutrophils also are common in patients with leukemia.

The study is published Jan. 6 in the journal Cell Metabolism.

"The link between these enzymes and neutrophils was a big surprise," said first author Irfan J. Lodhi, PhD, assistant professor of medicine. "We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking."

In the study, mice that couldn't make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

"This may be a pathway to limit inflammation," said senior investigator Clay F. Semenkovich, MD, the Herbert S. Gasser Professor of Medicine. "If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis."

Semenkovich, also a professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, said the enzymes specifically target neutrophils without affecting other immune cells.

"So ether lipids appear to be a very precise target," he said.

Working with Daniel Link, MD, the Alan A. and Edith L. Wolff Distinguished Professor of Medicine, the researchers learned that inactivating the enzymes didn't harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient's neutrophil count gradually would rise, allowing the immune system to return to normal.

Source: Washington University in St. Louis

Hormone that controls supply of iron in red blood cell production discovered by researchers

This is a microscopic image of erythroblasts, which are the bone marrow cells that secrete erythroferrone. Credit: Leon Kautz/UCLA

A UCLA research team has discovered a new hormone called erythroferrone, which regulates the iron supply needed for red blood-cell production.

Iron is an essential functional component of hemoglobin, the molecule that transports oxygen throughout the body. Using a mouse model, researchers found that erythroferrone is made by red blood-cell progenitors in the bone marrow in order to match iron supply with the demands of red blood-cell production. Erythroferrone is greatly increased when red blood-cell production is stimulated, such as after bleeding or in response to anemia.

The erythroferrone hormone acts by regulating the main iron hormone, hepcidin, which controls the absorption of iron from food and the distribution of iron in the body. Increased erythroferrone suppresses hepcidin and allows more iron to be made available for red blood-cell production.

"If there is too little iron, it causes anemia. If there is too much iron, the iron overload accumulates in the liver and organs, where it is toxic and causes damage," said senior author Dr. Tomas Ganz, a professor of medicine and pathology at the David Geffen School of Medicine at UCLA. "Modulating the activity of erythroferrone could be a viable strategy for the treatment of iron disorders of both overabundance and scarcity."

The early findings were reported online June 1 in the journal Nature Genetics.

"Our previous work anticipated that a regulator of hepcidin could be secreted by the bone marrow," said the study's first author, Leon Kautz, a postdoctoral fellow at UCLA. "In this research, we searched for new substances that were made in bone marrow that could fill that role."

Researchers first focused on what happens in the bone marrow after hemorrhage. From there, they focused on a specific protein that was secreted into the blood. This protein attracted their attention because it belonged to a family of proteins involved in cell-to-cell communication. Using recombinant DNA technology, they showed that the hormone suppressed the production of hepcidin and demonstrated the effect it had on iron metabolism.

The team foresees that the discovery could help people with a common congenital blood disorder called Cooley's anemia, also known as thalassemia, which causes excessive destruction of red blood cells and of their progenitors in the bone marrow. Many of these patients require regular blood transfusions throughout their lives. Most iron overload is attributed to the iron content of transfused blood. However, even patients who are rarely, or never, transfused can also develop iron overload.

"Overproduction of erythroferrone may be a major cause of iron overload in untransfused patients and may contribute to iron overload in transfused patients," said study author Elizabeta Nemeth, a professor of medicine at the David Geffen School of Medicine at UCLA and co-director of the UCLA Center for Iron Disorders. "The identification of erythroferrone can potentially allow researchers and drug developers to target the hormone for specific treatment to prevent iron overload in Cooley's anemia."

The discovery could also lead to treatments for other common anemia-related conditions associated with chronic kidney disease, rheumatologic disorders and other inflammatory diseases. In these conditions, iron is "locked up" by the effect of the hormone hepcidin, whose levels are increased by inflammation. Erythroferrone, or drugs acting like it, could suppress hepcidin and make more iron available for red blood-cell production.

The next stage of research is to understand the role of the new hormone in various blood diseases and study the molecular mechanisms through which erythroferrone regulates hepcidin.

Additional study authors included Grace Jung and Erika Valore of UCLA and Stefano Rivella of Weill Cornell Medical College in New York.

The study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung and Blood Institute.

The Board of Regents of the University of California is the owner of patent applications and uses directed at erythroferrone, which are managed by UCLA's Office of Intellectual Property and Industry Sponsored Research. This intellectual property is the subject of license negotiations with a company for which authors Ganz and Nemeth are scientific advisors and equity holders. Other disclosures are available in the manuscript.

Source: University of California, Los Angeles (UCLA), Health Sciences