Blocking a Specific Protein Receptor Decimates Leukemia Cells
Researchers at NYU Langone Medical Center and its Laura and Isaac Perlmutter Cancer Center are reporting a potentially important discovery in the battle against one of the most devastating forms of leukemia that accounts for as many as one in five children with a particularly aggressive form of the disease relapsing within a decade.
In a cover story set to appear in the journal Cancer Cell online June 8, researchers at NYU Langone and elsewhere report that they have successfully halted and reversed the growth of certain cancerous white blood cells at the center of T-cell acute lymphoblastic leukemia, or T-ALL, by stalling the action of a specific protein receptor found in abundance on the surface of T cells at the core of T-ALL.
In experiments in mice and human cells, researchers found that blocking CXCR4—a so-called homing receptor protein molecule that helps T cells mature and attracts blood cells to the bone marrow—halted disease progression in bone marrow and spleen tissue within two weeks. The experiments also left white blood cells cancer free for more than 30 weeks in live mice. Further, the research team found that in mice bred to develop T-ALL, depleting levels of the protein to which CXCR4 binds, called CXCL12, also stalled T-ALL progression.
Researchers say their study results for the first time “clearly establish CXCR4 signaling as essential for T-cell acute lymphoblastic leukemia cell growth and disease progression.”
“Our experiments showed that blocking CXCR4 decimated leukemia cells,” says co-senior study investigator and NYU Langone cell biologist Susan Schwab, PhD.
Schwab, an assistant professor at NYU Langone and its Skirball Institute of Biomolecular Medicine, says similar laboratory test plans are underway for more potent CXCR4 antagonists, most likely in combination with established chemotherapy regimens. She notes that anti-CXCR4 drugs are already in preliminary testing for treating certain forms of myeloid leukemia, and have so far proven to be well tolerated, but such treatments have not yet been tried for T-ALL.
Schwab says T-ALL is “a particularly devastating cancer” because there are not many treatment options. One American survey, she points out, showed that only 23 percent of patients lived longer than five years after failing to sustain remission with standard chemotherapy drugs.
Co-senior study investigator and cancer biologist Iannis Aifantis, PhD, says the study offers the first evidence that “drugs targeting and disrupting leukemia cells’ microenvironment—or what goes on around them—could prove effective against the disease.”
Aifantis, the chair of the Department of Pathology at NYU Langone and a member of its Perlmutter Cancer Center, and an early career scientist at the Howard Hughes Medical Institute, says experiments in his laboratory had shown that leukemia-initiating cells concentrate in the bone marrow near CXCL12-producing blood vessels. This finding prompted a collaborative effort to investigate expression and function of CXCR4 because it binds to CXCL12, which in turn led to the researchers determining the vital role played by CXCR4-CXCL12 molecular signaling in disease growth.
Aifantis says more research needs to be done to decipher how CXCR4 is able to promote and sustain T-ALL.
As part of the new study, researchers deleted CXCL12 production specifically from bone marrow vasculature in leukemic mice. Disease progression in the bone marrow stalled within three weeks and tumors were smaller than in similar mice that retained CXCL12 production. Deletion of the CXCR4 gene led to sustained T-ALL remission within a month in similar mice, as well as movement of the cancerous blood cells away from the bone marrow. Subsequent transplant of millions of human T-ALL cells into normal mice that were then treated with an anti-CXCR4 drug induced remission within two weeks, with diseased spleen and bone marrow tissue nearly returning to normal.
Funding support for the study was provided by the U.S. National Cancer Institute, National Institute of General Medical Sciences, and National Institute of Allergy and Infectious Diseases—all parts of the National Institutes of Health. Corresponding federal grant numbers are R01 CA133379, R01 CA105129, R01 CA149655, R01 CA173636, R01 CA169784, R01 GM088847, T32-CA009161-37, R01 AI085166, and P30 CA016087. Further funding support was provided by the William Lawrence and Blanche Hughes Foundation, the Leukemia and Lymphoma Society (corresponding grant numbers TRP#6340 -11 and LLS#6373-13), the Chemotherapy Foundation, the Irma T. Hirschl Trust; the V Foundation for Cancer Research, the St. Baldrick’s Foundation, the Children’s Leukemia Research Foundation, and the Dana Foundation.
Besides Schwab and Aifantis, other NYU Langone researchers involved in these experiments were lead study investigators Lauren Pitt, PhD, and Anastasia Tikhonova, PhD; and study co-investigators Hai Hu, BS; Thomas Trimarchi, PhD; Bryan King, PhD; and Yixia Gong, PhD; Aris Tsirigos, PhD; and Dan Littman, MD, PhD. Additional research support was provided by Marta Sanchez-Martin, PhD, and Adolfo Ferrando, MD, PhD, at Columbia University in New York; Sean Morrison at University of Texas Southwestern Medical Center in Dallas; and David Fooksman, PhD, at Albert Einstein Medical College in New York.