Research in mice and human cell lines has identified an experimental compound dubbed TTT-3002 as potentially one of the most potent drugs available to block genetic mutations in cancer cells blamed for some forms of treatment-resistant leukemia.
Results of the research by Johns Hopkins Kimmel Cancer Center investigators, described March 6 in the journal Blood, show that two doses a day of TTT-3002 eliminated leukemia cells in a group of mice within 10 days. The treatment performed as well as or better than similar drugs in head-to-head comparisons.
More than 35 percent of acute myeloid leukemia (AML) patients harbor a mutation in the gene FMS-like tyrosine kinase-3 (FLT3). Normal FLT3 genes produce an enzyme that signals bone marrow stem cells to divide and replenish. But when FLT3 is mutated in some AML patients, the enzyme stays on permanently, causing rapid growth of leukemia cells and making the condition likely to relapse after treatment.
Many investigators are developing and testing drugs designed to block the FLT3 enzyme's proliferation, several of which are now in clinical trials. So far, their effectiveness has been limited, according to Donald Small, M.D., Ph.D., the Kyle Haydock Professor of Oncology and director of pediatric oncology at Johns Hopkins. Small led a team of researchers who originally cloned the FLT3 gene and linked it to leukemia a decade ago.
"We're very excited about TTT-3002, because it appears in our tests so far to be the most potent FLT3 inhibitor to date," says Small. "It showed activity against FLT3-mutated cells taken from patients and with minimal toxicity to normal bone marrow cells, making it a promising new candidate for the treatment of AML."
In a series of experiments with the drug, Small, postdoctoral fellow Hayley Ma, Ph.D., and others found that the amount of TTT-3002 needed to block FLT3 activity in human leukemia cell lines was six- to sevenfold lower than for the most potent inhibitor currently in clinical trials. TTT-3002 also inhibited proteins made by genes further down the FLT3 signaling pathway, including STAT5, AKT and MAPK, and showed activity against the most frequently occurring FLT3 mutations, FLT3/ITD and FLT3/D835Y. Many cancer drugs are currently ineffective against FLT3/D835Y mutations.
When the Johns Hopkins team tested the drug in a mouse model of leukemia, they found that it not only eliminated the presence of leukemic cells within 10 days of treatment but also that the mice lived an average of more than 100 days following treatment, to study completion, and resumed normal bone marrow activity. By contrast, mice treated with a placebo died an average of 18 days following treatment.
Additional studies found that TTT-3002 performed as well as sorafenib, another FLT3 inhibitor, in treating leukemic mice, and that the drug was toxic to leukemia cell samples taken from newly diagnosed and relapsed patients with AML but did not affect normal bone marrow cells taken from healthy donors.
A single dose of the medication caused more than 90 percent inhibition against FLT3 signaling that lasted for 12 hours, Small says.
Co-authors of the study were Bao Nguyen, Li Li, Sarah Greenblatt, Allen Williams, Ming Zhao, Mark Levis, Michelle Rudek and Amy Duffield.
The work was supported by the Alex's Lemonade Stand Foundation for Childhood Cancer, the National Institutes of Health's National Cancer Institute (CA90668, CA70970, CA006973, RR025005), Giant Food Pediatric Cancer Research Fund, and the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
On the Web:
JOHNS HOPKINS MEDICINE
Johns Hopkins Medicine (JHM), headquartered in Baltimore, Maryland, is a $6.7 billion integrated global health enterprise and one of the leading health care systems in the United States. JHM unites physicians and scientists of the Johns Hopkins University School of Medicine with the organizations, health professionals and facilities of The Johns Hopkins Hospital and Health System. JHM's mission is to improve the health of the community and the world by setting the standard of excellence in medical education, research and clinical care. Diverse and inclusive, JHM educates medical students, scientists, health care professionals and the public; conducts biomedical research; and provides patient-centered medicine to prevent, diagnose and treat human illness. JHM operates six academic and community hospitals, four suburban health care and surgery centers, more than 38 primary health care outpatient sites and other businesses that care for national and international patients and activities. The Johns Hopkins Hospital, opened in 1889, was ranked number one in the nation for 21 years by U.S. News & World Report.
Vanessa Wasta | EurekAlert!
Nanotubes are beacons in cancer-imaging technique
23.05.2016 | Rice University
More light on cancer
20.05.2016 | Lomonosov Moscow State University
Characterization of high-quality material reveals important details relevant to next generation nanoelectronic devices
Quantum mechanics is the field of physics governing the behavior of things on atomic scales, where things work very differently from our everyday world.
When current comes in discrete packages: Viennese scientists unravel the quantum properties of the carbon material graphene
In 2010 the Nobel Prize in physics was awarded for the discovery of the exceptional material graphene, which consists of a single layer of carbon atoms...
The trend-forward world of display technology relies on innovative materials and novel approaches to steadily advance the visual experience, for example through higher pixel densities, better contrast, larger formats or user-friendler design. Fraunhofer ISC’s newly developed materials for optics and electronics now broaden the application potential of next generation displays. Learn about lower cost-effective wet-chemical printing procedures and the new materials at the Fraunhofer ISC booth # 1021 in North Hall D during the SID International Symposium on Information Display held from 22 to 27 May 2016 at San Francisco’s Moscone Center.
Staphylococcus aureus usually is a formidable bacterial pathogen. Sometimes, however, weakened forms are found in the blood of patients. Researchers of the University of Würzburg have now identified one mutation responsible for that phenomenon.
Staphylococcus aureus is a bacterium that is frequently found on the human skin and in the nose where it usually behaves inconspicuously. However, once inside...
Using ultrashort laser pulses an international team at the Max Planck Institute of Quantum Optics and the Ludwig-Maximilians-Universität Munich has managed to manipulate the positions of atoms in hydrocarbon molecules.
Light can conduct the play of atoms and molecules in the microcosm. Humans manage to interfere with this play. Researchers from the Laboratory of Attosecond...
20.05.2016 | Event News
19.05.2016 | Event News
17.05.2016 | Event News
23.05.2016 | Information Technology
23.05.2016 | Architecture and Construction
23.05.2016 | Earth Sciences