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!
Investigators may unlock mystery of how staph cells dodge the body's immune system
22.09.2017 | Cedars-Sinai Medical Center
Monitoring the heart's mitochondria to predict cardiac arrest?
21.09.2017 | Boston Children's Hospital
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
22.09.2017 | Life Sciences
22.09.2017 | Medical Engineering
22.09.2017 | Physics and Astronomy