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!
Second cause of hidden hearing loss identified
20.02.2017 | Michigan Medicine - University of Michigan
Prospect for more effective treatment of nerve pain
20.02.2017 | Universität Zürich
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
20.02.2017 | Materials Sciences
20.02.2017 | Health and Medicine
20.02.2017 | Health and Medicine