"By sequencing the FLT3 gene in AML patients who have relapsed on therapy targeted against FLT3, we have determined that FLT3 is a valid therapeutic target, and this will certainly help us better understand the physiology of this type of leukemia in order to help us develop new therapies in the future," said Andrew Kasarskis, PhD, who performed the research with colleagues at Pacific Biosciences prior to becoming Vice Chair of the Department of Genetics and Genomic Sciences at Mount Sinai School of Medicine. "In addition, sequencing hundreds of single molecules of FLT3 allowed us to see drug resistance mutations at low frequency. This increased ability to see resistance will let us identify the problem of the resistance sooner in a patient's clinical course and help us take steps to address it."
Historically, DNA sequencing of individual molecules in a mixture has been difficult and time-consuming to achieve. However, Pacific Bioscience's single molecule real-time sequencer, the PacBio® RS, identified mutations in the sequence reads obtained in a single run even at low levels, on the order of 1 to 3 percent of total sequence reads.
"This finding may have great utility for drug development, as we can begin to test drugs or a combination of drugs in patients with AML who have relapsed," added Kasarskis, who is also Co-Director of the Institute for Genomics and Multiscale Biology at Mount Sinai. "Furthermore, if we can find out when the drug resistant mutations occur exactly, clinicians may be able to prescribe another drug more quickly."
In this era of personalized medicine, many drugs have been developed to target the mutations in genes that cause cancer - in an effort to attack the cancer with minimal side effects. Oftentimes, patients develop resistance to drugs and new therapeutic strategies must be applied, so physicians use a second line drug, or combination of drugs, in an effort to target the new gene mutations that develop. Knowing exactly when this mutation and subsequent resistance occurs may be very helpful in identifying when new therapies may be prescribed.
In this study, researchers worked with eight leukemia patients who had participated in a clinical trial involving a compound known as AC220, the first clinically-active FLT3 inhibitor. All eight patients relapsed after first achieving deep remissions with AC220. The relapse indicated that patients had developed a resistance to the drug.
AML is characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. Treatment includes chemotherapy in order to eliminate leukemic cells and stem cell transplantation. However, through the identification of a valid therapeutic target (FLT3), scientists can begin to develop new and more effective therapies in the future.
"Mount Sinai is deeply committed to addressing the problem of drug resistance in all diseases including cancer and infections with viruses or bacteria," said Kasarskis. "This study certainly tries to address the issue, and will look forward to making continued progress in this area."
Study authors include scientists from University of California, Berkeley; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Abramson Cancer Center of the University of Pennsylvania and Ambit Biosciences in San Diego.About The Mount Sinai Medical Center
The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2011, U.S. News & World Report ranked The Mount Sinai Hospital 16th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Of the top 20 hospitals in the United States, Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.
For more information, visit http://www.mountsinai.org/.Find Mount Sinai on:
Biofuel produced by microalgae
28.02.2017 | Tokyo Institute of Technology
Decoding the genome's cryptic language
27.02.2017 | University of California - San Diego
On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded after a glide flight with an Airbus A320 in ditching on the Hudson River. All 155 people on board were saved.
On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded...
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
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...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
28.02.2017 | Physics and Astronomy
28.02.2017 | Materials Sciences
28.02.2017 | Health and Medicine