PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

'Mutation accelerator' identified in gene mutation linked to common adult leukemia

Small study in mice and cells shows combination of gene-targeting drugs slows leukemia cell growth

2015-06-10
(Press-News.org) In preliminary experiments with mice and lab-grown cells, Johns Hopkins Kimmel Cancer Center scientists have found that a protein-signaling process accelerates the work of the gene most frequently mutated in a common form of adult leukemia and is likely necessary to bring about the full-blown disease.

The Kimmel team, in a report published in the June 10 issue of Science Translational Medicine, demonstrated the impact of the so-called Hedgehog protein signaling pathway by successfully using a combination of two drugs to both block the activity of the mutated gene, called FLT3, and a part of the Hedgehog pathway. The combination limited the growth of AML cells in mice and bone marrow cell lines.

"From our data, it appears that Hedgehog signaling is like an accelerator," says William Matsui, M.D., professor of oncology at the Johns Hopkins University School of Medicine. "It facilitates the cellular events that lead to cancer, but it itself is not the driver of the whole process."

The findings of the study, Matsui says, may eventually hold implications for the development of new or better combinations of gene-based therapies for AML, which strikes an estimated 20,000 people in the U.S. each year and kills 10,000. An estimated 35 percent of patients have a mutation in FLT3 that signals bone marrow stem cells to divide and replenish themselves at abnormal rates, causing the rapid growth of leukemia cells.

In the experiments, a combination of a FLT3 blocker called sorafenib, and an experimental Hedgehog-pathway blocker called IPI-926 reduced, by up to half, the percentage of leukemic cells in the blood and bone marrow of five mice, compared with two groups of five mice treated with either one of the drugs alone. In addition, three of five mice treated with the drug combination survived past the 16 days of the experiment without any further treatment, compared with none of the mice that received either drug alone.

The human FLT3 gene was first cloned by Kimmel Center scientists led by Donald Small, M.D., who also identified drugs that could block the activity of FLT3. Adult patients with the FLT3 mutation tend to have worse outcomes than those without the mutation, Matsui notes, and historically, drugs that inhibited FLT3's activity can eliminate leukemic cells from the blood, but without lasting effects. The reason, he says, is that tumor cells persist in the bone marrow.

Matsui says the new research, therefore, offers some promise of better outcomes for people with the FLT3 mutation by revealing the Hedgehog protein signaling as a possible second target for treatment in combination with drugs that directly hit the mutation.

"The Hedgehog protein signaling pathway plays a major role in the development of the embryo," says Matsui. "If the pathway stays active later in life, however, it can jumpstart the growth and survival of tumor cells," he explains.

"In the case of AML," he says, "if the FLT3 mutation is like a car that's going 55 miles an hour, then when you add Hedgehog, you put the 'pedal to the metal.'"

In their study, Matsui and his colleagues also found that mice that had both the FLT3 mutation and Hedgehog activity had a significantly shorter lifespan -- an average of 12 weeks -- compared with an average of 40 weeks for those that had just the FLT3 mutation.

"When we treat mice that have leukemia with both drugs," Matsui says, "they live longer than with either drug alone, and there is a portion of them that don't die at all."

It's likely, Matsui says, that Hedgehog signaling is involved in the progression of a number of cancers, and "this study brings home the idea that in treating these cancers, clinicians may need to inhibit Hedgehog along with specific gene mutations."

Scientists are continuing their search for more protein targets within the Hedgehog pathway, says Matsui, and he and his colleagues have begun work in the laboratory to see how Hedgehog inhibitors work when combined with newer drugs that target FLT3 more precisely than sorafenib.

If these lab tests continue to show signs that the two types of inhibitors can stop AML, "we think this would be a rational combination to try in patients," Matsui says.

Sorafenib, sold under the name Nexavar, is approved by the FDA to treat certain types of liver, kidney and thyroid cancers, and is among a group of costly -- up to $10,000 per month -- gene-targeting, anti-cancer drugs. The scientists say the expense drives the urgency to find more potent combinations of such anti-cancer drugs with fewer doses needed for patients. IPI-926 is an experimental drug currently being tested in clinical trials for various cancer types.

INFORMATION:

Other scientists who contributed to the research include Yiting Lim, Lukasz Gondek, Li Li, Qiuju Wang, Haley Ma, Emily Chang, David L. Huso, Sarah Foerster, Luigi Marchionni, Mark Levis and B. Douglas Smith of the Kimmel Center; Karen McGovern of Infinity Pharmaceuticals; D. Neil Watkins of Garvan Institute of Medical Research; Craig D. Peacock of Cleveland Clinic; and Akil A. Merchant of the University of Southern California.

Funding for the study was provided by the National Institutes of Health (R01CA127574, R01CA174951, R01CA090668, R21CA155733, P30DK090868, P30CA006973, and UL1TR001079); the Leukemia and Lymphoma Society; the Gabrielle's Angel Foundation for Cancer Research; the Edward P. Evans Foundation; and the Petre Foundation.

Johns Hopkins Kimmel Cancer Center
Office of Public Affairs
Media Contacts:
Vanessa Wasta, 410-614-2916, wasta@jhmi.edu
Amy Mone, 410-614-2915, amone@jhmi.edu



ELSE PRESS RELEASES FROM THIS DATE:

Gold-standard clinical trials fail to capture how behavior changes influence treatment

Gold-standard clinical trials fail to capture how behavior changes influence treatment
2015-06-10
PRINCETON, N.J.--Double-blind clinical trials for new drugs are considered the "gold standard" of medical research because they're designed to determine the efficacy of a treatment free from doctor and participant bias. But one effect these trials fail to measure is how a medication's performance can vary based on patients' lifestyle choices, especially if patients change their habits because they are anticipating treatment, according to a new study published in PLOS ONE. A recent meta-analysis of six clinical trials, led by researchers from Princeton University, the ...

Plants may run out of time to grow under ongoing climate change

2015-06-10
A key potential 'benefit' of global warming--namely, that plants at northern latitudes will thrive in a warmer world--is challenged by a new study released by University of Hawai'i scientists today. The prevailing assumption ignores the fact that plants in the North will remain limited by solar radiation, curbing positive effects of warming and additional CO2 availability. In addition, that same warming could surpass plant temperature tolerances in tropical areas around the world, and further be accompanied by drought. "Those that think climate change will benefit plants ...

Risk for sleep disorders among college freshmen may predict retention, success

2015-06-10
DARIEN, Ill. -- A new study suggests that the risk for sleep disorders among college freshmen may be a predictor of retention and academic success. Results show that students at risk for a sleep disorder were more likely to leave the institution over the three-year period, although this association was weakened when covariates were included. Risk for sleep disorder also predicted grade point average (GPA) at the end of the first and second years. 'A survey that screens for sleep disorders administered when students first enter college may identify a potentially modifiable ...

Clinical trial launched to assess safety and efficacy of autism drug treatment

2015-06-10
Researchers at the University of California, San Diego School of Medicine have launched a clinical trial to investigate the safety and efficacy of an unprecedented drug therapy for autism. The phase 1 clinical trial, which is recruiting 20 qualifying participants, will evaluate suramin -- a century-old drug still used for African sleeping sickness -- as a novel treatment for children with a diagnosis of Autism Spectrum Disorder (ASD). Previous published research by Robert K. Naviaux, M.D., Ph.D., professor of medicine, pediatrics and pathology at UC San Diego School of ...

Fragile X proteins involved in proper neuron development

2015-06-10
MADISON, Wis. -- Fragile X syndrome is the most common inherited intellectual disability and the greatest single genetic contributor to autism. Unlocking the mechanisms behind fragile X could make important revelations about the brain. In a new study published June 4 in the journal Cell Reports, researchers from the University of Wisconsin-Madison Waisman Center and Department of Neuroscience show that two proteins implicated in fragile X play a crucial role in the proper development of neurons in mice. They also show that while the two proteins act through distinct mechanisms ...

Obesity linked to adrenal disorder in teens may increase risk for cardiovascular disease

2015-06-10
Researchers at Children's Hospital Los Angeles have demonstrated that adolescents and young adults with congenital adrenal hyperplasia (CAH) have significantly increased amounts of abdominal fat tissue, placing them at greater risk for harmful conditions linked to obesity, including cardiovascular disease (CVD). Their study, which reveals new information about the role of abdominal fat in patients with CAH and points to a need for targeted prevention and therapeutics to avoid these adverse effects, will be published online June 10, 2015 by The Journal of Clinical Endocrinology ...

Cutting-edge research unveiled at 2015 AAPS National Biotechnology Conference

2015-06-10
SAN FRANCISCO - Innovative vaccine and tumor research will be unveiled at the American Association of Pharmaceutical Scientists' (AAPS) National Biotechnology Conference (NBC). The meeting takes place Monday, June 8- Wednesday, June 10 at the San Francisco Marriott Marquis. This year's conference is organized into five meeting workstreams: Chemistry, Manufacturing, and Controls (CMC) including Formulation, Characterization, Stability and Biomanufacturing; Research and Discovery; Clinical Pharmacology, Pharmacokinetic/Pharmacodynamic (PK/PD), and Bioanalytics; Regulatory; ...

When modern Eurasia was born

When modern Eurasia was born
2015-06-10
Was it a massive migration? Or was it rather a slow and persistent seeping of people, items and ideas that laid the foundation for the demographic map of Europe and Central Asia that we see today? The Bronze Age (about 5,000 - 3,000 years ago) was a period with large cultural upheavals. But just how these upheavals came to be have remained shrouded in mystery. Assistant Professor Morten Allentoft from the Centre for GeoGenetics at the Natural History Museum of Denmark at the University of Copenhagen is a geneticist and is first author on the paper in Nature. He says: - ...

Ice sheet collapse triggered ancient sea level peak: ANU media release

Ice sheet collapse triggered ancient sea level peak: ANU media release
2015-06-10
An international team of scientists has found a dramatic ice sheet collapse at the end of the ice age before last caused widespread climate changes and led to a peak in the sea level well above its present height. The team found the events 135,000 years ago caused the planet to warm in a different way to the end of the most recent ice age about 20,000 to 10,000 years ago. The findings will help scientists understand the processes that control Earth's dramatic climate changes, said the leader of the study, Dr Gianluca Marino of The Australian National University (ANU). "We ...

Single protein causes Parkinson's disease and multiple system atrophy

2015-06-10
Several neurodegenerative disorders are caused by aggregates of a single protein known as alpha-synuclein. In collaboration with CNRS and the University of Antwerp, KU Leuven neurobiologists have discovered that the shape of these aggregates - 'cylinders' or 'ribbons' - determines whether a patient develops Parkinson's disease or Multiple System Atrophy, respectively. Typical of neurodegenerative disorders is the disrupted communication between brain cells together with a loss of cells in specific brain regions. For some brain diseases this phenomenon is linked to a ...

LAST 30 PRESS RELEASES:

New strategies to enhance chiral optical signals unveiled

Cambridge research uncovers powerful virtual reality treatment for speech anxiety

2025 Gut Microbiota for Health World Summit to spotlight groundbreaking research

International survey finds that support for climate interventions is tied to being hopeful and worried about climate change

Cambridge scientist launches free VR platform that eliminates the fear of public speaking

Open-Source AI matches top proprietary model in solving tough medical cases

Good fences make good neighbors (with carnivores)

NRG Oncology trial supports radiotherapy alone following radical hysterectomy should remain the standard of care for early-stage, intermediate-risk cervical cancer

Introducing our new cohort of AGA Future Leaders

Sharks are dying at alarming rates, mostly due to fishing. Retention bans may help

Engineering excellence: Engineers with ONR ties elected to renowned scientific academy

New CRISPR-based diagnostic test detects pathogens in blood without amplification

Immunotherapy may boost KRAS-targeted therapy in pancreatic cancer

Growing solar: Optimizing agrivoltaic systems for crops and clean energy

Scientists discover how to reactivate cancer’s molecular “kill switch”

YouTube influencers: gaming’s best friend or worst enemy?

uOttawa scientists use light to unlock secret of atoms

NJIT mathematician to help map Earth's last frontier with Navy grant

NASA atmospheric wave-studying mission releases data from first 3,000 orbits

‘Microlightning’ in water droplets may have sparked life on Earth

Smoke from wildland-urban interface fires more deadly than remote wildfires

What’s your body really worth? New AI model reveals your true biological age from 5 drops of blood

Protein accidentally lassos itself, helping explain unusual refolding behavior

With bird flu in raw milk, many in U.S. still do not know risks of consuming it

University of Minnesota research team awarded $3.8 million grant to develop cell therapy to combat Alzheimer’s disease

UConn uncovers new clue on what is leading to neurodegenerative diseases like Alzheimer’s and ALS

Resuscitation in out-of-hospital cardiac arrest – it’s how quickly it is done, rather than who does it

A closer look at biomolecular ‘silly putty’

Oxytocin system of breastfeeding affected in mothers with postnatal depression

Liquid metal-enabled synergetic cooling and charging: a leap forward for electric vehicles

[Press-News.org] 'Mutation accelerator' identified in gene mutation linked to common adult leukemia
Small study in mice and cells shows combination of gene-targeting drugs slows leukemia cell growth