Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

An Achilles heel of AML

16.04.2012
Gene mutations play critically important role in acute myeloid leukemia -- A promising development for new treatments

The key to treating one of the most common types of human leukemia may lie within mutations in a gene called FLT3, according to new research led by physician-scientists at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center.

Published this week in the journal Nature, the work validates certain activating mutations in the FLT3 gene as targets for acute myeloid leukemia therapy—a critically important finding for developing drugs.

"These mutations are critically important for the survival of leukemia cells that harbor them," said Neil Shah, MD, PhD, who led the research, and is co-leader of the Hematopoietic Malignancies Program at the Helen Diller Family Comprehensive Cancer Center at UCSF and the Edward S. Ageno Distinguished Professor of Hematology/Oncology. "Our results also identify drug-resistant mutations in FLT3 that represent high-value targets for future drug development, and will hopefully rekindle interest in developing potent FLT3 inhibitors for the treatment of acute myeloid leukemia."

The new work also suggests why a handful of older drugs developed to treat acute myeloid leukemia by targeting FTL3 have previously failed in clinical trials. The problem with these drugs was not lack of precision but of power—they were aimed at the right target needed to stop the cancer, but most likely did not hit this target hard enough.

Patients in the future may be better served by therapies that involve combinations of multiple, more potent drugs that can suppress all drug-resistant forms of FLT3, said Shah, whose lab is working to identify such compounds and bring them to the clinic as quickly as possible.

A COMMON AND DEADLY FORM OF CANCER

Acute myeloid leukemia occurs when the precursors of our own blood cells become corrupted by mutations in their DNA. The mutant precursors then fail to produce several critical components of blood: white cells, which fight infections; red cells, which carry the blood's oxygen supply; and platelets, which clog vessels when they are cut and help minimize blood loss.

Instead, the mutant precursors give rise to leukemia cells, which accumulate in the bone marrow and bloodstream, crowding out the healthy blood components, and commonly lead to life-threatening infections, anemia, and bleeding.

Over the last several decades, the five-year survival for acute myeloid leukemia has not improved, even as better diagnostic tests, imaging techniques and treatments have driven down mortality for other forms of cancer. According to the National Cancer Institute, 1 in 256 Americans will be diagnosed with acute myeloid leukemia in their lifetime and today nearly four out of five people with the disease die within five years of their diagnosis.

The goal of therapy is to eliminate cancerous cells altogether from the bone marrow, and the discovery several years ago that many people with acute myeloid leukemia have activating mutations in the FTL3 gene, coupled with the relationship of these mutations to poor prognosis, led scientists to speculate that targeting this mutated gene might be an effective way to fight the cancer—but only if the gene was critically important for the survival of leukemia cells.

Several drugs were tested in the clinic, but failed to put the disease into deep remission. The cause for these failures came down to one of two possible reasons: either the FTL3 gene mutations were not central "drivers" critical for cancer to develop and leukemia cells to survive, or the drugs themselves could not achieve the necessary degree of inhibition of FLT3.

The new work by Shah and his colleagues demonstrates the latter. They worked with eight leukemia patients who participated in a clinical trial involving a compound known as AC220, the first clinically-active FLT3 inhibitor. All eight relapsed after first achieving deep remissions with AC220.

In collaboration with Pacific Biosciences, a Menlo Park, Calif. company, a new sequencing technology was adapted to more sensitively and precisely detect drug-resistant mutations. The team showed that in all eight cases, one or more of these mutations evolved at the time AC220-resistant disease developed.

They are now searching for compounds that can specifically target these mutated, AC220-resistant forms of FTL3, and have identified several promising candidates, one of which is currently being evaluated in a clinical trial at UCSF by Catherine Smith MD, who works in Shah's laboratory and is the first author of the article.

The article, "Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia" by Catherine C. Smith, Qi Wang, Chen-Shan Chin, Sara Salerno, Lauren E. Damon, Mark J. Levis, Alexander E. Perl, Kevin J. Travers, Susana Wang, Jeremy P. Hunt, Patrick P. Zarrinkar, Eric E. Schadt, Andrew Kasarskis, John Kuriyan and Neil P. Shah is published in Nature on 4/15/12. After publication, the article can be accessed at:

This work was funded by grants from the Leukemia and Lymphoma Society, the Doris Duke Charitable Foundation, and the National Cancer Institute, one of the National Institutes of Health. Additional support was provided by Art and Alison Kern and the Edward S. Ageno family.

In addition to UCSF, authors of this study are affiliated with the University of California, Berkeley, Pacific Biosciences, Mount Sinai School of Medicine, Johns Hopkins University, the University of Pennsylvania and Ambit Biosciences in San Diego.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

http://www.UCSF.edu | http://www.Facebook.com/ucsf | http://www.Twitter.com/ucsf | http://www.YouTube.com/ucsf

Jason Socrates Bardi | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Life Sciences:

nachricht Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

nachricht The Nagoya Protocol Creates Disadvantages for Many Countries when Applied to Microorganisms
05.12.2016 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

IHP presents the fastest silicon-based transistor in the world

05.12.2016 | Power and Electrical Engineering

InLight study: insights into chemical processes using light

05.12.2016 | Materials Sciences

High-precision magnetic field sensing

05.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>