Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers identify leukemia-linked pathway targeted by a new kinase inhibitor

19.04.2004


New target blocks B-ALL, boosts Gleevec’s effectiveness against CML in mice



Three years ago, using the first of a new class of drugs known as "small molecule kinase inhibitors," medicine slammed shut a door used by cancer. Researchers at The Jackson Laboratory just found another door that kinase inhibitors may close to cancer.

The gene BCR-ABL1 causes two types of leukemia: chronic myelogeneous leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). In both cancers, enzymes that should regulate the growth and development of white blood cells go awry, resulting in uncontrolled growth of the cells. The Swiss-based pharmaceutical company Novartis developed Gleevec, the first kinase inhibitor used to fight cancer by blocking the errant enzyme. It proved effective against chronic phase of CML, but not the advanced phase or against B-ALL. In some patients, it seems CML can develop a resistance to Gleevec.


In the May 2004 issue of Nature Genetics, a research team headed by Shaoguang Li, M.D., Ph.D., of The Jackson Laboratory, announces success with another kinase inhibitor that blocks a different path used by cancer. Studying mice, the researchers discovered that the BCR-ABL1 gene activates three additional enzymes that lead to B-ALL leukemia. One of these enzymes may also be involved when CML patients no longer respond to Gleevec.

"Because of drug resistance, it becomes increasingly difficult to stop progression of and cure this disease by targeting at only one place in a multi-molecule-involved signaling pathway used by cancer," says Dr. Li. "So we needed to find a combined drug therapy targeting simultaneously more than one places in the pathway."

First, the team developed the first efficient and accurate mouse models of both forms of BCR-ABL1-induced leukemia. Next, they discovered that three of the Src kinase class of enzymes are required for B-ALL but not for CML, suggesting that different therapeutic strategies should be used for treating these two diseases although they are induced by the same BCR-ABL1 cancer-causing gene. Finally, in drug treatment studies, they found that the kinase inhibitor, known as CGP76030 produced by Novartis, blocked those three critical Src kinase enzymes. The drug impaired the proliferation of B-lymphoid leukemic cells and prolonged the survival of mice with B-ALL. Their findings suggest additional therapeutic agents for treating this type of leukemia in humans.

ALL is the type of leukemia that predominantly strikes children. Among ALL cases, 85% are of the B-ALL type.

According to oncologist-turned-researcher Dr. Li, the preclinical studies suggest a specific prediction: "Drugs targeting the Src kinases may be useful for the therapy of BRC-ABL1-induced acute leukemia, particularly B-ALL. While these drugs are not effective or useful during the chronic phase of myeloid leukemia, there may be a rationale for dual kinase inhibitor therapy of more advanced leukemia. Increased activation of Src kinases has been observed in CML patients who have become resistant to Gleevec."

Dr. Li and his team are currently developing additional mouse models lacking in different combinations of the Src kinases, in an effort to make available a range of targeted therapies for this category of cancer.

Collaborating with Dr. Li and members of his laboratory (Dr. Yiguo Hu, Dr. Yuhua Liu and Shawn Pelletier) were Drs. Richard Van Etten (Tufts-New England Medical Center, USA), Elisabeth Buchdunger and Doriano Fabbro (Novartis Pharma AG, Switzerland), Markus Warmuth (Novartis Pharma AG, USA), and Michael Hallek (Universität zu Köln, Germany). The research was supported by grants from the Irving A. Hansen Foundation and The V Foundation for Cancer Research to Shaoguang Li, and the National Institutes of Health and a Leukemia and Lymphoma Society SCOR grant to Richard A. Van Etten.

Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Y. Hu, Y. Liu, S. Pelletier, E. Buchdunger, M. Warmuth, D. Fabbro, M. Hallek, R.A. Van Etten, S. Li. Nature Genetics: vol. 35, no. 5, published online April 18, 2004.

Joyce Peterson | EurekAlert!
Further information:
http://www.jax.org/

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 >>>