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 In focus: Peptides, the “little brothers and sisters” of proteins
12.11.2018 | Technische Universität Berlin

nachricht How to produce fluorescent nanoparticles for medical applications in a nuclear reactor
09.11.2018 | Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB Prague)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

Im Focus: Coping with errors in the quantum age

Physicists at ETH Zurich demonstrate how errors that occur during the manipulation of quantum system can be monitored and corrected on the fly

The field of quantum computation has seen tremendous progress in recent years. Bit by bit, quantum devices start to challenge conventional computers, at least...

Im Focus: Nanorobots propel through the eye

Scientists developed specially coated nanometer-sized vehicles that can be actively moved through dense tissue like the vitreous of the eye. So far, the transport of nano-vehicles has only been demonstrated in model systems or biological fluids, but not in real tissue. The work was published in the journal Science Advances and constitutes one step further towards nanorobots becoming minimally-invasive tools for precisely delivering medicine to where it is needed.

Researchers of the “Micro, Nano and Molecular Systems” Lab at the Max Planck Institute for Intelligent Systems in Stuttgart, together with an international...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

In focus: Peptides, the “little brothers and sisters” of proteins

12.11.2018 | Life Sciences

Materials scientist creates fabric alternative to batteries for wearable devices

12.11.2018 | Materials Sciences

A two-atom quantum duet

12.11.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>