Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Targeted Agent Shows Promise For Chronic Lymphoid Leukemia

14.09.2010
Researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) have identified an experimental agent that targets chronic lymphocytic leukemia and perhaps other proliferative disorders of lymphocytes.

Their study shows that the small-molecule inhibitor CAL-101 directly promotes cell death by apoptosis in chronic lymphocytic leukemia (CLL) cells and disrupts several external survival pathways needed for CLL cell viability and proliferation.

The agent blocks a molecule called PI3K-delta, an isomer of the PI3K (phosphatidylinositol-3 kinase) pathway, which is activated mainly in blood-forming, or hematopoietic, cells.

The research was posted recently in the journal Blood.

“Overall, our findings provide a rationale for the development of CAL-101 as the first in a new class of targeted therapies for CLL,” says principal investigator Amy J. Johnson, assistant professor of hematology and medicinal chemistry, and a CLL researcher in the OSUCCC-James.

“A PI3K inhibitor hasn’t been developed yet because this pathway is required for many essential cellular functions, but the identification of PI3K-delta, which is hematopoietic-selective, unlocks a potential new therapy for B-cell malignancies,” Johnson says.

CLL is the most common from of adult leukemia in the United States, with about 15,000 new cases and 4,500 deaths annually. An estimated 100,760 people in the United States are living with or are in remission from CLL.

People with the asymptomatic phase of CLL can live many years, even without treatment. But once the disease progresses to its symptomatic phase, treatment is required. This is usually a chemotherapy-based regimen that often induces remission. But current therapies are not curative and nearly all patients relapse.

The PI3K pathway is essential for survival of cells generally. This made it an unsuitable target for small molecule inhibitors until recently when research showed that PI3K-delta expression occurs mainly in hematopoietic cell types. Preclinical studies suggest that blocking this molecule may kill B cells with little toxicity to other hematopoietic cells.

The present study, which used CLL cells from patients, found the following:

CLL cells show high PI3K pathway activity and PI3K-delta expression

CAL-101 preferentially kills CLL cells compared to normal B-cells

CAL-101 selectively inhibits PI3K-delta and directly promotes apoptosis in primary CLL cells, and it disrupts multiple external survival pathways

CAL-101 cell killing is caspase dependent and not diminished by the presence of stromal cells

CAL-101 does not kill normal T-cells or NK cells or reduce antibody-dependent cellular cytotoxicity, but it does lower production of inflammatory and anti-apoptotic cytokines by activated T-cells.

Note: A phase I clinical trial (NCT00710528) of CAL-101 is currently under way in select relapsed or refractory hematologic malignancies at Ohio State and other centers.

Funding from the Leukemia and Lymphoma Society, The D. Warren Brown Foundation, and Calistoga Pharmaceuticals supported this research. Amy Johnson is a Paul Calabresi Scholar.

Other researchers involved in this study were Sarah E. M. Herman, John C. Byrd, Amber L. Gordon, Amy J. Wagner, Nyla A. Heerema, Weiqiang Zhao, Joseph M. Flynn, Jeffrey Jones, Leslie Andritsos, Xiaoli Zhang and Lai Wei of Ohio State University; and Kamal D. Puri, Brian J. Lannutti, Neill A. Giese of Calistoga Pharmaceuticals.

The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute is one of only 40 Comprehensive Cancer Centers in the United States designated by the National Cancer Institute. Ranked by U.S. News & World Report among the top cancer hospitals in the nation, The James is the 180-bed adult patient-care component of the cancer program at The Ohio State University. The OSUCCC-James is one of only seven funded programs in the country approved by the NCI to conduct both Phase I and Phase II clinical trials.

Darrell E. Ward | EurekAlert!
Further information:
http://www.osumc.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

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”...

Im Focus: Dresdner scientists print tomorrow’s world

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...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>