Featured Research

from universities, journals, and other organizations

Targeted agent shows promise for chronic lymphoid leukemia

Date:
September 14, 2010
Source:
Ohio State University Medical Center
Summary:
New research may have identified an experimental agent that targets chronic lymphocytic leukemia (CLL) and perhaps other proliferative disorders of lymphocytes. This study using tumor cells from patients shows that the small-molecule inhibitor CAL-101 directly promotes cell death in CLL cells and disrupts several external survival pathways needed for CLL cell viability and proliferation. The findings provide a rationale for developing CAL-101 as the first in a new class of CLL targeted therapies.

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.


Story Source:

The above story is based on materials provided by Ohio State University Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. S. E. M. Herman, A. L. Gordon, A. J. Wagner, N. A. Heerema, W. Zhao, J. M. Flynn, J. Jones, L. Andritsos, K. D. Puri, B. J. Lannutti, N. A. Giese, X. Zhang, L. Wei, J. C. Byrd, A. J. Johnson. The phosphatidylinositol 3-kinase-δ inhibitor CAL-101 demonstrates promising pre-clinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood, 2010; DOI: 10.1182/blood-2010-02-271171

Cite This Page:

Ohio State University Medical Center. "Targeted agent shows promise for chronic lymphoid leukemia." ScienceDaily. ScienceDaily, 14 September 2010. <www.sciencedaily.com/releases/2010/09/100913172412.htm>.
Ohio State University Medical Center. (2010, September 14). Targeted agent shows promise for chronic lymphoid leukemia. ScienceDaily. Retrieved September 20, 2014 from www.sciencedaily.com/releases/2010/09/100913172412.htm
Ohio State University Medical Center. "Targeted agent shows promise for chronic lymphoid leukemia." ScienceDaily. www.sciencedaily.com/releases/2010/09/100913172412.htm (accessed September 20, 2014).

Share This



More Health & Medicine News

Saturday, September 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Sierra Leone's Nationwide Ebola Curfew Underway

Sierra Leone's Nationwide Ebola Curfew Underway

Newsy (Sep. 20, 2014) Sierra Leone is locked down as aid workers and volunteers look for new cases of Ebola. Video provided by Newsy
Powered by NewsLook.com
Changes Found In Brain After One Dose Of Antidepressants

Changes Found In Brain After One Dose Of Antidepressants

Newsy (Sep. 19, 2014) A study suggest antidepressants can kick in much sooner than previously thought. Video provided by Newsy
Powered by NewsLook.com
Could Grief Affect The Immune Systems Of Senior Citizens?

Could Grief Affect The Immune Systems Of Senior Citizens?

Newsy (Sep. 19, 2014) The study found elderly people are much more likely to become susceptible to infection than younger adults going though a similar situation. Video provided by Newsy
Powered by NewsLook.com
Jury Delivers Verdict in Salmonella Trial

Jury Delivers Verdict in Salmonella Trial

AP (Sep. 19, 2014) A federal jury has convicted three people in connection with an outbreak of salmonella poisoning five years ago that sickened hundreds of people and was linked to a number of deaths. (Sept. 19) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins