Featured Research

from universities, journals, and other organizations

Potential treatment for lethal childhood leukemia: Inhibiting two related enzymes significantly improves survival in mouse model

Date:
April 16, 2012
Source:
Columbia University Medical Center
Summary:
Researchers have demonstrated that two related enzymes -- phosphoinositide-3 kinase gamma and delta -- play a key role in the development of T-cell acute lymphoblastic leukemia, a highly aggressive childhood leukemia that is difficult to treat. The study also showed that a dual PI3K gamma/delta inhibitor can significantly prolong survival in a mouse model of the disease.

Researchers showed that a dual PI3K gamma/delta inhibitor can significantly prolong survival in a mouse model of a highly aggressive childhood leukemia.
Credit: Image courtesy of Columbia University Medical Center

Columbia University Medical Center (CUMC) scientists have demonstrated that two related enzymes -- phosphoinositide-3 kinase (PI3K) gamma and delta -- play a key role in the development of T-cell acute lymphoblastic leukemia (T-ALL), a highly aggressive childhood leukemia that is difficult to treat. The study also showed that a dual PI3K gamma/delta inhibitor can significantly prolong survival in a mouse model of the disease. Further, the dual inhibitor was shown to prevent proliferation and to reduce the survival rate of human T-ALL cells in laboratory cultures, setting the stage for clinical trials.

The study appears April 16 in the online edition of Cancer Cell.

"Clearly, we have a drug that is extremely effective against this type of cancer in mice," said study leader Thomas Diacovo, MD, associate professor of pediatrics and pathology and cell biology at CUMC. "If this treatment strategy can safely and selectively target the activity of these enzymes in T-ALL tumors, we might be able to reduce the need for conventional chemotherapies that more broadly affect proliferating cells, including those in healthy tissues. This would be a major advancement in helping to reduce drug toxicities in young patients."

The dual inhibitor was developed by Gilead Sciences.

T-ALL is a cancer that arises during the development of T-cells, a type of white blood cell. The abnormal T cells multiply rapidly, invading and impairing the function of organs critical for sustaining life. T-ALL typically begins in childhood but can also appear later in life. The disease is caused by mutations in DNA, which permit the cancer cell to continue growing and dividing, when a healthy cell would normally die. Left untreated, T-ALL is invariably fatal. It is highly resistant to chemotherapy, compared with other forms of leukemia. The relapse rate is about 25 percent in children and 50 percent in adults.

In studies of autoimmune disease done some years ago, Dr. Diacovo and his team found that inhibition of both PI3K gamma and delta not only reduced inflammation but also caused developing T cells to die at an accelerated rate. "This led us to ask in what disease states it would be advantageous to kill off aberrant T-cells," he said. "One of the first diseases that came to mind was T-ALL.

The current study was designed to take a closer look at the role of these enzymes in T-ALL and to see whether an experimental PI3K inhibitor called CAL-130 might affect disease progression.

In the first part of the study, using a mouse model of the disease, Dr. Diacovo and his team, led by Dr. Subramaniam, confirmed that both PI3K gamma and delta are essential for the development of T-ALL and the survival of leukemic (abnormal) cells. The researchers also demonstrated that administration of CAL-130 significantly lowered the number of leukemic T-cells in animals' general circulation. "The level of circulating leukemia cells dropped very rapidly, from an average of 100 million per ml to less than 1 million per ml within 24 to 48 hours," Dr. Diacovo said. "The counts remained low after just 7 days of therapy." The median survival time for mice treated with CAL-130 was 45 days, compared with 7.5 days for untreated controls.

The researchers also evaluated the effects of CAL-130 on blood samples taken from patients with T-ALL. The drug prevented proliferation of leukemic cells and promoted a self-destruct mechanism called apoptosis.

"We've made great strides in treating childhood acute lymphoblastic leukemias over the years, with an overall cure rate approaching 90 percent," said Dr. Diacovo. "Unfortunately, conventional treatment -- chemotherapy -- is quite toxic. This is a particular problem for children, who have an entire lifetime ahead of them and are likely to develop secondary cancers and other complications as a result of their treatment. So anything we can do to lessen associated toxicities would be a welcome advancement in the field."

Stephen G. Emerson, MD, PhD, director of the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center, said, "Even in cancers where cure rates are high -- such as this form of childhood leukemia -- our researchers are continually searching for less toxic ways to treat our patients, in an effort to improve their quality of life and to enable them to lead long, healthy lives. This is one of the key approaches to the future of cancer care."

Clinical trials of a dual PI3K gamma/delta inhibitor in patients with leukemia are in the planning stages, said Dr. Diacovo.

The paper is entitled, "Targeting non‐classical oncogenes for therapy in T-ALL." In addition to Dr. Diacovo, the study authors are Prem S. Subramaniam, PhD (CUMC); Dosh W. Whye, BSc (CUMC); Evgeni Efimenko, PhD (CUMC); Jianchung Chen, PhD (CUMC); Valeria Tosello, PhD (CUMC); Kim De Keersmaecker, PhD (CUMC); Adam Kashishian, BSc (Calistoga Pharmaceuticals and Gilead Sciences, Seattle, WA); Mary Ann Thompson, MD, PhD (Vanderbilt University Medical Center, Nashville, TN); Mireia Castillo, PhD (Mount Sinai School of Medicine, New York); Carlos Cordon-Cardo, MD (Mount Sinai); Upal Davé, MD (Vanderbilt); Adolfo Ferrando, MD, PhD (CUMC); and Brian J. Lamnutti, PhD (Calistoga Pharmaceuticals and Gilead Sciences).

Brian Lannutti and Adam Kashishian are employees of the company (Gilead Sciences) that manufactured CAL-130. None of the other authors report any financial or other conflict of interest.

This research was supported by the Department of Defense (grant # PR093714), the Leukemia & Lymphoma Society Translational Research Program, and Gilead Sciences.


Story Source:

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


Cite This Page:

Columbia University Medical Center. "Potential treatment for lethal childhood leukemia: Inhibiting two related enzymes significantly improves survival in mouse model." ScienceDaily. ScienceDaily, 16 April 2012. <www.sciencedaily.com/releases/2012/04/120416125321.htm>.
Columbia University Medical Center. (2012, April 16). Potential treatment for lethal childhood leukemia: Inhibiting two related enzymes significantly improves survival in mouse model. ScienceDaily. Retrieved September 20, 2014 from www.sciencedaily.com/releases/2012/04/120416125321.htm
Columbia University Medical Center. "Potential treatment for lethal childhood leukemia: Inhibiting two related enzymes significantly improves survival in mouse model." ScienceDaily. www.sciencedaily.com/releases/2012/04/120416125321.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

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
How The 'Angelina Jolie Effect' Increased Cancer Screenings

How The 'Angelina Jolie Effect' Increased Cancer Screenings

Newsy (Sep. 19, 2014) — Angelina's Jolie's decision to undergo a preventative mastectomy in 2013 inspired many women to seek early screenings for the disease. Video provided by Newsy
Powered by NewsLook.com
The Cost of Ebola

The Cost of Ebola

Reuters - Business Video Online (Sep. 18, 2014) — As Sierra Leone prepares for a three-day "lockdown" in its latest bid to stem the spread of Ebola, Ciara Lee looks at the financial implications of fighting the largest ever outbreak of the disease. Video provided by Reuters
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