Featured Research

from universities, journals, and other organizations

When Gleevec Is Not Enough: Researcher Demonstrates Value Of 'Helper' Compound In Treating Some Leukemias

Date:
November 10, 2006
Source:
Jackson Laboratory
Summary:
Researchers at the Jackson Laboratory, in collaboration with scientists at Bristol-Myers Squibb Oncology, discovered is that imatinib does not inactivate all BCR-ABL signaling pathways in the cascade. Proteins called SRC kinases are still activated by BCR-ABL in imatinib-treated mouse leukemic cells. Treatment with dasatinib, which inhibits the SRC proteins as well as BCR-ABL, was not only more effective for CML, but also led to complete B-ALL remission.

The abberant Philadelphia chromosome is not a problem local to Philadelphia, but that's where researchers discovered the genetic mutation that's the root cause of some leukemias, including chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). Led by Shaoguang Li, M.D., Ph.D., researchers at The Jackson Laboratory, in collaboration with scientists at Bristol-Myers Squibb Oncology, are discovering startling new information about the mechanisms of Philadelphia-positive (Ph+) leukemias that will affect how they are treated clinically.

The Philadelphia Chromosome is actually a faulty mixture of two chromosomes, 9 and 22, which typically work perfectly well independent of each other. But in rare circumstances they physically exchange genetic material in a specific way, and the combined Philadelphia chromosome merges two harmless genes into something destructive. The resulting protein, called BCR-ABL, unleashes a cascade of events that ultimately leads to unregulated cell proliferation in blood cells, leading to Ph+ leukemia.

Bone marrow transplants can cure these leukemia patients, but the procedure could be risky, and sufficiently compatible donors often cannot be found. Therefore the drug imatinib mesylate (sold by the pharmaceutical company Novartis as Gleevec), which disables the destructive function of the BCR-ABL protein, represented a huge step forward in treatment, especially for CML in chronic phase. Imatinib doesn't cure CML, but it inhibits the deadly cascade launched by BCR-ABL, and most patients can use it to better manage the disease with minimal side effects.

While imatinib helps many human patients, Li is using mice with the equivalent of the Ph+ leukemias to investigate why some do not respond to it. Also, imatinib has little positive effect for Ph+ leukemia patients that have progressed to blast crisis, the phase during which the cancer cells undergo additional changes that lead to their out-of-control reproduction. Progression to blast crisis currently necessitates a bone marrow transplant for survival.

"Sometimes the BCR-ABL protein itself has a mutation, which makes it less susceptible to imatinib," said Li. "But in some patients who do not respond to imatinib, there's no imatinib-resistant mutations detected and the disease still progresses. No one understood how that happens when the known disease cascade is inhibited."

In research published in online in the Proceedings of the National Academy of Sciences, Li's team discovered is that imatinib does not inactivate all BCR-ABL signaling pathways in the cascade. Part of the cascade, proteins called SRC kinases, are still activated by BCR-ABL in imatinib-treated mouse leukemic cells. When Li treated the mice with a compound, dasatinib, that inhibits the SRC proteins as well as BCR-ABL, he found that not only was it more effective for CML, but it also led to complete B-ALL remission.

While these results are encouraging, a small population of leukemic cells (fewer than 1 percent) persisted through treatment with imatinib or dasatinib and led to a recurrence of the leukemia. These cells, leukemic stem cells, present an additional challenge.

"These results show that clinicians need to address SRC kinase activity as well as BCR-ABL to get the best outcomes with Ph+ leukemia," said Li, "but it's not a real cure. The keys to a cure for Ph+ leukemia are the leukemic stem cells, and we've now isolated them in the mouse for the first time. We will be working hard to figure out how to target and eradicate them."


Story Source:

The above story is based on materials provided by Jackson Laboratory. Note: Materials may be edited for content and length.


Cite This Page:

Jackson Laboratory. "When Gleevec Is Not Enough: Researcher Demonstrates Value Of 'Helper' Compound In Treating Some Leukemias." ScienceDaily. ScienceDaily, 10 November 2006. <www.sciencedaily.com/releases/2006/11/061108111443.htm>.
Jackson Laboratory. (2006, November 10). When Gleevec Is Not Enough: Researcher Demonstrates Value Of 'Helper' Compound In Treating Some Leukemias. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/2006/11/061108111443.htm
Jackson Laboratory. "When Gleevec Is Not Enough: Researcher Demonstrates Value Of 'Helper' Compound In Treating Some Leukemias." ScienceDaily. www.sciencedaily.com/releases/2006/11/061108111443.htm (accessed July 30, 2014).

Share This




More Health & Medicine News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Xtreme Eating: Your Daily Caloric Intake All On One Plate

Xtreme Eating: Your Daily Caloric Intake All On One Plate

Newsy (July 30, 2014) The Center for Science in the Public Interest released its 2014 list of single meals with whopping calorie counts. Video provided by Newsy
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