Navigation Links
Moffitt researcher investigates 2-drug synergy to treat drug-resistant chronic myeloid leukemia
Date:10/25/2012

An interdisciplinary team of researchers has dissected a case of synergy in drug-resistant chronic myeloid leukemia to understand the mechanism by which two drugs, danusertib and bosutinib, work together to overcome resistance in the BCR-ABL gatekeeper mutation-specific disease. The team includes a researcher at Moffitt Cancer Center and colleagues at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Austria and the Massachusetts Institute of Technology. The goal is to address an unmet medical need because this BCR-ABL mutation confers resistance to all currently approved kinase inhibitors for chronic myeloid leukemia.

The study appeared in the Sept. 30 online version of Nature Chemical Biology.

"Treatment of chronic myeloid leukemia rapidly improved after the introduction of the first BCR-ABL inhibitor, Gleevec (imatinib)," said study co-author Uwe Rix, Ph.D., an assistant member of the Moffitt's Drug Discovery Department and Experimental Therapeutics Program. "However, it soon became apparent that a broad spectrum of possible resistance mechanisms necessitated second- and third-generation BCR-ABL inhibitors. Although these are mostly very successful, none of the currently approved options has been effective in patients with chronic myeloid leukemia who harbor the BCR-ABL gatekeeper mutation."

The researchers investigated the molecular mechanisms and logic underlying the synergistic interaction between danusertib and bosutinib, which is specific for BCR-ABL gatekeeper mutation-transformed cells. They applied a novel systems pharmacology approach involving a combination of different proteomics and gene expression profiling methods.

"We found previously unappreciated features of both agents," Rix said. "The synergy did not correlate with direct inhibition of BCR-ABL. Instead, our observations converged on the downstream MAPK signaling cascade as the predominantly affected pathway in the synergistic inhibition of BCR-ABL."

The researchers said the combination of both compounds impaired the activity of c-MYC, a gene regulator that codes a transcription factor playing a well-established but a not well understood role in a broad spectrum of human cancers.

"In the context of chronic myeloid leukemia, c-MYC is required for BCR-ABL-mediated transformation," Rix explained. "What is intriguing is that chronic myeloid leukemia cells with the BCR-ABL gatekeeper mutation seem to be more dependent on the MAPK/c-MYC signaling axis than BCR-ABL wild-type cells. Thus, challenging c-MYC with drugs appears promising in these resistant cells, but steps have only recently been made."

The researchers concluded that they have unraveled the action and impact of a "new synergistic drug interaction between danusertib and bosutinib in a clinically relevant, highly drug-resistant disease setting" by revealing a "non-obvious synergistic mechanism elicited by several off targets of the two small molecules."

"We believe this strategy of gaining a functional understanding of drug synergy may serve as a model for further mode-of-action studies," they concluded.


'/>"/>
Contact: Kim Polacek
kim.polacek@moffitt.org
813-745-7408
H. Lee Moffitt Cancer Center & Research Institute
Source:Eurekalert

Related medicine news :

1. Moffitt researchers find cancer therapies affect cognitive functioning among breast cancer survivors
2. Moffitt Cancer Center researchers: Quality of life as important as quantity of life
3. Moffitt Cancer Center researchers working at frontiers of melanoma research
4. Moffitt researchers find adolescents with cancer concerned about their future reproductive health
5. Moffitt researcher publishes book on nutritional management of cancer treatment effects
6. Moffitt researcher awarded GE grant to develop tool to detect breast cancer metastasis genetic risks
7. Researchers creating designer lymph nodes based on Moffitts Total Cancer Care initiative
8. Moffitt Cancer Center researchers identify drivers of sarcoma growth and survival
9. Moffitt Cancer Center researchers develop and test new anti-cancer vaccine
10. Moffitt researcher, colleagues find success with new immune approach to fighting some cancers
11. Moffitt researchers: Darwins principles say cancer will always evolve to resist treatment
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/6/2016)... ... 2016 , ... Canadian author Mark Black is a speaker, author, and life strategy ... the world … with the help of his publisher Strategic Book Group and its subsidiary ... a hospital bed waiting for a miracle: He needed a heart and double-lung transplant. From ...
(Date:5/6/2016)... York, NY (PRWEB) , ... May 06, 2016 , ... ... Hotel & Resort on the north end of the island close to the town ... July 17th- August 10th 2016. , “We continue to have an amazing experience ...
(Date:5/6/2016)... , ... May 06, 2016 , ... ... to Sleepopolis.com . , Since launching in September, 2014 Sleepopolis has resided ... testing areas, which now include pillows, sheets, mattress toppers, bed frames, and more. ...
(Date:5/6/2016)... ... May 06, 2016 , ... Multiple award winning plumbing company ... over 35 years. Maintaining core values of exceptional customer service, quality work at reasonable ... a leading name in San Diego plumbing, and other services including heating & air ...
(Date:5/6/2016)... ... , ... Yisrayl Hawkins, Pastor and Overseer at The House of Yahweh, has written a new ... the Bible about helping to stop cancer. Yisrayl says there are too many suffering and ... health and science industries will pay close attention and take action. The Pastor says that ...
Breaking Medicine News(10 mins):
(Date:5/5/2016)... Global NASH market report ... rise in obesity will fuel the demand for ... years. The NASH Market is growing at a ... of rising number of obesity among young population. ... with no FDA approved therapeutics. Antioxidants, anti-diabetic medications, ...
(Date:5/5/2016)... , May 5, 2016  Replikins Ltd. today reported initial promising results in animal ... Photo - http://photos.prnewswire.com/prnh/20160505/364345 ... ... ... of all Zika specimens recorded on Pubmed. The analysis identified the highest gene Replikin ...
(Date:5/5/2016)... , May 5, 2016  Endo International ... today announced that Brian Lortie , President, ... from his position upon the appointment of a ... led its U.S. Pharmaceuticals business with responsibility for ... and marketing, strategy and portfolio development, commercial operations, ...
Breaking Medicine Technology: