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:12/5/2016)... ... December 05, 2016 , ... ... "Best Surgical Facial Rejuvenation" at the 2016 Anti-Aging & Beauty Awards at ... , The Aesthetic & Anti-aging Medicine European Congress (AMEC) brings together the ...
(Date:12/4/2016)... ... 03, 2016 , ... "Perfect Harmony comes with 20 completely ... editors to create professional looking video in a matter of minutes," said Christina ... beautifully designed 3D environment for placing in personal media. Twenty pre-made layouts are ...
(Date:12/4/2016)... ... December 04, 2016 , ... Patients who wish to gain ... of a cosmetic procedure known as Carbon Dioxide (C02) Fractional Laser Resurfacing ... age spots, fine lines, uneven coloration, wrinkles, scarring, skin laxity or textural ...
(Date:12/2/2016)... (PRWEB) , ... December 02, 2016 , ... ... documentary on the perils of heroin that was watched live by 1 million ... Alfred I. duPont-Columbia University Award. , ASU students at the Walter Cronkite School ...
(Date:12/2/2016)... ... 02, 2016 , ... FlexiSpot, a trusted name in sit-stand ... program for all of the company’s desktop riser products. A simple application form ... , FlexiSpot’s unique desktop risers use an advanced dual gas spring hovering system ...
Breaking Medicine News(10 mins):
(Date:12/2/2016)... 2, 2016 According to ... Market by Product (Instruments, Reagents, Software), Technology (Immunoassay, ... Cardiology, Nephrology, Infectious Diseases) - Forecast to 2021" ... at USD 60.22 Billion in 2016. This market ... 5.5% during the forecast period (2016-2021) to reach ...
(Date:12/2/2016)...  The Addiction Treatment Advisory Group (ATAG), created ... Pharmacy (AMCP), has released detailed findings on how ... addiction crisis, including through improved access to naloxone ... newly released paper, "The Role of Managed Care ... issues around gaps and barriers to addiction treatment ...
(Date:12/2/2016)... , Dec. 2, 2016 Boston Scientific Corporation ... agreement to acquire certain manufacturing assets and capabilities of ... NVC) advanced biological tissue business, as well as a ... $75 million in cash. The Neovasc advanced biological tissue ... the Boston Scientific Lotus™ Valve System. * Upon ...
Breaking Medicine Technology: