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:10/13/2017)... ... , ... The Visiting Nurse Association (VNA) of Somerset Hills is proud to ... unique items from across the nation, this holiday-themed event will raise funds and awareness ... VNA. The boutique will be open Saturday, November 4 (10:00 a.m. – 5:00 ...
(Date:10/13/2017)... (PRWEB) , ... October 13, 2017 , ... ... will be giving viewers the lowdown on sciatica in a new episode of ... that focuses on current events and innovation and investigates each subject in-depth with ...
(Date:10/12/2017)... WILMINGTON, Del. (PRWEB) , ... October 12, 2017 ... ... technology and advisory services for healthcare compliance program management, will showcase a range ... and National Association for Assisted Living (NCAL) Convention and Expo to be held ...
(Date:10/12/2017)... (PRWEB) , ... October 12, 2017 , ... IsoComforter, Inc. ... products, announced today the introduction of an innovative new design of the shoulder pad. ... so you get maximum comfort while controlling your pain while using cold therapy. By ...
(Date:10/12/2017)... ... October 12, 2017 , ... Dr. Parsa ... contributed a medical article to the newly revamped Cosmetic Town journal ... the hair transplant procedure known as Follicular Unit Extraction (FUE). , ...
Breaking Medicine News(10 mins):
(Date:10/4/2017)... Korea , Oct. 4, 2017  South Korean-based ... next-generation CPR training aide "cprCUBE" on Kickstarter. The device ... compression during cardiac arrests with better efficiency compared to ... also offers real-time feedback on efficacy of the compression ... crowdfunding campaign has a goal to raise $5,000. ...
(Date:10/2/2017)... , Oct. 2, 2017  AllianceRx Walgreens Prime, the ... by Walgreens and pharmacy benefit manager Prime Therapeutics LLC ... brand, which included the unveiling of new signage at ... as well as at a few other company-owned facilities ... brand to patients, some of whom will begin to ...
(Date:9/27/2017)... -- Commended for their devotion to personalized service, SMP Pharmacy Solutions ... in the South Florida Business Journal,s 50 Fastest-Growing Companies, and ... the national specialty pharmacy has found its niche.  To that ... be honored by SFBJ as the 2017 Power Leader in ... receive his award in October, Bardisa said of the three ...
Breaking Medicine Technology: