Navigation Links
Combination overcomes breast cancer resistance to herceptin
Date:3/13/2011

HOUSTON - Breast cancer tumors take numerous paths to resist the targeted drug Herceptin, but a single roadblock at a crucial crossroads may restore a tumor's vulnerability to treatment, scientists at The University of Texas MD Anderson Cancer Center report on line at Nature Medicine.

Adding the drug saracatinib to Herceptin treatment shrinks previously resistant tumors by cutting off at least five different molecular pathways, each of which can resist, said senior author Dihua Yu, M.D., Ph.D., professor in MD Anderson's Department of Molecular and Cellular Oncology.

"Scientists have identified so many ways by which a tumor resists Herceptin that it raises an important issue for treatment," Yu said. "Will we have to give patients six drugs or 10 drugs to block them all? The side effects would be awful. Two pills are better. This combination is a promising therapy for those with Herceptin-resistant breast cancer."

Working in cell lines, mouse models of breast cancer and checking their work in human tumor samples, Yu and colleagues identified SRC, a known cancer-promoting protein, as the crucial common downstream component of multiple resistance pathways.

Saracatinib is an SRC inhibitor, thwarting that protein and allowing Herceptin to work again in tumors that have a high amount of the HER2 protein.

Only about 26 percent of women with HER2-positive breast cancer respond to Herceptin as single therapy. Between 40 and 60 percent respond to the drug when combined with other chemotherapy.

Combination is ready for clinical trials

Yu said saracatinib has been tested in phase I and phase II clinical trials as a single treatment against late-stage cancers. It has a favorable side effects profile.

"It didn't work as a single agent, but very few drugs work by themselves against late stage disease," Yu said. "Our experiments confirmed its lack of efficacy as a sole treatment. But combined with Herceptin, it's beautiful."

Another SRC inhibitor, dasatinib, has been approved by the U.S. Food and Drug Administration as an anti-cancer drug, but it has harsher side effects, said Siyuan Zhang, Ph.D., a postdoctoral fellow in Yu's lab and the paper's first author.

A tumor-suppressor's job

In 2004, Yu's lab discovered that loss of the tumor-suppressing gene known as PTEN led to Herceptin-resistant tumors. PTEN is a phosphotase - a protein whose function is to strip phosphate chemical groups off of other molecules.

PTEN has two components, one to remove phosphate groups from lipids, and another to remove them from proteins. PTEN's target protein however, was unknown.

Zhang discovered that SRC is a PTEN target. With its phosphate groups, SRC is active. PTEN stifles SRC by peeling away the phosphates.

If PTEN loss leads to Herceptin resistance, and PTEN targets SRC, would that make SRC the culprit?

On the trail of SRC

In a series of experiments the researchers found:

  • SRC is active in breast cancer cells once vulnerable but now resistant to Herceptin and in cells that are resistant from the start.
  • Activation of SRC drives resistance to Herceptin. Tumors with low SRC levels treated by Herceptin shrunk to 20 percent of their original volume in 21 days while SRC-heavy tumors increased by nearly 400 percent over the same time in mouse experiments.
  • SRC activity correlates with patient response to Herceptin. Assessing SRC activation in samples of 57 human breast cancer tumors, the team found that more than 90 percent of tumors with low SRC responded compared with 40 percent of tumors with active SRC.
  • Patients with little active SRC had a median survival of 57.9 months compared with 34.2 months in those with high SRC activity.
  • SRC is activated by a number of receptor tyrosine kinases that cause resistance, including IGF-1R, EGFR, ERBB2, HER3, and Met, separate pathways that work through SRC. "Block SRC, and you reverse them all," Zhang said.

Crushing resistance

Combining Herceptin and saracatinib to treat resistant tumors in mice reduced tumor volume by 90 percent in 25 days. Herceptin alone kept tumor volume about the same during the same period, while control and saracatinib alone permitted growth of more than 200 percent.

The difference was more striking in tumors deficient in SRC's enemy, the PTEN tumor-suppressor. The combination reduced tumor volume by more than 90 percent while the two drugs alone allowed growth of between 200 and 400 percent.

This study was funded by grants from the National Cancer Institute, MD Anderson Breast Specialized Program of Research Excellence; Department of Defense Center of Excellence; Susan G. Komen Breast Cancer Foundation Promise Grant; the Cancer Prevention and Research Institute of Texas, the MD Anderson Breast SPORE Career Development Award and Susan G. Komen Breast Cancer Foundation Postdoctoral Fellowship.


'/>"/>

Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

Related medicine news :

1. New combination therapy for solid tumors?
2. Certain Drug Combinations May Beat Back Aggressive Breast Cancer
3. Drug combination shows promise for newly diagnosed blood cancer patients, study finds
4. Combination therapy improves survival time for patients with advanced liver cancer
5. Best drug development results from computer/test tube combination
6. VCU study: Researchers discover a drug combination that shrinks tumors in vivo
7. Researchers at SUNY Downstate find drug combination may treat traumatic brain injury
8. Benefits of healthy lifestyle factors stronger in combination
9. Berkeley study shows ozone and nicotine a bad combination for asthma
10. Combination of Meniscus Allograft Transplantation and Repair of Articular Cartilage May Slow the Progression of Arthritis in the Knee
11. Combination MMRV vaccine linked with 2-fold risk of seizures
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Combination overcomes breast cancer resistance to herceptin
(Date:6/26/2016)... ... June 26, 2016 , ... On June 10-11, 2016, A ... 2016 Cereal Festival and World’s Longest Breakfast Table in Battle Creek, MI, where the ... history as home to some of the world’s leading providers of cereal and other ...
(Date:6/26/2016)... ... June 26, 2016 , ... ... have been diagnosed with endometriosis. These women need a treatment plan to not ... comprehensive approach that can help for preservation of fertility and ultimately achieving a ...
(Date:6/25/2016)... (PRWEB) , ... June 25, 2016 , ... "With 30 ... their specific project," said Christina Austin - CEO of Pixel Film Studios. , ... and all within Final Cut Pro X . Simply select a ProHand generator ...
(Date:6/25/2016)... , ... June 25, 2016 , ... On Friday, June ... a Bronze Wellness at Work award to iHire in recognition of their exemplary accomplishments ... of the 7th annual Maryland Workplace Health & Wellness Symposium at the BWI Marriott ...
(Date:6/24/2016)... ... , ... June 19, 2016 is World Sickle Cell Observance Day. In an ... of holistic treatments, Serenity Recovery Center of Marne, Michigan, has issued a ... Cell Disease (SCD) is a disorder of the red blood cells, which can cause ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... 2016 Research and Markets ... Electronics 2015-2025: Applications, Technologies, Forecasts" report to ... In-Mold Electronics, Smart Skin, Structural Health Monitoring, Composite ... Structural electronics involves electronic and/or electrical components and ... dumb structures such as vehicle bodies or conformally ...
(Date:6/24/2016)... -- According to a new market research ... Safety Pen Needles), Needle Length (4mm, 5mm, 6mm, 8mm, ... Purchase (Retail, Non-Retail) - Trends & Global Forecasts to ... for the forecast period of 2016 to 2021. This ... 2021 from USD 1.65 Billion in 2016, growing at ...
(Date:6/23/2016)... 23, 2016 Research and Markets has ... - Forecast to 2022" report to their offering. ... for the patients with kidney failure, it replaces the function ... the patient,s blood and thus the treatment helps to keep ... in balance. Increasing number of ESRD patients ...
Breaking Medicine Technology: