Navigation Links
Drug-resistant melanoma tumors shrink when therapy is interrupted
Date:1/9/2013

Researchers in California and Switzerland have discovered that melanomas that develop resistance to the anti-cancer drug vemurafenib (marketed as Zelboraf), also develop addiction to the drug, an observation that may have important implications for the lives of patients with late-stage disease.

The team, based at the University of California, San Francisco (UCSF), the Novartis Institutes for Biomedical Research (NIBR) in Emeryville, Calif., and University Hospital Zurich, found that one mechanism by which melanoma cells become resistant to vemurafenib also renders them "addicted" to the drug. As a result, the melanoma cells nefariously use vemurafenib to spur the growth of rapidly progressing, deadly and drug-resistant tumors.

As described this week in the journal Nature, the team built upon this basic discovery and showed that adjusting the dosing of the drug and introducing an on-again, off-again treatment schedule prolonged the life of mice with melanoma.

"Remarkably, intermittent dosing with vemurafenib prolonged the lives of mice with drug-resistant melanoma tumors," said co-lead researcher Martin McMahon, PhD, the Efim Guzik Distinguished Professor of Cancer Biology in the UCSF Helen Diller Family Comprehensive Cancer Center.

It is therefore possible that a similar approach may extend the effectiveness of the drug for people an idea that awaits testing in clinical trials.

Investigated through a public-private partnership, the research was spearheaded by the study's first author Meghna Das Thakur, PhD, a Novartis Presidential Postdoctoral Fellow, who was co-mentored by McMahon at UCSF and Darrin Stuart, PhD at NIBR.

McMahon is supported by the Melanoma Research Alliance, the National Cancer Institute and the UCSF Helen Diller Family Comprehensive Cancer Center, which is one of the country's leading research and clinical care centers, and is the only comprehensive cancer center in the San Francisco Bay Area.

Melanoma: A Deadly Form of Skin Cancer

Melanoma is the most aggressive type of skin cancer, and in 2012 alone, an estimated 76,250 people in the United States were newly diagnosed with it. Some 9,180 people died last year from the disease, according to the National Cancer Institute.

As with all forms of cancer, melanoma starts with normal cells in the body that accumulate mutations and undergo transformations that cause them to grow aberrantly and metastasize. One of the most common mutations in melanoma occurs in a gene called BRAF, and more than half of all people with melanoma express mutated BRAF.

In 2011, the U.S. Food and Drug Administration (FDA) approved the drug vemurafenib for patients who have late-stage melanoma with mutations in BRAF after clinical trials showed a significant increase in survival for such patients when taking the drug. The drug's benefits do not last forever, though, and while their tumors may initially shrink, most people on vemurafenib suffer cancer recurrence in the long run with a lethal, drug-resistant form of melanoma.

In the laboratory, the same phenomenon can be observed in mice. When small melanoma tumor fragments are implanted in mice, the tumors will initially shrink in response to drug, but eventually the mice will cease to respond to the drug and their tumors will re-emerge in a resistant form.

Targeting the Mechanism of Resistance

Working with such laboratory models, the UCSF and NIBR research teams were able to determine the mechanism of resistance. They discovered that when melanoma cells are subjected to vemurafenib, they become resistant by making more of the BRAF protein the very target of the drug itself.

The idea for intermittent dosing came directly from this insight. If by becoming resistant to vemurafenib's anti-cancer potency, melanoma also becomes addicted to it, Das Thakur and her colleagues reasoned, then drug-resistant tumors may shrink when the vemurafenib is removed. That's exactly what they observed.

The team discovered that when they stopped administering the drug to mice with resurgent, resistant tumors, the tumors once again shrank. In addition, mice continuously treated with vemurafenib all died of drug-resistant disease within about 100 days, whereas all the mice treated with vemurafenib but with regular "drug holidays" all lived past 100 days.

"Vemurafenib has revolutionized treatment of a specific subset of melanoma expressing mutated BRAF, but its long-term effectiveness is diminished by the development of drug resistance," said McMahon, the Efim Guzik Distinguished Professor of Cancer Biology in the UCSF Helen Diller Family Comprehensive Cancer Center. "By seeking to understand the mechanisms of drug resistance, we have also found a way to enhance the durability of the drug response via intermittent dosing."


'/>"/>

Contact: Jason Socrates Bardi
jason.bardi@ucsf.edu
415-502-6397
University of California - San Francisco
Source:Eurekalert  

Related medicine news :

1. Moffitt researcher investigates 2-drug synergy to treat drug-resistant chronic myeloid leukemia
2. Discovery of essential genes for drug-resistant bacteria reveals new, high-value drug targets
3. Molecule shows effectiveness against drug-resistant myeloma
4. Alarming Rise Seen in Drug-Resistant Tuberculosis
5. African Chimps Carry Drug-Resistant, Human-Linked Staph
6. Computational analysis identifies drugs to treat drug-resistant breast cancer
7. Scientists develop new strategy to overcome drug-resistant childhood cancer
8. Rare Drug-Resistant Bacteria Spotted in U.S. Hospital
9. New Medicine Might Fight Drug-Resistant TB, Study Says
10. Einstein awarded $6 million grant to develop new TB vaccine against drug-resistant strains
11. Kinase test may yield big gains for drug-resistant cancers
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Drug-resistant melanoma tumors shrink when therapy is interrupted
(Date:4/29/2016)... , ... April 29, 2016 , ... ... Spiritual Awakening , announces the addition Onnit brand Alpha BRAIN and New Mood ... of Onnit brain and mood optimization products to the store is just one ...
(Date:4/29/2016)... ... , ... On Tuesday, April 26, 2016 members of the HomeTown Health network, ... Nathan Deal on SB 258, the “Rural Health Care Relief” Bill. , The bill, ... credit to individuals and corporations which donate directly to a “rural hospital” in Georgia, ...
(Date:4/29/2016)... Torrance, CA (PRWEB) , ... April 29, 2016 ... ... physician advocating optimistic healthcare awareness and author of best seller "LOVE, MEDICINE and ... Talk Radio Monday, May 2, 2016 and podcasted thereafter . Dr. Bernie ...
(Date:4/29/2016)... (PRWEB) , ... April 29, 2016 , ... Conditions were ... at Cove Island Park on Sunday, with sunny skies, a light breeze and temperatures ... nearly $33,000. , The 5k Run and Walk and 1-mile walk were ...
(Date:4/29/2016)... ... April 29, 2016 , ... A ... born with severe congenital diaphragmatic hernia have better survival rates if surgery is ... hernia (CDH)—a condition where the diaphragm fails to form completely, letting abdominal organs ...
Breaking Medicine News(10 mins):
(Date:4/27/2016)... , April 27, 2016 Shire plc ... Jeff Poulton , Chief Financial Officer, will present at the ... Boston, MA on Wednesday, May 04, 2016, 10:00 ... will be available on the Presentations and Webcasts section of ... of the webcast will be available on this same website ...
(Date:4/27/2016)... 27, 2016 Oasmia Pharmaceutical ... of a new generation of drugs within human ... results for Paclical/Apealea in the Phase III study ... epithelial ovarian cancer. These preliminary results showed non-inferiority ... with carboplatin versus Taxol in combination with carboplatin. ...
(Date:4/27/2016)... , April 27, 2016 ... reach USD 2.06 billion by 2022, according to ... Increasing consumer awareness towards a healthy lifestyle is ... seven years.      (Logo: http://photos.prnewswire.com/prnh/20150105/723757 ... coupled with rising health treatment expenditure has urged ...
Breaking Medicine Technology: