Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Targeted drug leads to regression of metastatic melanoma with mutated BRAF gene

26.08.2010
Use of an experimental targeted drug to treat metastatic melanoma tumors with a specific genetic signature was successful in more than 80 percent of patients in a phase 1 clinical trial. Results of the trial of PLX4032, an inhibitor of a protein called BRAF that is overactive in more than half of all melanomas, appear in the August 26 New England Journal of Medicine.

"Metastatic melanoma has a devastating prognosis and is one of the top causes of cancer death in young patients," says Keith Flaherty, MD, director of Developmental Therapeutics at the Massachusetts General Hospital (MGH) Cancer Center, lead and corresponding author of the NEJM article. "Until now, available therapies were few and unreliable, so these findings can really change the outlook for patients whose tumors are fueled by this mutation."

Although surgical removal is usually successful in treating early-stage melanoma, once the skin tumor has spread to other sites in the body, the outlook has been grim. The two FDA-approved drugs – interleukin-2 and dacarbazine – produce a response in only 10 to 20 percent of patients. The current prognosis for survival in metastatic melanoma is 9 months or less, with 9,000 people dying in the U.S. each year.

The role in melanoma of the BRAF mutation – which keeps the protein constantly activated and driving cell growth – was discovered in 2002 by researchers at the Sanger Institute in Britain. Flaherty – who was then at the University of Pennsylvania Abramson Cancer Center – began to explore whether drugs targeting the mutation might interfere with tumor growth. After one potential drug was not effective, he began working in collaboration with Paul Chapman, MD, of Memorial Sloan-Kettering Cancer Center in New York to study PLX4032, an agent developed by Plexxikon and licensed to Roche Pharmaceuticals. Initial trial results were disappointing, but a new formulation that increased the bioavailability of PLX4032 proved to have rapid results that are being reported in the NEJM paper.

The initial stage of the study – led by Flaherty, Chapman and colleagues at six sites in the U.S. and Australia – was designed to establish the effective dose. It enrolled 55 cancer patients, most with metastatic melanoma, who received escalating doses of PLX4032 until unacceptable side effects occurred. BRAF mutations were present in the melanomas of 16 participants in the latter part of this stage, and in 11 of those patients, tumors quickly shrank or, in one instance, disappeared. Three participants with BRAF-mutated thyroid cancers also had their tumors shrink or stabilize in response to PLX4032 treatment.

The second stage enrolled 32 patients with BRAF-mutated melanoma who received the PLX4032 dosage established in the first phase: 960 mg twice a day. In 26 of those participants, tumors shrank more than 30 percent, meeting the criteria for clinical response, and completely disappeared in two. Since another two participants had some reduction in the size of their tumors, Flaherty projects that PLX4032 appears to shrink tumors in approximately 90 percent of patients with BRAF-mutated melanomas.

"One of the things that make these results truly remarkable is that this drug works so reliably," he explains. "And patients who have been experiencing symptoms like pain and fatigue begin to feel better within a week of starting treatment, giving them a much better quality of life.

As seen in trials of other targeted cancer treatments, resistance to PLX4032 developed in the tumors of many participants, leading to resumed tumor growth. Currently tumor suppression has been maintained from about three months to longer than two years, with an average progression-free survival of eight months, and follow-up studies are exploring how resistance occurs and potential strategies to get around it. Two additional MGH-based clinical trials are now underway – a phase 2 study in patients unsuccessfully treated with the FDA-approved drugs, enrollment for which is complete, and a larger phase 3 study that compares PLX4032 with dacarbazine in newly diagnosed patients.

"Until now, we've never had a credible first treatment option for metastatic melanoma, so this has completely transformed how we approach treatment for patients with the BRAF mutation," says Flaherty, who is a member of the Harvard Medical School faculty. "Although we don't know how long response may last, the ability to beat this disease down in the short term will buy us time to strategize second-line therapies and design the next generation of trials."

Along with senior author Paul Chapman, MD, Memorial Sloan-Kettering Cancer Center, co-authors of the NEJM article are Igor Puzanov, MD, and Jeffrey Sosman, PhD, Vanderbilt University; Kevin Kim, MD, M.D. Anderson Cancer Center; Antoni Ribas, MD, University of California at Los Angeles; Grant McArthur, MB, BS, PhD, Peter MacCallum Cancer Centre, East Melbourne, Australia; Peter O'Dwyer, MD, University of Pennsylvania Abramson Cancer Center; Richard Lee, MD, PhD, and Joseph Grippo, Roche Pharmaceuticals, and Keith Nolop, MD, Plexxikon. The study was funded by Plexxikon and Roche.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

Katie Marquedant | EurekAlert!
Further information:
http://www.mgh.harvard.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>