Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Genomic testing links 'exceptional' drug response to rare mutations in bladder cancer

13.03.2014

A patient with advanced bladder cancer in a phase I trial had a complete response for 14 months to a combination of the targeted drugs everolimus and pazopanib, report scientists led by a Dana-Farber Cancer Institute researcher, and genomic profiling of his tumor revealed two alterations that may have led to this exceptional response.

This information can help identify cancer patients who may respond to everolimus, according to the report published in Cancer Discovery, a journal of the American Association for Cancer Research.

"Studying exceptional responders can help us understand the specific reasons why some tumors are highly sensitive to certain anticancer agents," said Nikhil Wagle, M.D., of Dana-Farber Cancer Institute, the report's first author. "We can use that information to identify patients whose tumors have genetic alterations similar to those found in exceptional responders, and treat them with those same agents."

Exceptional responders are rare cancer patients whose cancers are extremely sensitive to drugs and who have long-lasting responses to therapy.

"We conducted a phase I clinical trial to test the efficacy of two anticancer agents—the mTOR inhibitor everolimus, and pazopanib, another drug that are approved for treatment of kidney cancers and sarcomas —and one of our patients developed near complete remission of his bladder cancer which lasted for 14 months," said Wagle, who is also an Associate Member of the Broad Institute of MIT and Harvard. A complete response to a drug is when all signs of a tumor disappear.

"We performed whole-exome sequencing of the patient's tumor, and to our surprise, we identified two mutations in the gene mTOR, which is the target for everolimus," said Wagle. The protein made by this gene plays a role in many cell functions, and has been found to be mutated in a number of cancers. MTOR inhibitors such everolimus have been approved for treatment of some cancers, including breast and kidney.

In this phase I trial, the investigators recruited nine patients with advanced solid tumors, including five with bladder cancer, whose diseases had progressed despite treatment with standard therapies. Patients received one to 13 cycles of everolimus and pazopanib.

One of five patients with bladder cancer had a complete response, as evaluated by imaging, which lasted for 14 months. To understand why his tumor responded dramatically, the investigators performed complete sequencing of the coding regions of his tumor genome, which included about 25,000 genes, and identified two mutations in mTOR.

The two mutations, mTOR E2419K and mTOR E2014K, had never been identified in humans, according to Wagle, although one of the mutations had previously been well studied by scientists in yeast and in human cell lines.

Wagle and colleagues conducted further laboratory studies to understand the nature of the two mutations, and found that they activated the mTOR-mediated cell signaling pathway, leading to sustained cancer cell proliferation. These mutations likely rendered the patient's cancer dependent on the mTOR pathway to survive, which is the likely reason the cancer became exquisitely sensitive to the mTOR inhibitor everolimus, explained Wagle.

"Results of our study suggest that we should make a catalogue of activating genome alterations in the mTOR pathway," said Wagle. "Patients with tumors that harbor these alterations might be particularly suitable for treatment with drugs like everolimus and other mTOR inhibitors.

"This is yet another example of how therapies targeted toward the genetic features of a tumor can be highly effective, and our goal moving forward is to be able to identify as many of these genetic features as possible and have as many drugs that target these genetic features as possible, so we can match the drugs to the patients," said Wagle. "There are many more patients out there with extraordinary responses to a variety of anticancer therapies, and it will be of great scientific and clinical value to study them."

###

Senior authors of the report are Levi Garraway, MD, PhD, of Dana-Farber and Senior Associate Member at the Broad, and Jonathan Rosenberg, MD, of Memorial Sloan-Kettering Cancer Center. Rosenberg was at Dana-Farber when the project began.

The research was funded by the Next Generation Fund at the Broad Institute of MIT and Harvard, the National Human Genome Research Institute, GlaxoSmithKline, and Novartis. Wagle is an equity holder and a consultant to Foundation Medicine.

About Dana-Farber Cancer Institute

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center, designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Boston Children's Hospital as Dana-Farber/Boston Children's Cancer and Blood Disorders Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Facebook: http://www.facebook.com/danafarbercancerinstitute and on Twitter: @danafarber.

Teresa Herbert | EurekAlert!

Further reports about: Cancer Dana-Farber Harvard alterations anticancer drugs identify mTOR mutations pathway sensitive tumors

More articles from Health and Medicine:

nachricht An ounce of prevention: Research advances on 'scourge' of transplant wards
28.08.2015 | University of Wisconsin-Madison

nachricht Hypoallergenic parks: Coming soon?
27.08.2015 | American Society of Agronomy

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: OU astrophysicist and collaborators find supermassive black holes in quasar nearest Earth

A University of Oklahoma astrophysicist and his Chinese collaborator have found two supermassive black holes in Markarian 231, the nearest quasar to Earth, using observations from NASA's Hubble Space Telescope.

The discovery of two supermassive black holes--one larger one and a second, smaller one--are evidence of a binary black hole and suggests that supermassive...

Im Focus: What would a tsunami in the Mediterranean look like?

A team of European researchers have developed a model to simulate the impact of tsunamis generated by earthquakes and applied it to the Eastern Mediterranean. The results show how tsunami waves could hit and inundate coastal areas in southern Italy and Greece. The study is published today (27 August) in Ocean Science, an open access journal of the European Geosciences Union (EGU).

Though not as frequent as in the Pacific and Indian oceans, tsunamis also occur in the Mediterranean, mainly due to earthquakes generated when the African...

Im Focus: Self-healing landscape: landslides after earthquake

In mountainous regions earthquakes often cause strong landslides, which can be exacerbated by heavy rain. However, after an initial increase, the frequency of these mass wasting events, often enormous and dangerous, declines, in fact independently of meteorological events and aftershocks.

These new findings are presented by a German-Franco-Japanese team of geoscientists in the current issue of the journal Geology, under the lead of the GFZ...

Im Focus: FIC Proteins Send Bacteria Into Hibernation

Bacteria do not cease to amaze us with their survival strategies. A research team from the University of Basel's Biozentrum has now discovered how bacteria enter a sleep mode using a so-called FIC toxin. In the current issue of “Cell Reports”, the scientists describe the mechanism of action and also explain why their discovery provides new insights into the evolution of pathogens.

For many poisons there are antidotes which neutralize their toxic effect. Toxin-antitoxin systems in bacteria work in a similar manner: As long as a cell...

Im Focus: Fraunhofer IPA develops prototype of intelligent care cart

It comes when called, bringing care utensils with it and recording how they are used: Fraunhofer IPA is developing an intelligent care cart that provides care staff with physical and informational support in their day-to-day work. The scientists at Fraunhofer IPA have now completed a first prototype. In doing so, they are continuing in their efforts to improve working conditions in the care sector and are developing solutions designed to address the challenges of demographic change.

Technical assistance systems can improve the difficult working conditions in residential nursing homes and hospitals by helping the staff in their work and...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Networking conference in Heidelberg for outstanding mathematicians and computer scientists

20.08.2015 | Event News

Scientists meet in Münster for the world’s largest Chitin und Chitosan Conference

20.08.2015 | Event News

Large agribusiness management strategies

19.08.2015 | Event News

 
Latest News

Interstellar seeds could create oases of life

28.08.2015 | Physics and Astronomy

An ounce of prevention: Research advances on 'scourge' of transplant wards

28.08.2015 | Health and Medicine

Fish Oil-Diet Benefits May be Mediated by Gut Microbes

28.08.2015 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>