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 Discovery points to a new path toward a universal flu vaccine
03.07.2015 | Rockefeller University

nachricht "CCS Telehealth Ostsachsen", Germany's largest telemedicine project, goes online in Dresden
02.07.2015 | Universitätsklinikum Carl Gustav Carus Dresden

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: Viaducts with wind turbines, the new renewable energy source

Wind turbines could be installed under some of the biggest bridges on the road network to produce electricity. So it is confirmed by calculations carried out by a European researchers team, that have taken a viaduct in the Canary Islands as a reference. This concept could be applied in heavily built-up territories or natural areas with new constructions limitations.

The Juncal Viaduct, in Gran Canaria, has served as a reference for Spanish and British researchers to verify that the wind blowing between the pillars on this...

Im Focus: X-rays and electrons join forces to map catalytic reactions in real-time

New technique combines electron microscopy and synchrotron X-rays to track chemical reactions under real operating conditions

A new technique pioneered at the U.S. Department of Energy's Brookhaven National Laboratory reveals atomic-scale changes during catalytic reactions in real...

Im Focus: Iron: A biological element?

Think of an object made of iron: An I-beam, a car frame, a nail. Now imagine that half of the iron in that object owes its existence to bacteria living two and a half billion years ago.

Think of an object made of iron: An I-beam, a car frame, a nail. Now imagine that half of the iron in that object owes its existence to bacteria living two and...

Im Focus: Thousands of Droplets for Diagnostics

Researchers develop new method enabling DNA molecules to be counted in just 30 minutes

A team of scientists including PhD student Friedrich Schuler from the Laboratory of MEMS Applications at the Department of Microsystems Engineering (IMTEK) of...

Im Focus: Bionic eye clinical trial results show long-term safety, efficacy vision-restoring implant

Patients using Argus II experienced significant improvement in visual function and quality of life

The three-year clinical trial results of the retinal implant popularly known as the "bionic eye," have proven the long-term efficacy, safety and reliability of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

World Conference on Regenerative Medicine in Leipzig: Last chance to submit abstracts until 2 July

25.06.2015 | Event News

World Conference on Regenerative Medicine: Abstract Submission has been extended to 24 June

16.06.2015 | Event News

MUSE hosting Europe’s largest science communication conference

11.06.2015 | Event News

 
Latest News

Siemens receives order for offshore wind power plant in Great Britain

03.07.2015 | Press release

'Déjà vu all over again:' Research shows 'mulch fungus' causes turfgrass disease

03.07.2015 | Agricultural and Forestry Science

Discovery points to a new path toward a universal flu vaccine

03.07.2015 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>