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 Zinc Deficiency Linked to Activation of Hedgehog Signaling Pathway
20.04.2015 | Rensselaer Polytechnic Institute (RPI)

nachricht UV light robot to clean hospital rooms could help stop spread of 'superbugs'
15.04.2015 | Texas A&M University

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: On the trail of a trace gas

Max Planck researcher Buhalqem Mamtimin determines how much nitrogen oxide is released into the atmosphere from agriculturally used oases.

In order to make statements about current and future air pollution, scientists use models which simulate the Earth’s atmosphere. A lot of information such as...

Im Focus: Advances in Molecular Electronics: Lights On – Molecule On

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and the University of Konstanz are working on storing and processing information on the level of single molecules to create the smallest possible components that will combine autonomously to form a circuit. As recently reported in the academic journal Advanced Science, the researchers can switch on the current flow through a single molecule for the first time with the help of light.

Dr. Artur Erbe, physicist at the HZDR, is convinced that in the future molecular electronics will open the door for novel and increasingly smaller – while also...

Im Focus: Pruning of Blood Vessels: Cells Can Fuse With Themselves

Cells of the vascular system of vertebrates can fuse with themselves. This process, which occurs when a blood vessel is no longer necessary and pruned, has now been described on the cellular level by Prof. Markus Affolter from the Biozentrum of the University of Basel. The findings of this study have been published in the journal “PLoS Biology”.

The vascular system is the supply network of the human organism and delivers oxygen and nutrients to the last corners of the body. So far, research on the...

Im Focus: Astronomers reveal supermassive black hole's intense magnetic field

Astronomers from Chalmers University of Technology have used the giant telescope Alma to reveal an extremely powerful magnetic field very close to a supermassive black hole in a distant galaxy

Astronomers from Chalmers University of Technology have used the giant telescope Alma to reveal an extremely powerful magnetic field very close to a...

Im Focus: A “pin ball machine” for atoms and photons

A team of physicists from MPQ, Caltech, and ICFO proposes the combination of nano-photonics with ultracold atoms for simulating quantum many-body systems and creating new states of matter.

Ultracold atoms in the so-called optical lattices, that are generated by crosswise superposition of laser beams, have been proven to be one of the most...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

HHL's Entrepreneurship Conference on FinTech

13.04.2015 | Event News

World Conference On Regenerative Medicine 2015: Registration And Abstract Submission Now Open

25.03.2015 | Event News

University presidents from all over the world meet in Hamburg

19.03.2015 | Event News

 
Latest News

Better battery imaging paves way for renewable energy future

21.04.2015 | Materials Sciences

Extending climate predictability beyond El Niño

21.04.2015 | Earth Sciences

Risk Perception: Social Exchange Can Amplify Subjective Fears

21.04.2015 | Studies and Analyses

VideoLinks
B2B-VideoLinks
More VideoLinks >>>