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

March 13, 2014, Dana-Farber Cancer Institute

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 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 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 .

One of five patients with 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 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 out there with extraordinary responses to a variety of anticancer therapies, and it will be of great scientific and clinical value to study them."

Explore further: Common genetic alteration found in head and neck cancers may not be key to effective treatment

Related Stories

Common genetic alteration found in head and neck cancers may not be key to effective treatment

January 29, 2013
Although a large majority of head and neck cancers have a deregulation of the PI3K/AKT/mTOR pathway, data recently published in Cancer Research, a journal of the American Association for Cancer Research, indicated that deregulation ...

The immune system's redesigned role in fighting cancerous tumors

March 12, 2014
Researchers in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute eradicated solid tumors in laboratory mice using a novel combination of two targeted agents. These two synergistic therapies stimulate an immune ...

Recurrent but rare mutations might underlie cancer growth

February 26, 2014
A potential new gene mutation that might drive lung cancer development and growth has been identified by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard ...

Patients with aberrations in two genes respond better to drugs blocking a well-known cancer pathway

November 7, 2012
Cancer patients with mutations or variations in two genes -– PIK3CA and PTEN -– who have failed to respond to several, standard treatments, respond significantly better to anti-cancer drugs that inhibit these genes' pathways ...

Breast cancer treatment halts bone metastases and also protects bones

March 12, 2013
A team of researchers at the MedUni Vienna, led by Michael Gnant from the University Department of Surgery at the MedUni Vienna, has discovered two further positive effects of the drug Everolimus, which is already being used ...

Recommended for you

Stem cell vaccine immunizes lab mice against multiple cancers

February 15, 2018
Stanford University researchers report that injecting mice with inactivated induced pluripotent stem cells (iPSCs) launched a strong immune response against breast, lung, and skin cancers. The vaccine also prevented relapses ...

Induced pluripotent stem cells could serve as cancer vaccine, researchers say

February 15, 2018
Induced pluripotent stem cells, or iPS cells, are a keystone of regenerative medicine. Outside the body, they can be coaxed to become many different types of cells and tissues that can help repair damage due to trauma or ...

Team paves the way to the use of immunotherapy to treat aggressive colon tumors

February 15, 2018
In a short space of time, immunotherapy against cancer cells has become a powerful approach to treat cancers such as melanoma and lung cancer. However, to date, most colon tumours appeared to be unresponsive to this kind ...

Can our genes help predict how women respond to ovarian cancer treatment?

February 15, 2018
Research has identified gene variants that play a significant role in how women with ovarian cancer process chemotherapy.

First comparison of common breast cancer tests finds varied accuracy of predictions

February 15, 2018
Commercially-available prognostic breast cancer tests show significant variation in their abilities to predict disease recurrence, according to a study led by Queen Mary University of London of nearly 800 postmenopausal women.

Catching up to brain cancer: Researchers develop accurate model of how aggressive cancer cells move and spread

February 15, 2018
A brief chat at a Faculty Senate meeting put two University of Delaware researchers onto an idea that could be of great value to cancer researchers.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.