Rogue breast tumor proteins point to potential drug therapies

If DNA can be described as the body’s genetic blueprint, proteins can be thought of as the construction workers who carry out the plan. Studying the blueprint can be vital to understanding genetic diseases, including cancer, but that focus also means that some problems arising with the workers may be missed. Studying mice with breast … Continue reading “Rogue breast tumor proteins point to potential drug therapies”

If DNA can be described as the body’s genetic blueprint, proteins can be thought of as the construction workers who carry out the plan. Studying the blueprint can be vital to understanding genetic diseases, including cancer, but that focus also means that some problems arising with the workers may be missed.

Studying mice with breast tumors transplanted from patients, researchers at Washington University School of Medicine in St. Louis, The Broad Institute of MIT and Harvard, and Baylor College of Medicine have analyzed the proteins present in these tumors. The researchers demonstrated that some protein alterations can be used to identify drugs that may work against some cancers. The work is part of the National Cancer Institute’s (NCI) Clinical Proteomic Tumor Analysis Consortium efforts.

The study is published March 28 in Nature Communications.

“Proteins carry out most of the biological functions in the cell,” said senior author Li Ding, PhD, an associate professor of medicine at Washington University. “Knowing the DNA sequence does not automatically tell us everything about the proteins doing work in the cells. This is another layer of tumor complexity that we need to explore to identify new therapies.”

Ding said recent advances in a technology called mass spectrometry and in techniques to analyze massive quantities of data have made complex studies of the proteins in tumor cells possible. Another reason to prioritize the systematic study of proteins in tumors — cancer proteomics — is that the vast majority of cancer therapies developed from genetic studies actually target proteins.

“Identifying the rogue proteins of cancer is an important pathway toward developing new drugs,” said co-author R. Reid Townsend, MD, PhD, a professor of medicine and director of the Proteomics Shared Resource at Washington University.

“We can use proteomics to confirm and validate our genomics findings,” said Ding, also an assistant director of The McDonnell Genome Institute at Washington University School of Medicine. “In addition, it’s another tool to uncover additional events that drive cancer and are specific to individual patient tumors, including the amount of the ‘rogue’ protein, its specific form, or the type and extent of chemical modifications of the proteins that we know are treatable with approved or investigational drugs. We also can test these therapies in the mice before we evaluate them in patients.”

Steven A. Carr, PhD, of the Broad Institute, said the team analyzed a chemical modification called phosphorylation, which plays a central role in how healthy, as well as diseased, cells communicate.

“Disruption or enhancement in such signaling is often directly related to disease mechanism and can be targeted for therapy,” Carr said.

The researchers studied 24 tumor samples from breast cancer patients after the samples were transplanted into mice. Twenty-two of the transplanted samples retained their genetic and proteomic identities as specific types of breast cancer. A proteomic analysis of the tumors also identified multiple protein targets that have the potential to respond to drugs.

For example, the researchers showed dialed-up activity of multiple protein pathways that could be targeted with investigational drugs called PI3K inhibitors and mTOR inhibitors, separately and in combination, depending on the tumor. They also showed that drugs against a type of breast tumor called HER2 positive breast cancer — such as the dual ERBB2/EGFR inhibitor lapatinib — potentially could benefit more patients than currently receive them, if analysis of the tumor proteins is taken into consideration.

While most of these tumor models recapitulated specific types of breast cancer, Ding said the scientists were surprised to see that two of the 24 tumors evolved into a completely different type of cancer after transplantation into the mice. Instead of breast cancer, they resembled lymphoma and were driven by the cancer-causing virus Epstein-Barr, according to the researchers. Lymphomas are cancers of immune cells that may have arisen from lymphatic tissue present in the breast tumors transplanted into the mice.

The analysis of the lymphoma-like cancers was the first proteomic study of this type of tumor. Though unintentional, Ding said the analysis provides an explanation for why investigational drugs that inhibit a protein called BTK have been effective in treating patients with lymphoma.

“Since it is the proteins that interact directly with drugs, the strength of studying proteomics in patient-derived tumor models is the ability to test drug treatment in the mice,” Ding said. “With advances in cancer proteomics that increase the speed of measurement, we are moving toward a future that includes genomic and proteomic analyses of patient tumors.”

Co-author Matthew J. Ellis, MD, PhD, of Baylor, agreed. “The mouse work is promising enough to adapt these technologies for real time analysis of patient materials so that clinical trials can be designed to test this new diagnostic and drug selection approach,” he said.

Interaction among proteins that cause cancer cells to metastasize

“In our paper, we identify a direct interaction between focal adhesion kinase and myosin that drives the production of secreted cancer-promoting proteins,” says Alexander Meves, M.D., a dermatologist at Mayo Clinic.

Dr. Meves says cancer cells use these secreted proteins to create stiff, insoluble scaffolds that inhibit anti-tumor immunity and support tumor growth and metastasis. Metastasis is a life-threatening condition in which cancer cells break away from the site where they formed to other areas of the body.

“Cancer cells are very responsive to their environment and try to adapt and fit in,” explains Dr. Meves. “Focal adhesion kinase provides these cells with input about their environment, specifically the rigidity or elasticity of the environment.”

Dr. Meves says myosin acts like a motor that transfers focal adhesion kinase from the cell membrane to its nucleus. He says once focal adhesion kinase and myosin interact, focal adhesion kinase is shuttled to the cell nucleus to help the cell adapt to its environment through gene transcription.

“Our hope is that, based on the structural data presented in our paper, it may be possible to develop drugs that inhibit cancer progression by blocking the interaction of focal adhesion kinase with other proteins,” says Dr. Meves.

This study was a result of a Mayo Clinic’s team based, patient-centered research that brings together renowned physicians, researchers and scientists to develop or provide the latest technologies and treatments to address unmet patient needs.

Prostate screening often occurs without discussion of benefits, risks

“That only about a third of patients reported having a discussion of advantages and disadvantages is an alarming statistic,” said study lead author Dr. George Turini III, clinical instructor in medical science at the Warren Alpert Medical School of Brown University and a urologist with the Southcoast Physician Group.

Co-author Dr. Joseph Renzulli, associate professor of surgery and a urologist at the Minimally Invasive Urology Institute at Miriam Hospital, added, “The concept of ‘shared decision making’ for prostate cancer screening is not occurring in the community.”

For example, in 2014 out of a sample of 111,241 men who responded to the national Behavioral Risk Factor Surveillance System survey, 29.5 percent reported discussing both advantages and disadvantages, 33.9 percent discussed neither, 35.7 percent reported discussing only advantages of PSA, and 0.8 percent reported discussing only disadvantages. In data from 2012, before the task force made its recommendation against the test, out of 105,812 men who responded to the survey, 30.1 percent discussed both, 30.5 percent discussed neither, 38.5 percent discussed only advantages, and 0.8 percent discussed only disadvantages.

Meanwhile, 63.0 percent of the men in 2012 had PSA tests, as did 62.4 percent of the men in 2014, according to the study published online in the journal Urology. In each year thousands of men had the test without having a discussion of how it could either benefit them, for instance via early detection of cancer, or lead to unnecessary adversity, such as a side effects from biopsy or unneeded treatment. They either got no information or only one side of the story.

In addition, the researchers found, men who have low incomes, did not finish high school, lack insurance, or are Hispanic were significantly less likely than men overall to report hearing about the pros and cons of screening via the PSA test, the study found.

“The most vulnerable men are getting less counseling,” said co-author Annie Gjelsvik, assistant professor of epidemiology in the Brown University School of Public Health.

A controversial topic

The PSA test reveals blood levels of a protein naturally secreted by the prostate. Levels could become elevated for a number of reasons including the normal enlargement of the prostate as men age, Turini said. But cancer could also elevate them.

When the task force in 2012 discouraged PSA testing, Turini said, it was because there are risks to what follows from screening. If cancer is suspected, it can only be confirmed with a biopsy and that could cause problems such as infection, bleeding or discomfort.

Beyond those concerns, if prostate cancer is confirmed, the risks inherent in treatment options such as surgery, radiation or hormonal alteration, can be “truly life altering,” he said.

“In some cases, a low volume of less aggressive prostate cancer may not necessitate treatment, but even in those cases where a ‘treatment’ is not performed in favor of active surveillance, the emotional distress of a cancer diagnosis shouldn’t be underestimated,” Turini said.

But whenever a cancer does present a threat to health, there are also clear advantages to catching it early. Therefore many urologists still believe that doctors and their patients should weigh these pros and cons of screening. For that reason, the authors wrote, the American Urologic Association and the American Cancer Society advocate thorough discussion and decision-making between doctors and patients.

The study authors sought to understand the state of those discussions and how the task force recommendation may have changed them. Gjelsvik noted that it’s important to measure and track the full spectrum of effects of public health actions, such as the new national recommendations.

The findings could be explained by factors independent of the U.S. Preventive Services Task Force recommendation, the authors acknowledged, but they concluded the paper with this concern: “We believe our findings may be indicative of a shift in practice patterns away from detailed pre-screening discussions among health care providers who have implemented the [USPSTF] recommendation into their care giving. Long-term evaluation of this trend is necessary, particularly to ensure that men who are given an order for a PSA test receive the absolutely necessary counseling required to allow them to appreciate the important consequences associated with the decision to pursue screening.”

Amid all the findings of concern, including the overall trend and disparities of income, education, insurance and ethnicity, the researchers did find one bright spot: Black men, who are known to be at higher risk for prostate cancer incidence and death, were more likely to report having discussed advantages and disadvantages than men on average.

Turini said the study suggests that urologists may be able to do more to help their primary care physician colleagues have balanced and informative conversations with their patients. Primary care physicians are increasingly pressed for time with each patient and it can seem easy to order an additional test if blood is going to be drawn for other purposes anyway, Turini said. But the moment when a PSA test comes back with an elevated reading is not the ideal moment to only begin the conversation of what that could mean.

“It’s our job in the urology community to make it as easy as possible for the primary care physicians and other general practitioners to comfortably disseminate as complete and balanced information as possible,” he said.