Advancing the Science

Mayo Clinic Medical Science Blog

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Thu, Jul 27 8:00am · Meet the Investigator: Kristin R. Swanson, Ph.D.

At the Mayo Clinic Cancer Center, hundreds of researchers dedicate their professional lives to reducing the burden of cancer. Each one has a unique story. In this video, Kristin R. Swanson, Ph.D., a brain cancer researcher at Mayo Clinic’s campus in Phoenix, Arizona, discusses her research.

This article originally appeared in Forefront, Mayo Clinic Cancer Center’s research magazine.

Tue, Jul 18 8:00am · Check Out the Latest Issue of Forefront Magazine

Forefront is the complimentary magazine of the Mayo Clinic Cancer Center. Published in print and online magazine editions annually and in email and online newsletter editions quarterly, Forefront highlights Mayo Clinic’s cutting-edge cancer research and the latest Cancer Center news.

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Tue, May 2 8:00am · Meet the researcher - Alex Adjei, M.D., Ph.D.: The Power of Hope

There’s a reason Mayo Clinic oncologist Alex A. Adjei, M.D., Ph.D., spends so much time in the lab testing molecular solutions to cancer — it gives his patients hope.

When Dr. Adjei started as a lung cancer specialist about 20 years ago, patients with the disease had a dismal prognosis. There was basically one treatment option, and if that didn’t work — and it usually didn’t — there was little else he could do.

“When I started in ’95, of my first 20 lung cancer patients, nobody had any tumor shrinkage,” Dr. Adjei recalls. “All they did was lose hair and lose weight. None lived a year. It was so depressing. But now I have patients with metastatic lung cancer who I’ve been taking care of since 2009 and 2010. Now the vast majority of metastatic lung cancer patients are living 2 years or more.”

Dr. Adjei recently returned to Mayo Clinic (after starting his career here, he spent 9 years at Roswell Park Cancer Institute in Buffalo) to develop even better options for people with cancer. In his new role he’ll help lead the Mayo Clinic Cancer Center’s Early Therapeutics Program.

The program involves first-in-human trials testing new cutting-edge treatments for patients with a variety of cancers for whom no life-prolonging treatments exist. This is a critical step in the development of all new promising treatments for cancer. As medical director of this program, Dr. Adjei will help build an enterprise-wide cohesive program, making these promising treatments available to all Mayo patients with all type of cancers across its centers in Minnesota, Florida and Arizona.
Dr. Adjei says this kind of work gives patients hope, which changes the way they face their disease.

“You may not always change how long they will live with the disease,” he says. “But it’s amazing how people react when they are told we can try something. People feel better that they aren’t just waiting to die, but they are trying something, they are fighting. I strive to not mislead a patient but also not to take away hope. I don’t want to take away hope completely because people don’t do well in that situation.”

And he’s just as hopeful. He talks about one patient who came to him with stage IV lung cancer in 2000. He enrolled her in a clinical trial testing a new drug. The drug failed the trial and was never approved. But for her, and only her, it worked. She’s still alive today.

“That kind of situation is certainly not common,” Dr. Adjei says. “And going in, we know the chances of survival may be really, really small. But they aren’t zero. And that gives patients, and me, hope.”

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This article, part of the “Meet the Researcher” series, originally appeared in Forefront, Mayo Clinic Cancer Center’s magazine.

Investigate some of Mayo Clinic’s available clinical trials online.

Tue, Apr 18 9:30am · Attack the Gap--New Immunotherapy May Help the Body Fight Ovarian Cancer

It was only when Kathi Schroeder took to the bone-chilling streets of Cedar Rapids, Iowa, on her bike last January that she noticed something was not right.

“I was having trouble breathing; just taking a deep breath was difficult,” she remembers.

Kathi went to her local doctor’s office and was prescribed a round of antibiotics and steroids to address what the doctor considered a respiratory issue.

“I felt better for a little while — but then by March, I just bloated up and was having increasing difficulty breathing,” she says. “It was terrible. I just thought, something is horribly wrong.”

As the symptoms progressed, Kathi’s concern grew, and on March 18, 2015, she went in for a chest X-ray. Her doctor took one look at the X-ray and sent her directly to the emergency room for a CT scan and additional X-rays.

The news was not what she was expecting. “Right there in the emergency room, they told me, ‘We think you might have ovarian cancer.’ “

A week later Kathi arrived at Mayo Clinic in Rochester, Minnesota, in search of answers. A series of biopsies on the fluid around her lungs confirmed her worst fears. “To be hit at that point with ‘You have stage IV cancer,’ you have to stop and say, ‘Where do I go from here?’“

Attacking the Cancer

Kathi had a general idea of the statistics. Even if she beat the cancer in the first round, upward of 80 percent of women with her diagnosis will have a recurrence of, and ultimately die of, the cancer. A main reason why is because, most of the time, ovarian cancer only presents after it has spread within the abdominal cavity. And since it is constantly bathed in abdominal fluid, the cancer tends to break off and spread before the tumor grows in size.

Unfortunately, the only approved treatments are surgery and chemotherapy.

Oncologist Matthew S. Block, M.D., Ph.D., co-principal investigator of the clinical trial Kathi is participating in.

“The standard options against ovarian cancer are maxed out,” explains Mayo Clinic oncologist Matthew S. Block, M.D., Ph.D. “We have drugs that work and surgery works, but they don’t work perfectly. They are reasonably effective when there’s a known tumor, but they’re not effective to continue throughout the remission. Unfortunately, the majority of my ovarian cancer patients still die of their cancer.”

Kathi didn’t want to accept that finality.

First of Its Kind

One of the trickiest aspects of cancer is its ability to outwit the body’s immune system. For instance, T cells are on the forefront of the immune system. It’s their job to recognize invasive cells and kill them. They do this by detecting proteins — cells with familiar proteins are left alone; cells with foreign proteins are destroyed. But as cancer cells grow, they devise ways to kill the T cells or trick them into leaving the cancer cells alone.

“The idea behind cancer vaccines is to present the tumor to the immune system in such a way that the immune system attacks it as if it were a virus or bacteria,” Dr. Block says. “Essentially, we need to tell the immune system that this is a threat, and we need to attack it.”

To help patients harness the power of their immune systems, Dr. Block and colleagues launched a clinical trial. The phase I trial targets a specific protein, folate receptor alpha, in the cancer cells. It also uses a specific type of T cell, Th17, to trigger an immune response. These T cells not only attack the tumor cells but regulate other T cells that suppress the immune system’s response.

The trial is the first of its kind. “There are plenty of other ovarian cancer vaccines, but to my knowledge, this is the first time something has that goal of attacking T-reg cells via Th17 cells,” Dr. Block says.

When Kathi heard about the study, she knew she wanted to participate. Fortunately, she met the criteria — have stage III or IV cancer, be in remission, and have completed both surgery and chemotherapy.

“I’m always like, This is the next step, this is the next step,” she says. “That’s just my nature. This study has helped a lot because it feels like I’m doing something. It just makes you feel very powerful. I want it to work not only for me but also for other women that are out there in this situation.”

Back on the Bike

Kathi arrives at Mayo Clinic every three weeks for a series of shots and to be tested for recurrence. After the first three months, she will reach the maintenance phase — only coming in every three months for two years. “This is so easy. You get a few little shots, and you’re free to go. It’s just a wonderful study.”

And so far so good.

Kathi is back to riding her bike and is training for RAGBRAI — a nearly 500-mile, seven-day bike ride across Iowa.

“You wonder, how much of my life can I cram into the next year, two years,” she says. “The people that live past five years are what, maybe 20 percent? Where do you go with that when you have a family? You look to your bucket list and say, ‘Let’s just plan it and do it.’

“There’s not a day that goes by that I don’t think about it. I try to keep a positive attitude. I mean, in this case, it feels like I’m doing something — but you still have to live day to day. You can’t just stop living. This study is helping me with that.”

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Read about Mayo Clinic’s work to develop a TH17-inducing dendritic cell vaccine for ovarian cancer.

This article originally appeared in the late 2016 print edition of Forefront, Mayo Clinic Cancer Center’s magazine. Read the whole issue online (pdf).

 

Tue, Apr 11 8:00am · Mayo Clinic researchers use zebrafish to identify potential treatment for pediatric cancer

zebrafish pictureUsing a novel zebrafish model, Mayo Clinic researchers have identified a molecule called GAB2 that is highly represented in the malignant cells of many patients with neuroblastoma. Neuroblastoma is a cancer that develops from immature neural cells found in several areas of the body.

The researchers believe that overexpression of GAB2 signals the activation of a protein called SHP2 that drives and maintains neuroblastoma.

“Neuroblastoma is one of the most common solid tumors in infants,” says Shizhen (Jane) Zhu, Ph.D., who led the research team. Dr. Zhu says the disease accounts for 10 to 13 percent of all childhood cancer deaths.

Shizhen (Jane) Zhu, M.D., Ph.D., Mayo Clinic Cancer Center researcher

“Once neuroblastoma spreads beyond its original site in children older than 18 months, it is considered “high risk” and generally does not respond well to conventional treatments, including high-dose chemotherapy,” says Dr. Zhu.

Dr. Zhu says that unlike researchers’ experience with other cancer types, efforts to identify molecules that could be developed into drugs to treat high-risk neuroblastoma have not been completely successful. The main reason is that this type of cancer has very few molecular abnormalities that are be suitable targets for drug therapy.

Using zebrafish, Dr. Zhu and her colleagues were able to show that GAB2-SHP2 hyperactivity increases the chances another gene, called MYCN can trigger a cancer.

“Overall, our observations validate the important role of GAB2 plays in regulating the generation of high-risk human neuroblastoma,” Dr. Zhu says.

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Dr. Zhu’s research was reported in the journal Cell Reports in March 2017. This research is part of ongoing research initiatives within Mayo Clinic Cancer Center, and informs the Pediatric Hematology and Oncology practice.

Tue, Feb 28 8:00am · More women eligible for Herceptin, benefit uncertain

Updated guidelines underscore need to identify the most optimal candidates for HER2-directed therapy.

Changes to HER2 testing guidelines for breast cancer in 2013 significantly increased the number of patients who test positive for HER2 breast cancer, Mayo Clinic researchers have found.

The researchers published their HER2 breast cancer study results online July 25, 2016, in the Journal of Clinical Oncology.

Cancers that have an excess of HER2 protein or extra copies of the HER2 gene are called HER2 positive and can be treated with drugs such as Herceptin that target the HER2 protein. HER2-positive cancers tend to be more aggressive and spread more quickly than do other breast cancers.

Mayo Clinic researchers found that the number of HER2-positive breast cancers doubled after the American Society of Clinical Oncology and the College of American Pathologists jointly changed testing guidelines in 2013.

Photograph of Robert B. Jenkins, M.D., Ph.D.

Robert B. Jenkins, M.D., Ph.D.

“The new guidelines were established to reduce the number of equivocal cases, where HER2 status is uncertain. But we found that they did just the opposite,” said senior study author Robert B. Jenkins, M.D., Ph.D., a professor of laboratory medicine and pathology at Mayo Clinic in Rochester, Minnesota, and the Ting Tsung and Wei Fong Chao Professor of Individualized Medicine Research. “The number of equivocal cases went up, resulting in additional testing and a much larger number of women with cancers ultimately labeled as HER2 positive.”

There will be more than 246,000 new cases of invasive breast cancer diagnosed in the U.S. in 2016, along with 61,000 new cases of noninvasive breast cancer, the American Cancer Society estimates. All newly diagnosed breast cancers are tested for human epidermal growth factor receptor 2 (HER2), a molecule that promotes the growth of cancer cells.

Dr. Jenkins said the development of drugs such as trastuzumab (Herceptin) and lapatinib (Tykerb), which target HER2, have greatly improved the prognosis for patients with HER2-positive breast cancer.

But it’s still not clear what level of HER2 is needed in cancer cells for these targeted therapies to be effective. Therefore, he said, it’s critical that clinicians accurately determine the HER2 status of a particular cancer.

HER2 testing is performed using two methods: immunohistochemistry, which detects how much of the HER2 protein is present on cancer cells, and fluorescence in situ hybridization (FISH), which measures how many copies of the HER2 gene are inside each cell.

The Food and Drug Administration (FDA) approved the first HER2 testing guidelines for determining eligibility for HER2-directed therapy for breast cancer in 1998. The American Society of Clinical Oncology and the College of American Pathologists published a new set of guidelines in 2007 (called AC2007), which was updated in 2013 (AC2013). The latest guidelines changed the cutoff for equivocal and positive cases.

Dr. Jenkins and his colleagues hypothesized that the new criteria outlined in AC2013 would lead to an increase in the number of breast cancers that test HER2 positive.

They analyzed FISH results for 2,851 breast cancer cases referred to Mayo Clinic for FISH testing between November 2013 and October 2014, and then compared the prevalence of HER2 FISH amplification using the three guidelines.

In their analysis, the researchers found a near doubling in the proportion of HER2 FISH-positive cases interpreted using AC2013 (23.6 percent), compared to the FDA criteria (13.1 percent) and AC2007 (11 percent). Mayo Clinic researchers previously reported a 13 percent HER2-positivity rate using the FDA criteria in their clinical practice in 2000, and that rate had remained constant until the implementation of AC2013.

Since the implementation of AC2013, an additional 10 to 15 percent of women with breast cancer are considered eligible for HER2-directed therapies, even though it’s not known if they would benefit from the addition of HER2-directed treatments.

“Women who receive false-positive results are not only exposed to the risks of HER2-directed therapies, but they also miss out on the treatments that could be effective against their cancer. That is counter to the goal of personalized medicine, which is to give the right drug to the right patient at the right time,” Dr. Jenkins said. “Given the medical, financial and psychosocial aspects of these targeted therapies, it is prudent that we prospectively identify the most optimal candidates for treatment.”

Dr. Jenkins said that the recent National Surgical Adjuvant Breast and Bowel Project B-47 trial could provide insight into whether the additional patients labeled as HER2 positive by AC2013 actually will benefit from HER2-directed therapies.

Ultimately, he said, the decision to use such targeted therapies should be made only after carefully considering the risks and benefits by patients and their physicians, as well as any additional information that can be gleaned from other HER2 test results, including immunohistochemistry.

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This article was originally published in Forefront, the online magazine of Mayo Clinic Cancer Center.

Thu, Feb 16 8:00am · Drug combo safe for diffuse large B-cell lymphoma

 

Drugs targeting the P13K-mTOR pathway add benefit when combined with standard R-CHOP therapy.

 

The drug everolimus can be safely combined with R-CHOP for new, untreated diffuse large B-cell lymphoma, according to the results of a pilot study by Mayo Clinic researchers.

The researchers published their study findings in the July 2016 issue of The Lancet Haematology.

R-CHOP is a combination of drugs used to treat lymphoma that includes rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.

Photograph of Patrick B. Johnston, M.D., Ph.D.

Patrick B. Johnston, M.D., Ph.D.

“There is an unmet need to develop new therapies based on R-CHOP to try to increase the cure rate for diffuse large B-cell lymphoma,” said Patrick B. Johnston, M.D., Ph.D., a hematologist at Mayo Clinic in Rochester, Minnesota, and lead author of the published study. “This pilot study suggests that adding mTOR inhibitors to standard therapy could improve outcomes, though it needs to be validated in a larger clinical trial.”

 

The combination of everolimus and R-CHOP was well-tolerated by patients, with no dose-limiting toxicity reached within the planned dose escalation. The vast majority of patients (96 percent) achieved an overall response, and all responders achieved a complete metabolic response to the treatment.

The findings indicate that drugs targeting the P13K-mTOR pathway — a cascade of molecules involved in cell growth and survival — add benefit when combined with standard R-CHOP therapy, the researchers said.

Lymphoma is the sixth most common cancer in the U.S., and diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma.

The standard accepted treatment for diffuse large B-cell lymphoma is R-CHOP delivered in a 21-day cycle for six cycles. However, this regimen typically cures only about 60 percent of patients.

Dr. Johnston and his colleagues scoured the scientific literature in search of ways to improve the cure rate. They found that two lines of evidence pointed toward targeting the P13K-mTOR pathway.

First, numerous studies have demonstrated the importance of this pathway in the pathogenesis of diffuse large B-cell lymphoma cells in the laboratory.

Second, clinical studies have documented the single-agent efficacy of everolimus (an mTOR inhibitor) in relapsed DLBCL.

Mayo Clinic researchers therefore decided to test a regimen that combined the standard R-CHOP with everolimus.

The researchers conducted a phase 1 feasibility study in 24 patients with new, previously untreated diffuse large B-cell lymphoma with the Alliance for Clinical Trials in Oncology, a National Cancer Institute cooperative group.

Patients received everolimus for 14 days in combination with R-CHOP-21. A large proportion of patients achieved an overall response (96 percent) and a complete metabolic response as assessed by positron emission tomography imaging (96 percent).

No relapses with diffuse large B-cell lymphoma occurred, and all patients achieved the predicted milestone of being event-free at 12 months from enrollment. The treatment was well-tolerated. The most common adverse events were hematologic in nature, such as grade 4 neutropenia (75 percent) and grade 3 febrile neutropenia (21 percent).

“This study is the first to integrate a P13K-mTOR agent with standard R-CHOP,” Dr. Johnston said. “The encouraging outcome results and toxicity profile of this new regimen, along with the worldwide availability of everolimus, make it potentially applicable to the large population of DLBCL patients.”

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This article was first published in Forefront, the online magazine from Mayo Clinic Cancer Center. This research project is from within the Hematologic Malignancies Program—one of 10 special-focused cancer research programs in the center.

Sun, Feb 5 8:00am · Researchers identify unique breast microbiome

A team of Mayo Clinic researchers has identified evidence of bacteria in breast tissue and found differences between women with and without breast cancer.

These research findings were published in the August 3, 2016, issue of Scientific Reports.

Photograph of Tina J. Hieken, M.D.

Tina J. Hieken, M.D.

“Our research found that breast tissue samples obtained in the operating room under sterile conditions contain bacterial DNA, even when there is no sign of infection,” said Tina J. Hieken, M.D., a breast surgical oncologist at Mayo Clinic in Rochester, Minnesota. “Furthermore, we identified significant differences in the breast tissue microbiome of women with cancer versus women without cancer and the presence of a distinct breast tissue microbiome, and that it is different than the microbiome of the overlying breast skin.”

A microbiome is a collection of micro-organisms and viruses that live in a specific environment in the human body.

Breast cancer accounts for nearly one-quarter of all cancers globally and is the leading cause of cancer death among women. While there are established risk factors for breast cancer, at least 70 percent of breast cancer cases occur in women of average risk, and current prediction models are poor at identifying risk of cancer for individual women, Dr. Hieken said.

Photograph of Amy C. Degnim, M.D.

Amy C. Degnim, M.D.

“Differences in the microbiome have been implicated in cancer development at a variety of body sites, including the stomach, colon, liver, lung and skin,” said co-investigator Amy C. Degnim, M.D., a breast surgical oncologist at Mayo Clinic in Rochester.

Nicholas Chia, Ph.D.

“There is mounting evidence that changes in the breast microbiome may be implicated in cancer development and the aggressiveness of cancer, and that eliminating dangerous micro-organisms or restoring normal microbiota may reverse this process,” said Nicholas Chia, Ph.D., a microbiome researcher at Mayo Clinic in Rochester.

It remains unclear whether small shifts in microbial communities, the presence of a virulent pathogenic strain or the absence of a beneficial one might be responsible for promoting the development of cancer in the breast microbiome, Dr. Hieken said. However, findings from this study will spur further research to identify potential causes of breast cancer development and new microbial-based prevention therapies.

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This article was first published in Forefront, the online magazine from Mayo Clinic Cancer Center.

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