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5 days ago · Mayo researchers studying 'promising' new approach to treating advanced cancer, 1 patient at a time, 1 tumor at a time

George Vasmatzis, Ph.D., stands in a Mayo Clinic laboratory dedicated to the Ex Vivo study, which tailors the most effective drug, or drug combination, to each individual cancer tumor.

A collaborative team of Mayo Clinic scientists is studying an innovative strategy for treating advanced cancer, using genomics and human tumor samples as their guide. The novel approach, called Ex Vivo, creates a miniature cancer replica for testing therapies outside a patient’s body, combined with a comprehensive genomic analysis of a patient’s cancer cells.

“We are now at the cusp of understanding cancer at the individual level, the molecular complexity level, says George Vasmatzis, Ph.D., study leader and co-director of Mayo Clinic’s Biomarker Discovery Program within the Center for Individualized Medicine.

Dr. Vasmatzis says Ex Vivo ultimately tailors the most effective drug, or drug combination, to each individual cancer tumor. He envisions the study leading to a transformation in how patients with cancer are diagnosed and treated.

“We were blind and now we can see,” Dr. Vasmatzis says, “because if you can understand cancer, you can manage it.”

Reshaping precision medicine

More than 1.8 million people in the U.S. were diagnosed with cancer in 2019, according to the American Cancer Society, and an estimated 610,000 deaths were attributed to the disease. A majority of the cancer deaths were the result of metastases, when clusters of cancer cells circulate and spread to vital organs.

Panos Anastasiadis, Ph.D., studies cell-to-cell adhesion and cell interactions in cancer tumors at a Mayo Clinic laboratory. 

The Ex Vivo strategy centers on finding treatment options where none have existed, by knowing the full story of each tumor and recognizing every patient’s cancer as a unique disease of mutated cells.

A former electrical engineer who has dedicated his career to unlocking the mysteries of cancer, Dr. Vasmatzis says cancer can no longer be viewed as one disease, or even a dozen diseases.

“Because even within the same tumor, different cells can have different genetic changes,” he explains. “Cancer cells evolve and multiply, and when cancer becomes advanced it loses the connection of where it started from — the lung, breast, brain — and it becomes more individual. It is why drugs that are fully effective in some patients provide little or no response in others.” 

 

Ex Vivo in action

The Ex Vivo process starts with taking a small biopsy of a patient’s cancer tumor and dissecting the genetic details at high resolution to find out where the cancer is going and what it is doing. Dr. Vasmatzis says peeling away the many layers of complex information takes a team of highly specialized medical experts in oncology, pathology, biology, genetics and more.

“Our team is carefully constructed to run like an engine, and this is where it happens,” he says, walking through the laboratory, where clinicians and scientists are peering into microscopes, running high-tech machines and studying whole genome images on large computer screens.

“We are now at the cusp of understanding cancer at the individual level, the molecular complexity level.” – George Vasmatzis, Ph.D.

George Vasmatzis, Ph.D. (left) and Sotiris Sotiriou, M.D., look at images of DNA and RNA extracted from tumor cells, at a Mayo Clinic laboratory.

“For example, a very sophisticated tissue acquisition team is extremely important in making sure we are extracting the right cell types,” he explains. “We need molecular biology expertise to get billions of bits of data out of the cells and amplify that information for sequencing. Then, you need analytics people and mathematicians to be able to interpret and develop algorithms.”

Dr. Vasmatzis says, many times, the entire lab is focused on just one patient’s cancer.

“One person at a time, one tumor at a time,” he says.

Replicating cancer tumors

After uncovering the cancer’s genomic roadmap, the second part of the study begins with testing existing FDA-approved drugs on the cancer cells.

Overseeing the microcancer portion of the study and co-leading the project is Panos Anastasiadis, Ph.D., a cancer biologist and chair of the Mayo Clinic Department of Cancer Biology, with expertise in cell-to-cell adhesion and cell interactions in cancer tumors. 

Dr. Vasmatzis says early results of the first 100 Ex Vivo tests are “promising.”

“Ex Vivo enables us to stay ahead of the cancer instead of behind it,” he says. “This is the way forward for individualized medicine.” 

Dr. Anastasiadis and his team use a second piece of a patient’s tumor to create 3-D miniature cancer replicas.

Image of DNA

“We separate all the cells that formed that tumor,” he explains. “So whatever that tumor was, now it is individual cells.”

Then, small numbers of cells are divided into liquid droplets, where the cells regroup, he describes.

“The cells that were originally part of the tumor structure were adhering to each other,” he explains. “And they adhere to each other again in the 3-D cultures.”

Dr. Anastasiadis says the cells form miniature versions of the tumor that was originally inside the patient’s body.

“Only now it is outside of the patient’s body and we can test drugs on it,” he says. “And we’re looking for the drugs and drug combinations that target the genomic alterations in each patient’s individual tumor, and that will kill most, or all of the cells,” he explains. 

Each miniature cancer model can screen dozens of drug candidates, including combinations not tried before, as well as immunotherapies and viral therapies.

“Using advanced genomics, we usually identify quite a few, maybe 10 to 20 potential targets for treatment,” he says. “Microcancer screening identifies the most effective therapy outside the body. Our theory is that when we treat the patient with this therapy, we will also have a strong response to treatment.”

“Ex Vivo enables us to stay ahead of the cancer instead of behind it. This is the way forward for individualized medicine.”  – Panos Anastasiadis, Ph.D.

Strength in numbers

Dr. Anastasiadis emphasizes the strength of Ex Vivo is in doing both parts: the genomics and the miniature cancers. He says doing just one or the other only paints a portion of the picture.

“Through genomics, we know only certain mutations or amplifications, which we call ‘driver genes’ or ‘driver mutations,’” he says. “Knowing just the genomics is inconclusive. You need both.”

He points to the “HER2 protein” in breast cancer as a good example. Patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer, accounting for one in five breast cancer cases, are treated with HER2-targeted therapy, but it is not always effective.

“We don’t know why just 70% of patients respond to the HER2-targeted therapy while 30% do not,” he says.  “Complicating things, in most cases you have more than one potential driver, but you don’t know where to target therapy”.

Dr. Anastasiadis says that by testing a drug on the tumor before testing it in the patient can clear these uncertainties. He says Ex Vivo seeks to eliminate the trial and error of patients being exposed to drugs that are often toxic and provide no benefit.

“Ex Vivo is the paradigm we need. There are very few metastatic or advanced cancers for which available therapies provide meaningful longevity.” – Minetta Liu, M.D.

Minetta Liu, M.D.

From innovation to patient care

After the completion of each Ex Vivo test, researchers and clinicians gather for a comprehensive review, including Minetta Liu, M.D., a Mayo Clinic medical oncologist and research chair for the Department of Oncology. 

“Ex Vivo is the paradigm we need,” says Dr. Liu, whose clinical focus is on breast oncology.

Dr. Liu emphasizes the study is not designed to treat patients yet, but when it does translate to clinical care at Mayo Clinic, she believes it could be life-changing.

“There are very few metastatic or advanced cancers for which available therapies provide meaningful longevity,” Dr. Liu says. “Precision drug selection is clearly needed. This will be accomplished through genomics and functional modeling to gauge which therapies will work best for an individual at that particular point in their disease course.”

The Ex Vivo team plans to continue the study for one- to two more years before bringing the procedure to the clinic.

“What I’m hoping is that as we gain knowledge, we will start seeing patterns that will work,” Dr. Vasmatzis says. “We have a lot of work to do to take the next step, but we are all passionate in bringing this to our patients in the near future.”

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Dec 30, 2019 · In Florida, a powerhouse of cancer research

By Sara Nick

The Mayo Clinic Cancer Center, which spans Mayo Clinic’s Arizona, Florida and Minnesota locations, has 10 distinct research programs funded by the National Cancer Institute that are centered on broad areas such as immunology and gene therapy, or specific tumor types such as brain and gastrointestinal. Each research topic is treated with a multidisciplinary approach that ties together science, clinical relevance and prevention — a depth and breadth that lends itself to discovery and patient application.

Researchers with Mayo Clinic’s Center for Individualized Medicine are working to develop and test a new strategy to improve cancer care. In one initiative, scientists take a sample from a patient’s tumor, subject it to a number of high-tech analyses, and convene a multidisciplinary team to identify which existing therapies are most likely to work in each case. Then their suggestions are tested in the laboratory using miniature 3D cultures of the patient’s original tumor. If a cancer treatment is found to be effective there, then it could be used to help the individual. 

“Not only is this a testament to what’s possible for individualized medicine, it’s a way for cancer researchers to work closely with clinicians to help patients,” says Dr. Anastasiadis. 

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Dec 11, 2019 · In a first, researchers sequence single bacterial cells, paving path for rapid sepsis test

Mayo Clinic senior research fellow Yuguang Liu, Ph.D., looks into the microfluidic platform she developed for sequencing genomic contents of single bacterial cells.

For the first time, Mayo Clinic researchers are sequencing the genomic contents of single bacterial cells. The technique may pave the way for a potential lifesaving test for sepsis, a serious and sometimes deadly condition caused by the body’s response to an infection. Rather than waiting for days to identify the source of a patient’s infection, the new test could provide an answer in hours and help pinpoint an effective therapy.

“When you’re dealing with bacteria, it only takes a few resistant cells to give a patient a bad outcome,” says Marina Walther-Antonio, Ph.D., associate consultant in the department of Surgery, and assistant professor in the Mayo Clinic Center for Individualized Medicine Microbiome Program, with a joint appointment in the department of Obstetrics and Gynecology.

“In principle, the research will enable the identification of pathogens within a few hours, buying precious time in what is often a life threatening battle,” Dr. Walther-Antonio says.

Mayo Clinic researchers, Yuguang Liu, Ph.D. (left) and Marina Walther-Antonio Ph.D. (right), look at bacterial cells.

Rocketed
to space

Mayo Clinic’s vast achievement of extracting DNA and RNA from single bacterial cells started as a study on the International Space Station as part of a large multidisciplinary team effort designated as BIOMEX (Biology and Mars Experiment), where three types of tiny microorganisms spent almost two years in orbit. Once back on Earth, Dr. Walther-Antonio, an astrobiologist who worked with NASA Astrobiology Institute during her training, set out to investigate whether the cells had mutated in order to survive in space, away from Earth’s protection. She believed the study would play a key role in understanding how to treat diseases in humans. 

The
only thing missing was the tool needed to retrieve the genomic details that
were locked tightly inside the cells. 

Dr.
Walther-Antonio turned to Mayo Clinic senior research fellow Yuguang Liu,
Ph.D., an electrical engineer from Shanghai, China, who received her Ph.D. in
biological applications at the University of Cincinnati.

“Dr. Liu is one of the only engineers in the world with this kind of expertise,” Dr. Walther-Antonio says. 

Dr.
Liu, an expert in microfluidic platforms, recalls when she eagerly accepted the
challenge.

“I
knew it had never been done before, but I came here to identify problems that
needed to be solved,” she says.

Yuguang Liu, Ph.D. connects a microfluidic platform to a machine to isolate and sequence single bacterial cells.

Bacterial cells, found in every habitat on Earth, are generally smaller than a pinhead, with a thick protective outer wall to enable survival in harsh environments, such as the human gut, bloodstream, soil and waters in extreme temperatures or under high radiation. Some bacterial cells help plants absorb nitrogen, others assist with human digestion. Many cause diseases. All can divide and multiply exponentially, with mutations occurring throughout the process. 

A
unique tool

“Genomic
sequencing has been done in human cells, but there is tremendous difficulty to
do it in bacterial cells because they are very hard to break down without
damaging the minute amount of DNA inside with methods compatible with
downstream processing,” Dr. Liu explains.

Against
great odds and in just months, Dr. Liu accomplished the unprecedented task by
formulating a chemical-based “cocktail” to help break down the strong cell wall
while keeping its fragile ingredients intact. She also made a special
microfluidic platform — a credit card-sized piece of plastic with short,
pin-like plastic spikes and raised lines that form a grid design for controlling
and manipulating fluids. The chip contains nano-sized chambers for
compartmentalizing single bacterial cells. 

“This
tool can take the bacterial single cells and extract the DNA and RNA and
amplify them and sequence them to see exactly what they are and what they are
doing,” Dr. Liu explains, as she connects the chip to a machine with dozens of
clear thin tubes that distribute gas pressure to operate the chip for isolating
the cells and DNA/RNA amplification.

“We
are now able to look at the genome to understand what drugs they are resistant
to,” Dr. Liu explains.

Yuguang Liu, Ph.D., looks at single bacterial cells through a microscope.

Dr.
Walther-Antonio says she was amazed with how quickly Dr. Liu accomplished the task.

“She came to me with the results and said, ‘I think it kind of worked,’” Dr. Walther-Antonio recalls. “And I said, ‘Did you try it again?’ And she said, ‘Yes, 10 times.’”

Rapid
sepsis diagnosis

Dr.
Walther-Antonio says her team is now able to expand the technique to develop a
real-time test for sepsis, which is often hard to diagnose and difficult to
determine the most effective antibiotics to use on a patient. Without rapid
treatment, sepsis can lead to septic shock, organ failure and death. In 2018,
nearly 270,000 people in the U.S. died as a result of sepsis, according to the
Centers for Disease Control. 

“The
standard of care for sepsis currently involves culturing a patient’s blood
sample and that always takes at least a couple of days,” she says. “In the
meantime, you’re given a cocktail of antibiotics to try to save your life, and
those who survive suffer lifelong side effects.”

Dr.
Walther-Antonio envisions an automated process for identifying bacterial
pathogens in sepsis within a few hours for time sensitive intervention, with an
overall goal of saving lives.

Yuguang Liu holds up a microfluidic platform she designed for separating bacterial cells from human cells .

At
the heart of the project, called “Answers in Hours,” is another microfluidic
platform made by Dr. Liu — this one will separate human cells from bacterial
cells.

“In a
blood sample, there are very low amounts of bacteria,” Dr. Liu says. “Most are
human cells, which overwhelmingly hide the bacterial cells. So in this
platform, we have a measure to remove the human component so we are only
detecting the bacteria.”

Dr. Walther-Antonio says knowing the genomic makeup of a tiny single bacterial cell opens the door to a world of discoveries, such as detecting the recurrence of pathogens early, and for basic science to understand what promotes the emergence of resistant strains.

She says research of patient sample testing is estimated to start in 2020, with plans to eventually incorporate the test into a clinical setting if success is reached.

The project was originally conceptualized by Heidi Nelson, M.D., and is also led by Nicholas Chia, Ph.D., Bernard and Edith Waterman co-director for the Mayo Clinic Center for Individualized Medicine Microbiome Program, and Robin Patel, M.D., chair of the Division of Clinical Microbiology and director of the Infectious Diseases Research Laboratory.

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Sep 19, 2019 · One Discovery Square provides a hub for innovation, state-of-the-art labs, top researchers

One Discovery Square combines innovative Mayo Clinic labs with medical businesses and creative start-up companies in the heart of downtown Rochester, MN. 

Researchers, physicians and staff with the Advanced Diagnostics Laboratory, a joint collaboration between the Mayo Clinic Department of Laboratory Medicine and Pathology and the Center for Individualized Medicine, will take part in a community celebration of One Discovery Square on Sept. 19 from 4-6 p.m.

The grand
opening event, held in conjunction with the Destination Medical Center’s annual
meeting, is open to the public and features interactive displays, tenant
activity booths, music, food, games and self-guided tours. The
90,000-square-foot, four-story bioscience building is located at 201-299 4th
Street SW in the heart of downtown Rochester
.

Keith Stewart, M.B., Ch. B.

“By putting some of the world’s top medical researchers and
state-of-the-art laboratories under one roof, we now have an extraordinary
opportunity to accelerate discoveries of life-saving therapies and test
development in individualized medicine for patients with complex diseases,
including cancers,” says Keith
Stewart, M.B., Ch.B.
, Carlson and Nelson Endowed Director of Mayo Clinic
Center for Individualized Medicine.

Dr. Stewart
says the Advanced Diagnostic Laboratory will initially support 14 projects in
areas of disruptive technology, such as multi-omics, artificial intelligence
and digital pathology, bringing together current and new testing platforms with
multidisciplinary staff.

“The
collaboration represents a new era in transforming human health through
individualized medicine,” says Dr. Stewart. “Researchers will be encouraged to
innovate with a goal of accelerating the development and launch of new products
and services.”

In addition,
the Advanced Diagnostic Laboratory will collaborate with companies, both inside
and outside of One Discovery Square, to increase laboratory testing
capabilities at Mayo Clinic and to provide alternate revenue sources through
business partnerships.

One Discovery Square will also be home to two other Mayo Clinic departments: Biomedical Technology and Advanced Manufacturing of Regenerative Products. The building is part of a planned 16-block sub-district designed to be a hub for science and research.

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to read more stories like this one?

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