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Deepak Nagrath’s Lab Highlighted in Rogel Cancer Center’s “Illuminate” Magazine

The latest issue of the U-M Rogel Cancer Center’s “Illuminate” magazine highlights the work of Deepak Nagrath, Professor, Biomedical Engineering. The publication examines how his lab studies the way the tumor microenvironment communicates with and fuels cancer cells.

“We’ve seen that the microenvironment can supply nutrients like amino acids to cancer cells,” Dr. Nagrath said. “We’ve also shown that the microenvironment supplies vesicles, which are loaded with that the cancer cells engulf to use for their own growth.”

Like the other members of the working group, Dr. Nagrath is hopeful that understanding metabolism in the lab will eventually lead to new treatment options, given that, as he describes, most conventional therapies have failed to meet the mark. “In some cancers, like pancreatic and ovarian, we’ve been using the same drugs for 40-50 years. There aren’t many new therapies,” he said. “And these have failed because cancer cells adapt and come up with ways to compensate.”

To accomplish advances, Nagrath says that a complete and dynamic understanding of the metabolic environment is necessary to truly starve the cancer and incapacitate its growth.

“That’s why the metabolic goal is systemic. It systematically starves cancer cells, so there’s no way for them to get around it,” he continued.

For metabolic treatments to have a clinical impact, Nagrath’s lab focuses on a two-pronged approach. Using patient genomic data in integrated machine learning, along with a state-of-the-art metabolic flux analysis framework, his lab has identified backup metabolic genes, or collateral genes, on which cancer cells rely for their growth. Dr. Nagrath’s lab is also developing a novel platform for predicting in vivo metabolic fluxes in patients, which will be a cornerstone for targeting therapy.

Tumor-destroying soundwaves receive FDA approval for liver treatment in humans

Technique developed at the University of Michigan provides a non-invasive alternative to surgery, chemotherapy and radiation treatments for cancer.

BY: JIM LYNCH

The U.S. Food and Drug Administration has approved the use of sound waves to break down tumors—a technique called histotripsy—in humans for liver treatment.

Pioneered at the University of Michigan, histotripsy offers a promising alternative to cancer treatments such as surgery, radiation and chemotherapy, which often have significant side effects. Today, Food and Drug Administration’s (FDA) officials awarded clearance to HistoSonics, a company co-founded in 2009 by U-M engineers and doctors for the use of histotripsy to destroy targeted liver tissue.

A human trial underway since 2021 at the U-M Rogel Cancer Center and other locations has treated patients with primary and metastatic liver tumors via histotripsy, demonstrating the technology’s ability to meet the testing’s primary effectiveness and safety targets.

“Histotripsy is an exciting new technology that, although it is in early stages of clinical use, may provide a non-invasive treatment option for patients with liver cancer. Hopefully it can be combined with systemic therapies for a synergistic therapeutic effect,” said Mishal Mendiratta-Lala, an assistant professor of radiology with Michigan Medicine and principal investigator on the trial at U-M.

HistoSonics can now market and sell its histotripsy delivery platform, called Edison, to hospitals and medical professionals for use in liver treatments. The company is headquartered in Minneapolis, while its advanced research and development is located in Ann Arbor.

A man stands at the device making adjustments while monitoring the computer screen nearby — Dr. Ryan Miller, Ph.D., Manager of Advanced Systems at HistoSonics, adjusts the transducer head on the Edison Platform as he observes a histotripsy treatment plan at HistoSonics in Ann Arbor. Photo: Erica Bass/Michigan Medicine

Histotripsy works by using targeted ultrasound waves to form microbubbles within the tumor. The forces created as those bubbles form and collapse cause the mass to break apart, killing tumor cells and leaving the debris to be cleaned up by the immune system.

What that could mean for patients is treatment without the physical toll of radiation or chemotherapy, fewer concerns with drug compatibility, far shorter recovery times than with surgery and less treatment discomfort.

A handle is submerged in a liquid adjusting the test material — Dr. Alex Duryea, Ph.D., Manager of Applied Research at HistoSonics, adjusts an ultrasound “phantom”—a gel mixed with red blood cells that serves as the test’s tumor—prior to performing a histotripsy treatment demonstration at HistoSonics. Photo: Erica Bass/Michigan Medicine

This is possible because it is much easier to ensure that histotripsy treatments are hitting the tumor, and not healthy tissue, compared to radiation or invasive procedures. Histotripsy relies on focusing acoustic waves of high energy ultrasound to concentrate the energy enough to form bubbles, and the Edison machine can make sure that region is confined to the tumor. In contrast, radiation affects everything in its path through the body.

In addition, the histotripsy system has onboard diagnostic ultrasound imaging, the kind used to see babies in the womb. It is used to plan and observe the treatment in real time. Physicians have a live view of the “bubble cloud” and how tissue is responding to the therapy.

And histotripsy’s potential benefits go beyond tumor destruction. In the last year, a pair of pre-clinical studies in rodents suggest that in the clean-up process, the immune system learns how to identify cancer cells as threats. This can enable the body to continue fighting the initial tumor and help activate a natural immune response to the cancer.

In the first study, even after destroying only 50% to 75% of the liver tumor volume by histotripsy, the rats’ immune systems were able to clear away the rest, with no evidence of recurrence or metastases in more than 80% of animals.

Earlier this year, a second study showed that histotripsy breaks down the cancer cell wall’s “cloak”—revealing proteins that the immune system can use to identify threats, known as antigens. These antigens are removed during surgery or destroyed during chemotherapy and radiation. By instead destroying a cancer cell’s outer wall, histotripsy lays bare the tumor antigens for the immune system to identify and use for targeted attacks on other cancer cells.

“We want to leverage histotripsy’s immuno stimulation effects and hopefully combine them with immunotherapy or drug delivery,” said Zhen Xu, a U-M professor of biomedical engineering, an inventor of the histotripsy approach and a co-founder of HistoSonics. “That will move histotripsy from a local therapy into one that can treat tumors globally all over the body and eventually into a cure. In terms of the cancer treatment, that will be the next step, and I feel very excited about the potential.”

Mendiratta-Lala, Xu and the University of Michigan have a financial interest in HistoSonics. The company was formed with support from U-M’s Coulter Translational Research Program and Innovation Partnerships, U-M’s hub for research commercialization.

BME Students Triumph in Michigan Business Challenge

BME medical product development graduate student Walker McHugh (MSE ’17) hopes the device he’s helping bring to market will transform treatment in the intensive care unit.

Called MicroKine, the microfluidic sensor enables doctors to determine quickly and from only a drop of a patient’s blood which cytokines are causing a hyperinflammatory state that can lead to organ failure.

After working on the product and the science behind it for more than a year in the lab of his advisor, Pediatric Critical Care Professor Timothy Cornell, MD, McHugh proposed using the MBC to explore the path to commercialization.

Cornell agreed, and McHugh teamed up with business student Caroline Landau (MBA '16) to form a company, PreDxion, based on an initial application for the device: monitoring cancer patients receiving chimeric antigen receptor T-cell (CAR-T) therapy. CAR-T uses a patient’s own immune cells which have been genetically engineered to recognize a specific protein on tumor cells. Once reintroduced into the body, these cells seek out and destroy the patient’s cancer.

Though this treatment has had promising results, a potential downside is that a patient’s immune system can overreact, producing a flood of inflammatory cytokines which can quickly lead to organ failure. MicroKine can determine in just 30 minutes which cytokines are out of the normal range, allowing doctors to prescribe the specific anti-cytokine medication that matches those elevated in the patient.

The technology has already achieved proof of concept. In late 2014, Cornell’s lab received an emergency use exemption from the FDA to use the device in a patient experiencing cytokine release syndrome in late 2014. The case was a success, and the team began envisioning a larger impact.

That’s what impelled McHugh to throw his hat into the MBC. He hoped to use its structure – the deadlines, the coaching from Zell Lurie, and partnership with a business student – to explore potential markets, walk through financial models, and flesh out a business plan.

Their work has paid off; the team won $30,000 in the MBC, which they will add to awards from The Coulter Foundation and U-M’s Michigan Translational Research and Commercialization for Life Sciences Program, to continue down the path to commercialization. One of the challenges, says McHugh, is that the product is in a new, niche area of the companion diagnostic space, so the FDA and potential drug-company partners need to assess how to approach it. Ultimately, PreDxion hopes it can structure a pharmaceutical-company partnership that could open the door to cooperative clinical trials and marketing efforts.

McHugh is hopeful that the technology will one day be a game-changer. “Things haven’t changed much over the last 25 years in terms of how we treat organ failure in the ICU,” he says. “We’re are still largely limited to supporting the failing organs. By targeting the inflammatory processes that are actually driving that dysfunction, we hope MicroKine will bring personalized medicine to the ICU.”
Other contributors to MicroKine include Professor Katsuo Kurabayashi and postdoc Pengyu Chen.

Taking fourth place in the MBC social impact category is a team from M-HEAL (Michigan Health Engineered for All Lives), the U-M student-run organization that brings biomedical engineering to global health work.

The team, which includes several BME undergraduates, used the competition to evaluate its plans to scale up work on a portable gynecological exam table for use by mobile health workers traveling to remote villages.

Evolution of Project MESA portable exam table prototypes: A (2011 original); B (2013 with stirrups), C (2014 with adjustable backrest), D (2016 with integrated backpack).

Called Project MESA, the team has been working with partner clinics and NGOs in Nicaragua since 2010 on iterative designs for the table. They hoped to use the MBC to test their assumptions about producing and distributing the table on a larger scale to make a bigger impact on healthcare delivery.

Project MESA’s business lead, Katherine Chen, says the coaching was invaluable in helping these mostly engineering students think more critically about issues such as customer preferences, pricing strategies, and business models. “Originally, we designed the product to be produced in the U.S. with the idea that it should be repairable with locally available materials,” she says. “But through customer discovery, we learned that most clinics don’t have the resources to do repairs, so we’ve decided to design the table to be more durable in the first place. In addition, we assumed that a distribution channel in Nicaragua would be hard to manage, but the MBC judges encouraged us to explore that option.”

With $1,200 in prize money from the MBC, the team returns to Nicaragua in May to, among other things, talk with local machinists and distributors; delve into how clinics make their purchasing decisions; assess potential market size; develop new partnerships; and solicit feedback on the newest iterations of the table, which better address durability, portability, aesthetics, and patient positioning.

Chen says the MBC is a great resource for BME design students. “Developing the business plan really helps you define your end goal and determine if it’s financially and logistically feasible,” she says. “It helps you gain an even stronger sense of direction for your design.”

Project MESA’s co-lead is BME student Erik Thomas; other members include: Maya Ben-Efraim, Val Coldren, Bansili Desai, Sabrina Deutsch, Samantha Fox, Hannah Heberle-Rose, Steven Houtschilt, Christina Khouri, Jaime Landsman, Lillian Lantis, Jennifer Lee, Siri Manam, Andrea Mathew, Keely Meyers, Kyle Morrison, Molly Munsell, Madhu Parigi, Monica Patel, Maddie Price, Bharathi Ramachandran, Jen Spiegel, Alejandra Vaquiro Valencia, Shreya Wadwhani, Eldy Zuniga.

Fighting Cancer with Microfluids

When fighting cancer, speed is of the utmost importance. A microfluidic chip developed by Michigan engineers has enabled a breakthrough in testing the efficacy of specialized cancer drugs. This means getting the right drug to the right patient in a fraction of the time. These chips could make a huge difference in how fast we can develop a new drug or nanodrug.

Until recently, a cancer drug lab screening could test ten variables in one day. A new microfluidic chip developed by Michigan engineers can now test one thousand different variable in one hour. This allows doctors to more quickly identify the best treatment for the individual patient based on their type of cancer and biology. These chips are especially useful for testing photodynamic cancer treatments in which drugs are only activated when exposed to light. This kind of hyper localized cancer treatment reduces the negative side effects of other options, like chemotherapy.

About the Professor

Euisik Yoon is a Professor in both the Electrical Engineering and Computer Science and Biomedical Engineering departments at the University of Michigan’s College of Engineering. Professor Yoon is also the director of the Solid-State Electronics Laboratory and the Lurie Nanofabrication Facility. His research focuses on MEMS, integrated microsystems, and VLSI circuit design.

Raoul Kopelman, Professor of Chemistry, Physics, Applied Physics, and the Biomedical Engineering departments at the University of Michigan. His research focuses on Autonomous Nano-Devices for Biomedical Applications

New technology could lead to tailor-made cancer treatments

By Gabe Cherry
Michigan Engineering

Tailor-made cancer treatments? New cell culture technique paves the way.

Electron microscopy shows cultured CTC cells (circled in red) growing on the chip device used in the study. Photo Credit: Jennifer Zhuo Zhang

In a development that could lead to a deeper understanding of cancer and better early-stage treatment of the disease, University of Michigan researchers have devised a reliable way to grow a certain type of cancer cells from patients outside the body for study. The new technique is more than three times as effective as previous methods.

Researchers say it’s a major step forward in the study of circulating tumor cells, which are shed from tumors and circulate through the blood of cancer patients. They’re believed to cause metastasis, the spread of cancer through the body that’s responsible for nearly 90 percent of cancer-related deaths.

The cells also hold valuable genetic information that could lead doctors to more informed treatment decisions and even tailor-made therapies for individual patients. And because the cells circulate in the blood, they can be gathered with a blood draw rather than a more invasive tissue biopsy. But progress has been slow, largely because the cells are rare in early-stage cancer patients.

The new capture and culture method changes this by providing a reliable way to get usable numbers of circulating tumor cells from even early-stage patients. It grew new cells from 73 percent of the patients in a recent study, more than three times the success rate of previous methods and a first for early-stage cancers. It’s a major game changer, according to Sunitha Nagrath, an assistant professor of chemical engineering who is working to develop the new technology.

“This culture method gives clinicians a way to study each patient’s cancer much earlier and much more frequently,” Nagrath said. “We can look for resistance to therapy and test potential therapeutics. It also moves us closer to being able to predict metastasis.”

The technique may also bring doctors closer to their goal of capturing cancer cells for diagnosis with a quick, non-invasive “blood biopsy” instead of the tissue biopsies that are currently used. This could enable them to keep closer tabs on each patient’s status and make more informed treatment decisions.

“We envision a point-of-care solution in four to five years,” said Nithya Ramnath, an associate professor of medical oncology at U-M. “You’d give blood and a short time later, doctors would have a whole repertoire of what’s going on with your tumor.”

The capture and culture process starts with a microfluidic chip device that captures cancer cells as a blood sample is pumped across it. The research team used a chip made of polydimethylsiloxane (PDMS) on a 1-inch by 3-inch glass slide. They covered the chip with microscopic posts that slow and trap cells, then coated it with antibodies that bind to the cancer cells.

After the cancer cells were captured on the chip, the team pumped in a mixture of collagen and Matrigel growth medium. They also added cancer-associated fibroblast cells that were grown in the lab of Diane Simeone, surgical director at the Multidisciplinary Pancreatic Cancer Clinic of the U-M Cancer Center. This created a three-dimensional environment that closely mimics the conditions inside the body of a patient.

The captured cancer cells prospered in the mixture, reproducing additional cells in 73 percent of tested samples. It was a dramatic improvement over earlier methods, which studied later-stage cancer patients and saw success rates of only around 20 percent.

“Primary cancer cells don’t grow well on a flat surface, and like people, they need neighbors to really prosper,” Nagrath said. “The collagen and Matrigel provide a three-dimensional environment for the cells to grow, while the cancer-associated fibroblasts give them the neighboring cells they need.”

The technology can be applied to most cancers, including breast, lung, pancreatic and others. It could enable doctors to follow the progression of each patient’s disease much more closely, says Max Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center, who is working to develop the technology.

“Cancer cells change constantly and they can quickly develop resistance to a given treatment,” Wicha said. “A device like this will enable us to follow the cancer’s progression in real time. If a cancer develops resistance to one therapy, we’ll be able to quickly change to a different treatment.”

The next step for the researchers is to fine-tune the design of the chip device, optimizing its ability to both capture cells and grow new ones. They also envision larger studies that test more treatments on cultured cells and examine the correlation between the ability to grow cancer cells from individual patients and those patients’ long-term outcomes.

A paper on the findings titled “Expansion of CTCs from early stage lung cancer patients using a micro-fluidic co-culture model” is published online in Oncotarget. It will appear in a forthcoming print edition. The research is conducted under the Translational Oncology Program, which brings together scientists from across U-M to translate research findings into potential new treatments for cancer. Funding is provided by the National Institutes of Health (NIH) Director’s New Innovator Award (1DP2OD006672-01).

Liquid biopsy could improve cancer diagnosis and treatment

By Kate McAlpine
Michigan Engineering

A microfluidic chip developed at the University of Michigan is among the best at capturing elusive circulating tumor cells from blood—and it can support the cells' growth for further analysis.

The device, believed to be the first to pair these functions, uses the advanced electronics material graphene oxide. In clinics, such a device could one day help doctors diagnose cancers, give more accurate prognoses and test treatment options on cultured cells without subjecting patients to traditional biopsies.

"If we can get these technologies to work, it will advance new cancer drugs and revolutionize the treatment of cancer patients," said Max Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center and co-author of a paper on the new device, published online this week in Nature Nanotechnology.

"Circulating tumor cells will play a significant role in the early diagnosis of cancer and to help us understand if treatments are working in our cancer patients by serving as a 'liquid' biopsy to assess treatment responses in real time," said co-author Diane Simeone, M.D., the Lazar J. Greenfield Professor of Surgery at the U-M Medical School and director of the Translational Oncology Program.

"Studies of circulating tumor cells will also help us understand the basic biologic mechanisms by which cancer cells metastasize or spread to distant organs—the major cause of death in cancer patients."

Yet these cells aren't living up to their promise in medicine because they are so difficult to separate from a blood sample, the researchers say. In the blood of early-stage cancer patients, they account for less than one in every billion cells, so catching them is tougher than finding the proverbial needle in a haystack.

"I can burn the haystack or use a huge magnet," said Sunitha Nagrath, an assistant professor of chemical engineering, who led the research. "When it comes to circulating tumor cells, they almost look like—feel like—any other blood cell."

On their microfluidic chip, Nagrath's team grew dense forests of molecular chains, each equipped with an antibody to grab onto cancer cells.

Even after the cells are caught, it's still hard to run a robust analysis on just a handful of them, the researchers say. That's why this demonstration of highly sensitive tumor cell capture, combined with the ability to grow the cells in the same device, is so promising.

Hyeun Joong Yoon, a postdoctoral researcher in the Nagrath lab with a background in electrical engineering, was instrumental in making the microfluidic chip. He started with a silicon base and added a grid of nearly 60,000 flat gold shapes, like four-petaled flowers, each no wider than a strand of hair.

The gold flowers naturally attracted a relatively new material called graphene oxide. These sheets of carbon and oxygen, just a few atoms thick, layered themselves over the gold. This layered formation allowed the team to grow the tumor-cell-catching molecular chains so densely.

"It's almost like each graphene has many nano-arms to capture cells," Nagrath said.

To test the device, the team ran one-milliliter samples of blood through the chip's thin chamber. Even when they had added just three-to-five cancer cells to the 5-10 billion blood cells, the chip was able to capture all of the cells in the sample half the time, with an average of 73 percent over 10 trials.

"That's the highest anybody has shown in the literature for spiking such a low number of cells," Nagrath said.

The team counted the captured cancer cells by tagging them with fluorescent molecules and viewing them through a microscope. These tags made the cancer cells easy to distinguish from accidentally caught blood cells. They also grew breast cancer cells over six days, using an electron microscope to see how they spread across the gold flowers.

"When you have individual cells, the amount of material in each cell is often so small that it's hard to develop molecular assays," Wicha said. "This device allows the cells to be grown into larger quantities so you can do a genetic analysis more easily."

The chip could capture pancreatic, breast and lung cancer cells from patient samples. Nagrath was surprised that the device was able to catch about four tumor cells per milliliter of blood from the lung cancer patients, even though they had the early-stage form of the disease.

Working in a team that comprises both engineers and medical professionals at U-M, Nagrath is optimistic that the new technique could reach clinics in three years.

The paper is titled "Sensitive capture of circulating tumor cells by functionalized graphene oxide nanosheets." The university is pursuing patent protection for the intellectual property and is seeking commercialization partners to help bring the technology to market.

This research is supported by the National Institutes of Health Director's New Innovator Award No. 1DP2OD006672-01.

Histotripsy, a non-invasive cancer treatment

Michigan Engineering Professor Charles Cain outlines a new technique called “Histotripsy,” which is a non-invasive ultrasonic approach for the treatment of benign disease and cancer. Cain says the knifeless surgical approach generates energetic microbubbles that oscillate very rapidly, almost like a “nano-blender.” The procedure can be used for multiple applications, including treating newborn infants with heart defects, prostate patients and potentially diseases such as breast cancer.

ABOUT THE PROFESSOR: Professor Cain is the Founding Chair of Biomedical Engineering at the University of Michigan and the Richard A. Auhll Professor of Engineering. He and his research team have been developing the histotripsy technique for the last five years.