Tag: breast cancer

FastForward U

Bioengineering by Degrees to Treat Breast Cancer

Bioengineering by Degrees to Treat Breast Cancer

Aug. 19, 2019

The following was originally published in The Hub.

Bailey Surtees always wanted to become an inventor. Growing up, she spent her time designing and building—Erector sets, small engineering projects, and other things.

But while Surtees worked on her inventions, she also dealt with health complications that often kept her out of school. When she was 12, Surtees—who is deaf in her left ear—had an operation that involved reconstructive work. The procedure fascinated her. Her doctor, noticing her interest, explained the surgery and introduced her to the larger world of bioengineering.

Bailey Surtees, right, and Yixin Hu of Kubanda Cryotherapy, (Will Kirk/Homewood Photography)

“He was the one who made me realize you can engineer with the human body,” Surtees says. “You could take this beautiful, natural thing, and you could add man’s creativity to it and create something even cooler.”

Now a research assistant in the Department of Biomedical Engineering at Johns Hopkins University, Surtees is using her passion for biomedical technology to lead a team working to increase the survival rate of breast cancer patients in South Africa.

Kubanda—named for the Zulu word for cold—has developed a low-cost tissue-freezing device that can be used in low-resource settings where more conventional treatments are difficult to access. In April, the company won the inaugural Bisciotti Foundation Prize for Student Entrepreneurship

The team formed in 2016, and Surtees, then a junior, served as technical lead. At the beginning, it wasn’t a medical tech startup, but an undergraduate design team formed to improve access to breast cancer diagnostics and therapeutics in South Africa.

During the group’s two trips to South Africa, Surtees and the team visited hospitals in Johannesburg, Cape Town, and more rural areas to learn about existing treatments and needs. Surgery, chemotherapy, and radiation are often too expensive and impractical for many patients, contributing to a high mortality rate for those who are diagnosed.

The team also discovered that mastectomies and lumpectomies were the standard treatment for a breast cancer diagnosis in South Africa, but because they require a sterile environment and an anesthesiologist, they are only offered in urban hospitals. For those living in rural environments, travel to urban centers made this form of treatment too difficult and expensive.

To tackle these issues, the Kubanda team created a device that uses cryoablation to kill cancer tissue by freezing it at extremely cold temperatures. The tool swaps out hard-to-find argon gas with carbon dioxide, which can be procured cheaply and easily worldwide, making it more accessible in remote communities.

“Thanks to the globalization of the soft drink industry, you can find CO2 tanks everywhere,” Surtees says. “But when we talked to the big players in cryotherapy and asked why aren’t you using carbon dioxide, they told us what we’re trying to do with it is impossible. It won’t get cold enough.”

But after two years of experimentation, the team was able to defy the experts and devised a way to use CO2 to cool the surgical needle to the freezing temperatures needed to kill cancer tissue. Their device uses a positive feedback loop that moves the CO2 from high to low pressure, dropping the gas in temperature with every cycle. This pressurized cooling, known in thermodynamics as the Joule-Thomson effect, can be seen in the fact that cold air is blown through pursed lips, while hot air is released when you breathe out with your mouth wide open.

The Kubanda team currently consists of Surtees and co-founder Clarisse Hu, as well as seven undergraduate members. Together, they recently had their first animal study published in PLOS One, a major step on the road from student innovators to leaders of a medical technology company working at the front lines of women’s health.

Publication has been a moment of validation for the group, Surtees says. From here, Kubanda can continue their research, shepherd their studies through FDA review, and get their device to the women who need it.

It’s been a long journey for Surtees. After two years with the group as an undergraduate, she decided to stay on with Kubanda after her graduation in 2017 to see the project through and mentor the next wave of student collaborators.

“I was worried about the transition at first, but I realized that management is just watching your team shine, and looking at the big picture and finding the right parts to do what you need to do,” Surtees says. “There’s something so special about watching the freshmen on my team become seniors who know more about what they’re doing on our project than I do.”

Nicholas Durr, an assistant professor in the Department of Biomedical Engineering and Kubanda’s faculty advisor, says he’s thrilled by the progress Kubanda and Surtees have made.

“When she was considering spinning out the company, we had a lot of conversations about what it would look like,” Durr says. “Worst case, she’ll have an intense learning experience and know that she gave it her best. Best case, she’ll be responsible for saving the lives of people that desperately need help.”

While working on the project, Surtees also served as a student-teacher at a local high school. She says it was really inspiring to be able to tell the girls in her class that there are 18-year-olds on her team working on innovative cancer treatments, and that these kinds of professional breakthroughs can happen at any point in life.

When she was their age, Surtees says, she had no idea that in just six years she would already be achieving breakthroughs in her chosen field. Every day in the lab, she adds, is an exciting opportunity to push forward.

“I have so many moments where I’m just like, ‘Pinch me, I’m dreaming,'” Surtees says. “I didn’t know if I’d be able to finish high school with some of the health problems I had going on, so to be here now is wild. It’s a dream.”

Technology Transfer

Researchers Advance Search For Laboratory Test to Predict Spread…

Researchers Advance Search For Laboratory Test to Predict Spread of Breast Cancer

June 17, 2019

The following was originally published in Johns Hopkins Medicine’s Newsroom.

Researchers at The Johns Hopkins University and other institutions report that a new laboratory test that induces cancer cells to squeeze through narrow spaces has the potential to accurately predict which breast cancers and other solid tumors are likely to spread, or metastasize, to other sites. The test, they say, might also help clinicians select the best drugs to prevent cancer’s spread.

Examples of migratory and non-migratory MDA-MB-231 breast cancer cells migrating in MAqCI (Courtesy of Christopher L. Yankaskas)

The team received a United States patent on the test, called Microfluidic Assay for quantification of Cell Invasion (MAqCI), which uses a device to assess three key features of metastasis: cancer cells’ ability to move, to compress in order to enter narrow channels and to proliferate. In laboratory experiments, the MAqCI device accurately predicted the metastatic potential of breast cancer cell lines and of patient-derived tumors grown in animals in a majority of specimens.

A description of the experiments is published online in the current issue of Nature Biomedical Engineering. The technology is available for license through Johns Hopkins Technology Ventures.

While additional studies are needed to confirm and expand the test’s capabilities, researchers are encouraged by their results so far, says senior study author Konstantinos Konstantopoulos, Ph.D., the William H. Schwarz Professor of Chemical and Biomolecular Engineering at the Johns Hopkins Whiting School of Engineering and member of the Johns Hopkins Kimmel Cancer Center Cancer Invasion and Metastasis Program. Konstantopoulos also is professor of biomedical engineering and of oncology at Johns Hopkins, and is a core researcher for the Johns Hopkins Institute for NanoBioTechnology.

The challenge of predicting which patients with breast cancer will develop metastases — the hallmark of life-threatening disease — can lead to overtreatment of patients with benign disease, as well as inadequate treatment of more aggressive cancers, he says. “When a lump is detected in a patient’s body, the doctor can determine if the mass is benign or malignant through a biopsy, but they cannot really say with confidence if a malignant tumor is going to be highly aggressive and metastasize to other locations,” says Konstantopoulos.

Current technologies for the prediction or early detection of breast cancer metastasis rely on gene expression profiling and measurement of circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) shed by cancer cells. But by the time CTCs are detected, patients may have a limited lifespan, says Konstantopoulos. Gene expression tests measure the expression levels of a subset of genes linked to particular cancers to predict prognosis. However, it is unlikely that one lab test will be effective for all patients given that breast cancer progression can be caused by gene mutations in different biological pathways, at different checkpoints within the same pathway, or even because of different alterations within the same gene, he says. In addition, cells within each tumor are highly varied, and evidence suggests only a tiny fraction of cells within a primary tumor are capable of forming metastases.

Moreover, he says, “Although liquid biopsies or circulating tumor DNA measurements can be very good at monitoring a patient’s response to therapy after it is administered, they do not provide a means to help physicians select optimal drugs to prevent spread.”

In a bid to develop a test of metastatic potential that would fill in some of these gaps and be used in conjunction with current technologies, the investigators took advantage of a somewhat serendipitous finding, says Konstantopoulos. While he and his colleagues were studying the movement of nonmetastatic breast cancer cells through engineered environments consisting of Y-shaped channels of varying dimensions, they observed that these cells couldn’t enter the narrower sections of the device. “The ability to move and deform in order to enter narrow spaces is required by the metastatic tumor cells to be able to move from the primary tumor to a distant site within the patient’s body, while uncontrolled growth is also needed for the cells to colonize distant tissues.”

The dimensions of the Y-shaped microchannels were chosen to mimic aspects of the complexity and variety of the cross-sectional areas of tissue tracks found in or along different locations in the body, such as in the fibrillar interstitial tissues; in the nerve, muscle or epithelium; in bone cavities; and in the brain. The MAqCI device is placed onto the stage of an inverted microscope that has phase contrast and fluorescence imaging capabilities and is connected to a computer. Cell migration is monitored in real time via time-lapse phase contrast microscopy.

For the current proof-of-principle study, Konstantopoulos and colleagues first took cells from 25 different human breast cancer cell lines and put them in the device, finding that breast cancer cell lines already known to be metastatic had a larger than threshold percentage of cells that could compress and fit through narrower channels in the device and therefore had a higher potential for metastasis. The threshold percentage was determined to be 7% migratory cells. The device was 96% accurate in predicting metastatic potential among different breast cancer cell specimens, compared with a commercially available test assay, which was 72% accurate among the same cell lines.

When the researchers added in an additional element — measuring a protein called Ki-67 that is found in the nucleus of actively proliferating cells — it increased the device’s ability to predict migration/metastatic potential to 100% of their specimens.

Next, they isolated cells with a high rate of migration through MAqCI’s channels — cells believed to initiate metastasis — to see if they were more metastatic than the parental population of cancer cells that were not specifically isolated for metastatic properties (so called “unsorted” cells). They injected the two cell populations into mice, and found that while both cell populations formed tumors, 4 of 8 mice injected with migratory cells developed metastases in the bone after eight weeks, a common site of breast cancer metastasis, whereas no mice injected with unsorted cells metastasized to this tissue. Mice injected with migratory cells developed metastatic tumors in the lung and liver that were eight times larger than those found in mice injected with unsorted cells.

To further examine which factors contribute to the increased metastatic potential of migratory cells, investigators compared the characteristics of these cells to nonmigratory cells, finding they were more elongated and moved with higher velocity and persistence. Studying RNA from each type of cell, investigators found that, compared with the heterogeneous unsorted population, migratory cells had gene expression changes in multiple signaling pathways related to cell survival and migration.

Next, they compared the metastatic potential of four additional human breast cancer cell lines as predicted by MAqCI to the actual behavior of these tumor cells implanted in living mice and verified MAqCI’s accurate predictions.

In additional experiments, investigators studied two well-characterized tumor specimens (HCI-001 and HCI-002) from patients with metastatic triple-negative breast cancer. These cells — which are missing the three most common receptors that promote cancer growth — were able to migrate through the channels in the MAqCI device, and also were found to have levels of Ki-67 cells consistent with metastatic disease, indicating that the device found both specimens to be metastatic.

Finally, the investigators tested MAqCI’s ability to predict the effectiveness of potential therapies that inhibit cell motility. They looked at the drugs trametinib, FDA-approved for melanomas, and BKM120, a PI3K inhibitor undergoing study in clinical trials for breast cancer. The team found that trametinib was effective in reducing the percentage of migratory cells in three triple-negative breast cancer cell lines with high metastatic potential. However, the other drug, BKM120, reduced the percentage of migratory cells in just two of these three cell lines, and actually increased the migratory capability of cells in the third cell line, which investigators found was due to the different gene mutations in each of the cell lines — a common confounding factor in cancer treatment.

“This finding illustrates the varied responses of tumor cells to different drugs, and why we need ways to further subclassify tumors beyond classic molecular activity like triple negative, HER2, etc.,” Konstantopoulos said.

If additional studies affirm the capabilities of the MAqCI test, it could be used to monitor the migratory and proliferative tendencies of cells isolated from a biopsy or removed breast cancer or other solid tumor, the team said.

Study co-authors were Christopher L. Yankaskas, Colin D. Paul, Panagiotis Mistriotis, Daniel J. Shea, Kristen M. Manto and Andreas C. Chai of Johns Hopkins; Keyata N. Thompson, Michele I. Vitolo, Aikaterini Kontrogianni-Konstantopoulos and Stuart S. Martin of the University of Maryland School of Medicine; Ankit Mahendra and Navin Varadarajan of the University of Houston; and Vivek K. Bajpai of Stanford University.

The work was supported by the National Cancer Institute through grants R01-CA183804, R01-CA216855, R01-CA154624, R01-CA174385 and K01-CA166576; the Cancer Prevention and Research Institute of Texas (CPRIT) grant RP180466; the Melanoma Research Alliance Award 509800; the Congressionally Directed Medical Research Programs (CDMRP) grant CA160591; and Department of Defense grant W81XWH-17-1-0246. Vitolo was supported by an American Cancer Society Research Scholar Grant, RSG-18-028-01-CSM.

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