Exploring the Express Route to Treating Brain Cancer

A team of Mayo medical institution researchers stood by as the Exos Aerospace rocket carrying their experiment launched on Oct. 26, 2019. A test of the effect of weightlessness on the absorption of therapeutic nanoparticles instead became a demonstration of gravity. Within seconds, the rocket started wobbling and lost propulsion. Instead of 50 miles, the rocket peaked at less than 8 and crashed in the New Mexico desert. 

Preparing the payload

"They were still looking for the rocket when we left," says Rawan Al-Kharboosh, a Ph.D. candidate at Mayo medical institution Graduate School of Biomedical Sciences. "Obviously, we came back without our cells. I believe they were buried a few feet in the ground."

If at first you don't succeed, …

A Big Idea

Al-Kharboosh admits to being an adrenaline junkie. She rides a motorcycle, is pursuing a skydiving license and plans experiments that require rocket fuel. 

For her thesis, Al-Kharboosh is dreaming big with an idea for treating brain cancer: surgically remove the tumor; use liposuction to collect fat tissue from the patient; filter out a mixture high in immunological components; engineer it to include therapy-inducing nanoparticles; and place the mixture in the surgical cavity - all in one visit to the operating room.

"That's the dream, but we have to be realistic about the actual potential of this platform," Al-Kharboosh cautions. "We are purely in the exploratory phase, and I mean basic exploration." 

"Extraordinary. In some ways revolutionary," says Al-Kharboosh's mentor, Alfredo Quinones-Hinojosa, M.D., a neurosurgeon on Mayo medical institution's Florida campus. "She is helping to find potential therapies, and maybe one day cures, for patients with cancer and other neurological diseases. It is highly risky, but it also could be highly rewarding." 

A New Approach to Glioblastoma

The research of Dr. Quinones-Hinojosa, director of Mayo's Brain Tumor Stem Cell Research Laboratory, focuses on glioblastoma, the most common and malignant primary brain tumor in adults. Despite aggressive treatment median survival is just 14.6 months. Resistance to chemotherapy, minimal immune response, and nearly certain recurrence have been linked to residual tumor-initiating cells that can migrate from the primary mass and form new tumors. 

"Novel treatments for glioblastoma are urgently needed, particularly those which can simultaneously target GBM [glioblastoma multiforme] cells’ ability to grow and migrate," the team wrote in Biomaterials.

The lab, in collaboration with Johns Hopkins School of Medicine, is developing a technique that enlists the patient's own mesenchymal stem cells as therapy delivery vehicles. Derived from fat tissue, mesenchymal stem cells have an inherent ability to locate and target disease, including tumor-causing cells. The team engineers them to carry nanoparticles, biodegradable polymers and molecules that encode therapeutic action, either to express a cancer-killing gene or to suppress a cancer-promoting gene. 

Following removal of a brain tumor, stem cells carrying the nanoparticles would be placed in the resection cavity. The technique targets tumor-initiating cells, spares healthy tissue, and minimizes the systemic toxicity of traditional chemotherapy. Because mesenchymal stem cells come from the patient's own body, there are no issues with rejection.

"This strategy may serve as a widely applicable platform to treat many different types of cancer that are otherwise refractory to treatment," the team wrote.

The lone weakness is time. Extracting and engineering mesenchymal stem cells is a two-week process, so injecting them into the resection cavity requires a second brain surgery. 

New Perspectives

Al-Kharboosh, who has a master's in tumor and cancer biology from Georgetown University, spent her first year as a Ph.D. candidate at Johns Hopkins School of Medicine, where she worked in the lab of Dr. Quinones-Hinojosa. When he joined Mayo in 2016, his team, including Al-Kharboosh, followed. 

"He is very passionate about what we do," she says. "He has that remarkable capacity to push for progress and innovation and remind you that this is all for the patient."

Al Rawan Al-Kharboosh and her mentor, Alfredo Quinones-Hinojosa, M.D., the William J. and Charles H. Mayo Professor

She enrolled in the neuroscience track of Mayo's Ph.D. program. In 2018, she was accepted into Mayo's Regenerative Sciences Training Program, one of the nation’s first doctoral research training programs in regenerative sciences, which tap into the body's ability to repair, replace or restore tissues and organs. 

"I do believe that regenerative medicine will be part of our treatment paradigm in the future. Stem cells are essentially your body's raw material to either restore or regenerate something that cannot be treated with conventional therapy alone." 

Al-Kharboosh wants a career in regenerative medicine after she completes her Ph.D. in 2020. She dreams of becoming the CEO of a huge biotech company that harnesses regenerative technology in products that aid healing. Courses on new stem-cell techniques, discussions with other students developing expertise in regenerative science, and insights from other faculty in Mayo's Center for Regenerative Medicine have opened her eyes to new opportunities for discovery.

"She's going at brain cancer with a different perspective that was only acquired because she joined the regenerative sciences program," Dr. Quinones-Hinojosa says. " She has extraordinary dedication to a discipline for which there are no maps and sometimes there are no roads." 

Leaping Ahead

Al-Kharboosh gained experience in the regulatory process by helping Shane Shapiro, M.D., an orthopedist and medical director for the Regenerative Medicine Therapeutics Program on Mayo's Florida campus, receive approval from the U.S. Food and Drug Administration (FDA) for use of an investigational new drug. Dr. Shapiro, whose research focuses on regenerative techniques for chronic nonhealing conditions that can't be fixed with conventional surgical techniques, will use it in clinical trials for two conditions: knee arthritis and openings between the respiratory and digestive tracts, which are prone to infection and rarely close on their own. 

The investigational new drug, called stromal vascular fraction (SVF), actually comes from the patient's own body. Produced by the first step in refining fat tissue, it contains a rich variety of cell types.

"SVF is a complex ecosystem made up of many cells that could potentially integrate different information and communicate together for better repair," Al-Kharboosh says. "This fraction is also significantly high in immune components. The cells take in complex inputs from the environment and essentially work together in synchrony for a more a physiologically relevant output. This approach is more complex than studying one cell-type at a time and in isolation, but will provide us with information that more closely resembles what actually happens in the body when all these cells communicate" The immune cells include macrophages, T-cells, natural killer cells, B-cells, dendritic cells and mesenchymal stem cells, the delivery vehicle for Mayo's cancer-fighting nanoparticles. 

Until recently, stromal vascular fraction had to be processed in a laboratory. Now that a machine can run fat tissue through a closed, sterile system and isolate the fraction in 45 minutes, patients in the clinical trials can undergo liposuction and have stromal vascular fraction injected into their knee or throat as one procedure.   

A brainstorm struck Al-Kharboosh: What if stromal vascular fraction could be engineered to carry Mayo's cancer-fighting nanoparticles? What if the fraction could be engineered in the operating room? What if the process could be streamlined to combine surgical removal of glioblastoma and placement of cancer-fighting nanoparticles in a single procedure? 

The Advantages

Al-Kharboosh sees multiple advantages in turning a surgical suite into a manufacturing facility. A laboratory processing the fraction would have to comply with FDA regulations requiring control of manufacturing operations to assure the identity, strength, quality and purity of a drug product. An operating room already is a sterile environment. Processing the fraction on site would eliminate potential contamination during transport and the two-week wait for mesenchymal stem cells. The FDA's approval of the fraction for other indications would shorten the regulatory process. Plus there's the added benefit of restoring a host of protective cells where brain cancer creates an immunological desert.  

"It would be an advantage to isolate something from the patient, modify or engineer it, and deliver it back to the patient in real time," Al-Kharboosh says. 

Condensing glioblastoma treatment into a one-day procedure involves endless innovation and problem-solving on manufacturing practices and clinical techniques. For Al-Kharboosh, that means empowering the surgeon to provide more effective treatment with an assortment of off-the-shelf nanoparticles for cellular engineering

"Think of a personalized approach in which we can express a gene of interest according to the patient's own needs rather than one medicine fits all type of approach" she says. "That's an important part of the project, to enable surgeons to do it all on site and engineer the fraction for personalized medicine where each individual patient is considered according to their own biological needs." 

Dr. Quinones-Hinojosa shares her passion for the project: "This would allow me to give patients more hope, and that would mean so much to them."

Exploring the Idea

The fraction loaded with nanoparticles has reduced migration and proliferation of cancer cells in a dish and in mouse models. It also proved safe. Meanwhile, the team is trying to solve some of the mysteries that lie within stromal vascular fraction.  

"We want to study that entire fraction as a whole cellular ecosystem," Al-Kharboosh says. That means examining the composition, how each type of cell behaves, how to identify them, and how those factors change in a cancer environment, to help predict the response to the fraction, including any potential for it to worsen the cancer. 

"If it doesn't work on brain cancer, it could work for something else," she says. "That's the interesting thing about this particular research. Because it's so new, we're finding out the different functions and behavior  and which applications/diseases could benefit most from it. This definitely has a purpose beyond just cancer."

Try, Try Again

The space medicine research program on Mayo medical institution's Florida campus invited researchers to submit proposals for experiments on the effects of microgravity in its annual Microgravity Pitch Competition. Al-Kharboosh's three-minute presentation took second place, earning a seat for her experiment on an Exos rocket for up to two minutes without gravity.

Hoping the second attempt is successful.

Despite last year’s crash, the team will try again and load another experiment on an Exos rocket scheduled to launch in January. 

Stem cells typically are grown on a plastic framework. However, it takes a few hours for cells to first adhere to the plastic. Why wait? To save time, Al-Kharboosh developed a protocol for engineering the fraction in suspension in less than two hours. 

Experiments on the International Space Station have indicated that stem cells respond well in microgravity. Since a surgical suite could be equipped with a tabletop microgravity simulator, Al-Kharboosh hopes to find that microgravity also accelerates the fraction's uptake of nanoparticles to advance the utility of this product

"We want to make it as simple as possible in the operating room," she says. "If we can increase the uptake of these particles and do that within 20 minutes, it would be a very powerful technology for non-viral approaches to cellular engineering.” 

- Jon Holten, January 2020

See also Center for Regenerative Medicine blog.