When the world needs to understand brain tumor cells to find a cure
The six words every cancer patient hopes to hear from their surgeon are, “We got all of the tumor.” But for patients diagnosed with glioblastoma (GBM)—the most common and aggressive form of brain cancer—those words can ring hollow: In more than 90 percent of patients, the tumor returns; the average length of survival is 14 months.
An ongoing research collaboration led by Maryland Engineering Ph.D. candidate James Shamul could renew hope for patients and their families by leading to novel therapies that one day may eradicate the cancer for good. Together with Maryland Engineering Professor Xiaoming “Shawn” He, National Cancer Institute (NCI) Stadtman Investigator Shuo Gu, and Mayo Clinic Chair of Neurosurgery Alfredo Quiñones-Hinojosa, M.D. (known to colleagues—and viewers of Netflix’s "The Surgeon’s Cut"—as Dr. Q), the team is developing an unconventional approach to treatment, inspired by the building blocks of human life.
“Glioblastoma is an extremely lethal cancer: Even with months of chemotherapy and radiation, recurrence is virtually inevitable,” says Shamul. “What we’re doing right now to treat the primary tumor is not enough.”
The reason GBM tumors are so tenacious lies in their origin: GBM stem cells, the provenance of almost all cells within the tumor. Stubbornly drug-resistant and highly tumorigenic, it’s estimated that GBM stem cells comprise up to 1–5 percent of the tumor. When a GBM tumor is resected, on average 2–10 percent of it is inadvertently left behind. Chemo and radiation make handy work of eradicating non-stem cells but do little to damage true GBM stem cells, which self-renew and build a new tumor.
The key, explains Shamul, is to identify which cells are true GBM stem cells in the first place, a process that, until now, had not yet been done. But by isolating individual tumor cells from Dr. Q’s patients and observing which ones replicate, Shamul and his colleagues in He’s lab have successfully created a pure population of true GBM stem cells.
“We call this approach ‘bio-inspired’ because it mimics early embryonic development,” explains He. “By isolating true GBM stem cells we can then identify what characteristics make them unique to develop targeted therapies.”
Shamul first researched GBM as a student at Johns Hopkins, connecting with Dr. Q through his advisor at the time, Professor Jordan Green. One of the foremost brain surgeons in the world, Dr. Q became both a collaborator and cheerleader for Shamul, inviting him into the operating room and bolstering his hours in the lab. When Shamul chose bioengineering at Maryland for his Ph.D., he proposed to He the idea of continuing his work with Quiñones-Hinojosa.
“I know these cells well, and I wanted to keep working with Dr. Q on finding a cure,” says Shamul. “Dr. He said to go for it. Really, Dr. He and Dr. Q are the ultimate pair: They both love developing impactful, cutting-edge therapies that shift the landscape of medicine for the benefit of patients.”
In 2020, a NCI fellowship connected Shamul with Gu’s RNA research expertise. Gu is now working with Shamul and He to identify novel targets of GBM stem cells, and use a nanotechnology-driven platform to either destroy the cells or transform them into cells susceptible to therapies like chemo and radiation.
That they are inching closer to solving the puzzle, says Shamul, would not be possible without key pieces in place: Dr. Q’s clinical perspective combined with Shamul, He, and Gu’s research prowess is a magic formula that could lead to a different outcome for GBM patients: permanent remission. “We have to change the narrative to one that doesn’t include the expectation of recurrence for these patients,” says Shamul. “Advancing the field requires thinking differently. While risky, we’re nowhere without that mentality and nowhere without the overwhelming support of bold and fearless collaborators.”
To decimate brain tumor, researchers bring the heat
For 20 percent of GBM cases, the biggest obstacle to treatment is the tumor’s location. When a tumor is beyond the reach of a doctor’s scalpel, neurosurgeons like Graeme Woodworth, M.D. at UMD Baltimore opt for a new, minimally invasive approach called laser interstitial thermal therapy (LITT). The procedure blankets the tumor in light using robotically controlled laser probes, heating it to a temperature high enough to kill the tumor cells.
“LITT is minimally invasive, and it can also help patients who do not respond to radiosurgery,” says Assistant Professor Huang Chiao “Joe” Huang. “But what Dr. Woodworth and others in the field noticed is that up to 40 percent of patients treated with LITT experience side effects, such as brain swelling and seizures, from the heating. Heat transfer in the brain is a complicated process and very tough to control.”
A collaboration between Huang’s lab at Maryland Engineering and UMD Baltimore’s Department of Neurosurgery are working to minimize thermal damage to healthy brain tissue, which can cause intense pain and seizures, with the help of targeted gold nanoparticles. Prior to the laser treatment, the nanoparticles are injected into the brain and latch onto cancer cells by looking for overexpression of proteins unique to brain tumors; when the laser is applied, the nanoparticles absorb the light energy and convert it into concentrated, tumor-targeting heat.
The therapy, says Huang, could prove effective for tumors that are hard to reach and those that metastasize or recur—and potentially for other complex cancers like liver and prostate tumors.
It’s a great example of the cross-institutional collaborations critical to creating promising treatments and hope for patients, Huang says. Behind the scenes is a big team, including bioengineering Ph.D. student Sumiao Pang and Woodworth, Anthony Kim, Jeffrey Winkles, Paul Anastasiadis, and their lab members at UMD School of Medicine.
While LITT probably won’t replace existing therapies like chemotherapy or radiosurgery, it will likely make them more effective. “If you treat a tumor with LITT and follow it with radiosurgery, the radiosurgery will be much more pronounced,” says Huang. “Like us, LITT will be an excellent team player.”