New Tool Could Shed Light on Brain Cancer

An interdisciplinary team of Northern faculty and student researchers is developing a new test that shows promise in diagnosing certain brain cancers quickly, affordably and non-invasively. Their work revolves around a novel biosensor called D2HGlo. When mixed with bodily fluids such as urine, plasma and serum, the tool lights up like a fluorescent beacon when it detects the presence of an abnormal molecule that plays a key role in tumor development. This "liquid biopsy" method could improve outcomes and reduce the physical and emotional toll on brain cancer patients.

Mutations to an enzyme known as isocitrate dehydrogenase (IDH) cause cells to produce high levels of the molecule D-2-HG, driving the formation of glioma tumors in the brain or spinal cord.

"Historically, identifying these mutations required invasive procedures and long wait times," said Clinical Sciences Professor Dr. Matt Jennings, who also serves as laboratory director for the campus-based Upper Michigan Brain Tumor Center. The UMBTC was founded in 2005 by Dr. Rob Winn, now dean of the College of Arts and Sciences, and neurosurgeon Dr. Richard Rovin.

"You might have to remove tumor tissue surgically, send it out for sequencing and wait weeks for results. That delay matters when you're making treatment decisions. But wouldn't it be nice to someday use the biosensor to detect D-2-HG in a clinical setting so that individuals could basically urinate into a cup, send it to a lab and get the results in 15 minutes? That's our big-picture idea related to gliomas, and there are potential applications for other cancers and conditions as well."

Student Zoe Moreno began participating in the D2HGlo project during her senior year and is continuing the research in her master's program.

"Knowing that I may play a small part in possible clinical advances in oncology is rewarding because the work that continues on projects like this will improve health care for cancer patients and provide them with a better chance of fighting a horrible disease like gliomas," she said. "Those with IDH mutations tend to respond better to standard treatment options and also have the option of taking oral drugs that inhibit IDH activity. The rapid and reliable detection of the IDH mutation subtype through this test would help patients get on treatment plans sooner, ultimately prolonging their survival post-diagnosis and providing clinicians with a technique that is much less invasive for their patients. "

The genesis of the project originated with Chemistry Professor Dr. Evan Pratt. He joined the faculty during the Covid pandemic and was pondering different ways to collaborate with colleagues to get his NMU research program started. Pratt had studied some papers on IDH-mutant gliomas and thought his background in biosensors could be helpful in developing a tool to monitor D-2-HG within an individual cell.

"At the time, it was just a theoretical concept on paper," he said. "I wasn't sure if it would ever get off the page or function as intended. I reached out to Matt and others from the UMBTC. They were already working on projects to develop a methodology to rapidly detect IDH-mutant gliomas. The biosensor provided them with a new approach. Matt had a graduate student, Kristian Choat ('22 BS, '24 MS), who talked with me about the tool and then just ran with it. In six months, she generated enough data to write a paper and demonstrate that the sensor could work. Our collaboration quickly gained momentum from there."

The work has been supported by external grants, starting with a $35,427 KickStart award from the Michigan Translational Research and Commercialization (MTRAC) Life Sciences Innovation Hub. That early funding helped to demonstrate that the sensor could work on patient samples and has the potential to be used for clinical care, taking it from the idea stage to proof of concept.

Since then, the team has received two major grants from the National Institutes of Health's National Cancer Institute. One is a three-year, $462,153 Academic Research Enhancement Award (R15), which supports basic research using the sensor to study how D2HG behaves inside living cells. The second is a multi-year UH3 grant, with $194,787 awarded in its first year, focused on validating the test for clinical use.

The validation process to ensure standardization is rigorous. Researchers must show that the test is accurate, precise and produces reliably uniform results across different conditions and locations. As part of this effort, the team is collaborating with physicians at Johns Hopkins University, who will test the tool alongside existing patient care methods.

Medicinal plant chemistry graduate Brennan Cast ('24 BS) is now a full-time research associate with the UMBTC working on clinical validation of the sensor. He leverages bacteria to produce massive quantities of the sensor in a glass column, then drains out all of the impurities so that only the "pure yellow goodness" of the D2HGlo remains.

"My role has helped me learn what it takes to bring a clinical diagnostic tool from an initial idea to a practical solution, with the potential to help real-world patients-a process I plan to repeat throughout my career," he said. "Working on this project has also helped me prepare to focus my future career on analytical biochemistry. I have now seen how much potential this field has to make a meaningful difference. While my career will always be rooted in chemistry, my true motivation for entering science is to solve problems that help real-world people, something I believe all individuals at UMBTC share and will continue to pursue moving forward. The work we are doing with the D2HGlo biosensor also helps pave the way for new biosensors that can detect oncometabolites characteristic of other diseases, which is exciting for future applications."

Both federal NIH grants support the involvement of four NMU undergraduate students in the research each semester. Biochemistry major Megan Yorke's work focuses on how the metabolite D2HG interacts with other molecules inside cancer cells. Understanding how it is regulated could explain how tumors grow and respond to treatment.

"Getting involved in research early in my academic career has allowed me to move beyond the classroom and engage directly with the mechanisms underlying disease," she said. "Working closely with my faculty mentor Dr. Pratt has not only accelerated my technical development, but also sharpened my critical thinking and problem-solving skills as I've learned how to design experiments, interpret data and adapt when results don't go as expected. As a student pursuing a career in medicine, this experience has been invaluable. It has given me a deeper appreciation for the scientific foundation of healthcare and reinforced the importance of curiosity, persistence and collaboration."

Grace Wisniewski is focusing on sensor optimization, and exploring a different type of fluorescent biosensor that may make identifying D-2-HG easier and more efficient. She was introduced to the UMBTC by Clinical Sciences Professor Paul Mann, her faculty adviser.

"Undergraduate research is so accessible at NMU," Wisniewski said. "In my opinion, that sets it apart from other universities. Dr. Jennings has sat down with me many times to ask me about my future after graduation and assisted me in applying to a variety of on- and off-campus internships to gain valuable experience and figure out what I like. The UMBTC gives undergraduates an opportunity to not only get involved in research early on in their academic journey, but also a range of professors who genuinely care about your success."

IDH mutations lead to the development of low-grade gliomas, but they are also responsible for secondary glioblastomas and acute myeloid leukemia. Diagnosing the type of tumor often requires surgery, followed by weeks of additional testing. Even after treatment begins, tracking whether the tumor is responding can be difficult; imaging tools such as MRI scans may not show changes until months later.

The D2HGlo biosensor could help to close that gap by predicting how a tumor is behaving earlier than current methods. That would give clinicians a longer period to adjust treatment, if needed. The timing of this research is especially significant because new drugs targeting IDH-mutant gliomas have recently become available. A faster way to monitor treatment response could help doctors determine whether those therapies are working.

A provisional patent has been issued for the D2HGlo, and a full patent has been submitted and is undergoing review.

This story is one of several innovaton-related features in the summer issue of Northern Magazine. View the full issue here.