Providing a clearer view to lung cancer’s pathways and metabolic process

Advanced imaging technology, a quartercentury of foundational radiological studies, and extensive resources focused on lung cancer and metabolism are bearing fruit in innovative new research at UT Southwestern.

The new, multidisciplinary research may reveal whether specific metabolic traits of lung cancer cells are related to their propensity to metastasize. It also might help researchers devise better diagnostic imaging methods or more quickly determine with noninvasive scans whether a lung cancer is responding to a particular therapy, says Dr. Craig Malloy of the Advanced Imaging Research Center (AIRC) at UT Southwestern.

Crucial elements of the research are high-strength MRI magnets, among the only such facilities in the Southwest, and the expertise of AIRC Director Dr. Dean Sherry and Medical Director Dr. Malloy. The new work exploits 13-carbon—a stable natural isotope—as a tracer to help figure out how cancer cells rearrange normal metabolic pathways to produce energy that fuels cell growth.

“Our whole careers have been a partnership in developing these stable isotope methods, understanding how to use 13-carbon nuclear magnetic resonance (NMR) and how to apply it to biological systems,” Dr. Malloy says.

Molecules that are 13-C-labeled are not radioactive, which enables their safe and routine use in clinical experiments. By administering glucose heavily enriched with 13-carbon, researchers can learn key details about the cancer’s metabolic activity.

The work focusing on non-small cell lung cancer is spearheaded by medical geneticist Dr. Ralph DeBerardinis, who designed the experiments, and thoracic surgeon Dr. Kemp Kernstine. Patients participating in the study are infused with the enriched glucose just before surgery to remove their lung tumors. Upon excision, the tumors are quickly frozen and sent to Dr. DeBerardinis’ lab. There, using NMR and gas chromatography–mass spectrometry, the research team can carefully trace the activity of tumors’ core energy-producing metabolic pathways and contrast this with metabolic activity in healthy lung tissue.

“A reprogramming of metabolic activity allows cancer cells to survive and grow abnormally,” Dr. DeBerardinis says. “If we can determine which metabolic pathways specifically stimulate tumor cell growth, then it may be possible to treat cancer by inhibiting those pathways.”

The team will deploy complementary techniques to obtain “snapshots” capturing the quantities of hundreds of individual metabolites in many pathways at once. The research is also incorporating genetic and other data from each tumor to create a comprehensive portrait of lung cancer metabolism.

In work spearheaded by the Department of Radiology’s Vice Chair of Research, Dr. Robert Lenkinski, investigators hope to correlate their data from the surgical samples with information about tumor variations such as oxygen levels and blood supply that can be gleaned noninvasively and without any radiation danger, using cutting-edge magnetic resonance (MR) approaches.

Imaging lung cancer is particularly tricky because as the patient breathes, the lung and tumor are moving. “In Radiology, the development and implementation of advanced imaging has led to a program utilizing advanced MRI fusion techniques that very few people can do,” Dr. Lenkinski says.

MRI fusion uses multiple MR techniques to characterize different features of a tumor, then layers the images for a more complete picture of the cancer, “an approach that has never previously been applied to lung cancer in humans,” he says. “Using that imaging, we can see heterogeneity in the tumors and guide tissue procurement,” helping project investigators select the most useful tissue for the metabolism experiments.

That capability builds off previous research by Dr. Lenkinski; Chair of Radiology Dr. Neil Rofsky (who is also Director of Translational Research at the AIRC); Division of MRI Chief Dr. Ivan Pedrosa; and Assistant Professor Dr. Daniel Costa. Their work, which has devised innovative MR approaches to help diagnose, stage, and treat various cancers, began about six years ago when all four were at Harvard and has been carried forward at UT Southwestern.

One key advance was developing sophisticated methods to speed up acquisition of the images, making it possible to do multiple studies on the same patient. Along with Deputy Cancer Center Director Dr. Joan Schiller, the AIRC and Radiology “felt that optimizing the imaging so it could be used clinically would change the standard of care,” Dr. Rofsky says. “It was one of the projects we identified at UT Southwestern where we could make a difference.”

In the metabolism research, preliminary data has already yielded insights, Dr. Kernstine says, such as whether lung tumors compensate for abnormal cell metabolism and gain the fuel to proliferate by increased blood flow. That doesn’t appear to be the case, he says.

He notes that current patients typically have a CT scan of the chest, then a PET scan, and often bronchoscopy. “What if we had a single study that would provide all this information at once and tell us more than these current studies? It would give us an idea of tumor health—and perhaps we could give small doses of chemotherapy to patients and see whether it altered the tumor’s function. Then we’d know it works.”