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The hope of metabolic pathways in cancer research

contributed by Anna Megdell

Metabolism pathways make tumors sensitive or resistant to treatments. A collaborative group of Rogel researchers is leveraging these avenues to explore the growing foundation of new potential therapies.

Metabolism is having a moment. Not a flash in the pan kind of moment, but one that highlights possible opportunities that might have otherwise stayed in the dark.

Advances in the lab like improved measurement of metabolism in tumors using PET scans, mass spectrometry and stable isotope tracing, the development of new and better drugs that can block metabolic pathways in cancer and a deeper understanding of the relationship between metabolism and the immune system all point to real hope that the time is now to target metabolism to improve cancer therapy, especially in those forms of cancer that don’t respond well to current treatments.

At Rogel, a collaborative group of researchers have formed the Cancer and Immune Metabolism Working Group to unravel the nuances of metabolism across the spectrum of
cancer research. But as program co-director Costas Lyssiotis, Ph.D., notes, understanding just what metabolism means in this context, and the potential it holds for unlocking discoveries, takes a minute to process.

“The term metabolism is so wide-ranging,” Lyssiotis, Maisel Research Professor of Oncology, says. “It is used by scientists and the lay public alike. The lay public uses it to refer to how quickly you’re able to digest the apple you had at lunch. But scientists understand it as all of the biochemical reactions that occur in a system, be it a cell or a person, that allow that system to carry out a certain function. In cancer, that means turning nutrients into tumor cells.”

Pancreatic cancer cells under the microscope
“Scientists understand [metabolism] as all of the biochemical reactions that occur in a system, be it a cell or a person, that allow that system to carry out a certain function,” says Costas Lyssiotis, Ph.D.
Photos: Erica Reist Bass, Bryan McCullough

Lyssiotis’s lab studies immune metabolism in pancreatic cancer. “We’re trying to understand how the metabolic alterations in pancreatic cancer cells can prime them to be treated,” he explains. The lab studies different metabolic pathways that pancreatic cancer cells use to grow and researches ways to target them.

The team has described important roles for metabolites like the amino acids methionine and arginine, as well as non-traditional metabolites, to see how these nutrients fuel and sensitize cancer cells and the immune system.

Recently, they discovered that pancreatic cancer cells can grow by eating hyaluronic acid. The molecule is most well-known for its role in joint lubrication and skin tension as a supplement and beauty care product.

But in this case, non-cancer cells in the tumor make hyaluronic acid, a phenomenon that is unrelated to supplements and joint health. The results, published in eLife, provide insight into the ways pancreatic cancer cells grow, which could indicate new possibilities to treat them.

And while the research is not implying that the presence of hyaluronic acid causes pancreatic cancer, their data illustrate that how pancreatic tumors make hyaluronic acid to feed the cancer cells could reveal new therapeutic targets.

“A central driving theme in my research lab is that pancreatic cancer doesn’t respond to the common arsenal of treatment approaches. We need to think about this challenge differently, and we have taken the approach of defining and targeting the spectrum of nutrients from which cancer cells derive their energy,” Lyssiotis says. “Then we use this information to design new, tumor-specific drug targets to starve cancer cells.”

Collaboration and Context

One way of doing this is looking at how metabolism research intersects with other research disciplines, like immunotherapies, to create the right context for drugs to work more effectively. Lyssiotis’s lab worked with Marina Pasca di Magliano, Ph.D., Maude T. Lane Professor of Surgical Immunology, on an experiment in mice that showed how pancreatic tumors actively deplete the amino acid arginine. Blocking this metabolism did not slow tumor growth, but it did lead to more anti-tumor immune cells in the tumor. This prompted a test with immunotherapy. By blocking arginine metabolism together with immunotherapy, pancreatic tumor growth was considerably decreased.

Similarly, in a study with Weiping Zou, M.D., Ph.D., director of the Center of Excellence for Cancer Immunology and Immunotherapy at Rogel, they found that an increase in the amount of methionine, another amino acid, promotes anti-tumor activity of the immune system. “You have competition between tumor cells and immune cells for methionine. If you starve the tumor cells of methionine, the immune cells don’t get it either. You want to selectively delete the methionine for the tumor cells and not for the immune cells,” Zou says.

Yoshie Umemura, M.D. and Daniel Wahl, M.D., Ph.D.
Yoshie Umemura, M.D. and Daniel Wahl, M.D., Ph.D., members of the Cancer and Immune Metabolism Working Group
Photos: Erica Reist Bass, Bryan McCullough

“Just changing methionine alone would do nothing,” Lyssiotis adds. “But the increased amount of methionine creates the right context for immune therapies to work better.”
Lyssiotis collaborates with program co-director Daniel Wahl, M.D., Ph.D., associate professor of radiation oncology, as part of the Cancer and Immune Metabolism Working Group. Wahl’s work focuses on making an impact for patients with glioblastoma. “In the lab, we found that certain metabolites called purines cause brain tumors to be resistant to standard treatments. Once we knew this, we knew we needed to figure out how to measure purine metabolism in brain tumors, something no one has done before,” he says. That work originated in the lab, but Wahl and his team have now measured this metabolic pathway in about 10 patients with brain tumors. “Once we saw that blocking this pathway made treatment work better in mice, we knew we had to get it to the clinic.”

Wahl worked with a team that included co-principal investigator and clinical assistant professor of neurology Yoshie Umemura, M.D., to write, fund and open a clinical trial where a purine inhibitor is combined with standard brain tumor treatments. The trial is about halfway complete, and Wahl is optimistic about the results. “Along the way, the frequent input and collaboration from members of the Cancer and Immune Metabolism Working Group have been critical for getting this work done,” he says.

Sriram Venneti, M.D., Ph.D., and Carl Koschmann, M.D.
Sriram Venneti, M.D., Ph.D., and Carl Koschmann, M.D., members of the Cancer and Immune Metabolism Working Group
Photos: Erica Reist Bass, Bryan McCullough

Partnerships formed in the working group have led researchers to new possibilities in the treatment of childhood brain cancer as well. Sriram Venneti, M.D., Ph.D., associate professor of pathology and scientific research director of the Chad Carr Pediatric Brain Tumor Center, is also a co-director of the program. The Venneti lab researches the core mechanisms that drive diffuse intrinsic pontine gliomas, or DIPG, and ependymomas in children.

They do this by examining the relationship between metabolism and epigenetics. As Venneti explains, the main drivers of childhood brain cancer are epigenetic: changes in the way DNA is “read” rather than changes to the DNA itself. Recent work has shown that metabolism is a primary regulator of epigenetics. “When looking to see how metabolism drives the growth of childhood brain tumors, we need to understand the link between epigenetics and metabolism because there’s crosstalk between them,” he says. “Epigenetics says something to metabolism, and metabolism says something back to epigenetics. They’re constantly talking to each other to keep the cancer growing.”

When targeting metabolism, the idea is to find the metabolic pathways that fuel cancer cell growth and stop them. Venneti says that these metabolic endpoints act as gas or brake pedals to access the other elements that drive the tumor. “Cancer cells feed a lot because they’re continuously dividing,” he says. “If you inhibit these feeding mechanisms, then you can cause the cells to die. We’re using this strategy to prevent energy production in cells, but at the same time we’re also suppressing epigenetics by using the same targets. That’s the goal.”

In one study, Venneti’s lab found an unexpected result in childhood ependymoma: repurposing metformin, a drug used to manage diabetes, was helpful when looking at animal models of ependymoma. Metformin not only suppressed mitochondrial metabolism, but also changed the epigenetics, which has implications for disease recurrence. The ability to target metabolic and epigenetic endpoints at the same time speaks to the importance of the immune system in this research.

“Playing with metabolic pathways is important because you have immune cells in the tumor microenvironment, apart from the tumor cells, that react in different ways to different metabolites, or they produce different metabolites,” Venneti says. “Some therapies can kill tumor cells but simultaneously activate the immune system.

There is a dual advantage as we look to the future and immunotherapies become more prevalent.”

“Playing with metabolic pathways is important because you have immune cells in the tumor microenvironment, apart from the tumor cells, that react in different ways to different metabolites, or they produce different metabolites.”

~~Sriram Venneti, M.D., Ph.D.

Where We’ve Been, Where We’re Going

For the working group, understanding cancer metabolism to identify new drug targets lies at the heart of their research. However, cancer cells are highly adaptable and readily evade metabolism-directed strategies. Thus, an area of active research lies in understanding how cancer cells adapt.

For Deepak Nagrath, Ph.D., associate professor of biomedical engineering, targeting metabolism allows researchers to crack open that foundation of the cancer cells, inhibiting them from rewiring the microenvironment.

“In our lab, the thought process has been that cancer cells cannot die because they’re more focused on scavenging things from the microenvironment so they can grow,” he explains.

Nagrath is a biomedical engineer, and his lab looks at how the tumor microenvironment communicates with and fuels these cancer cells. “We’ve seen that the microenvironment can supply nutrients like amino acids to cancer cells. We’ve also shown that the microenvironment supplies vesicles, which are loaded with that the cancer cells engulf to use for their own growth.”

Like the other members of the working group, Nagrath is hopeful that understanding metabolism in the lab will eventually lead to new treatment options, given that, as he describes, most conventional therapies have failed to meet the mark. “In some cancers, like pancreatic and ovarian, we’ve been using the same drugs for 40-50 years. There aren’t many new therapies,” he says. “And these have failed because cancer cells adapt and come up with ways to compensate.”

But to accomplish this, Nagrath says that a complete and dynamic understanding of the metabolic environment is necessary to truly starve the cancer and incapacitate its growth.

“That’s why the metabolic goal is systemic. It systematically starves cancer cells, so there’s no way for them to get around it,” he continues.

For metabolic treatments to have a clinical impact, Nagrath’s lab focuses on a two-pronged approach. Using patient genomic data in integrated machine learning, along with a state-of-the-art metabolic flux analysis framework, the lab has identified backup metabolic genes, or collateral genes, on which cancer cells rely for their growth. They’re also developing a novel platform for predicting in vivo metabolic fluxes in patients, which will be a cornerstone for targeting therapy.

When thinking about the future of metabolic research, Lyssiotis has his eye on diet and cancer, a realm that he says for-profit companies and false marketing exploit, despite zero evidence that changing diet alone meaningfully affects cancer growth.

Still, Lyssiotis says that understanding the principles of metabolism, and how cancer cells feed, can create a context for diet to act as medicine. For Yatrik Shah, Ph.D., this means researching to see if dietary changes or probiotics can enhance the anticancer metabolites, or alter microbial gases, generated in the microbiome.

His lab focuses on the intersection of metabolism, microbes and diet in colon cancer. As he explains, the microbiome is a dense community of bacteria mostly localized to the colon that generates thousands of unique metabolites and dozens of biologically active gases, all of which are dynamically changed by the diet.

“In the lab, we found microbial metabolites can alter cancer metabolism and impact cell growth and treatment response,” says Shah, Horace W. Davenport Collegiate Professor of Physiology. “We identified several metabolites generated by microbes that enhance cancer growth by providing key nutrients. We also found microbial metabolites that selectively kill cancer cells by altering and inhibiting key metabolic steps in cancer.”

Lyssiotis uses the popular ketogenic diet as another example. Recent studies have shown that, like people, animals on a ketogenic diet have lower glucose and insulin. And in the context of low glucose and low insulin, tumors are now more susceptible to certain drugs.

“If you recognize what the ketogenic diet does to the body, then you can harness that information to make drugs more effective,” he says. “We know that immunotherapy sometimes works great, and sometimes it doesn’t. But if you can make it work in an area where it’s not currently working, like in pancreatic cancer, by influencing diet, then it’s going to change the paradigm.

“I’m not saying that changing diet automatically changes the disease,” Lyssiotis continues. “There’s still work to be done there. But it’s about using the principles and a molecular understanding of metabolism to improve drug effectiveness.”

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