Energy Source: How Metabolic Research Is Powering New Approaches to Cancer Treatment

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By Robert Levy

Long before anyone had seen a gene or probed a chromosome, scientists noticed a curious difference between cancer cells and normal cells.

Many normal cells get much of their energy by using oxygen to break down glucose, a blood sugar. In 1923, a German scientist named Otto Warburg discovered that tumors are glucose gluttons, gobbling up far more of the sugar than their normal counterparts. Such an appetite might seem unsurprising, given cancer cells' riotous growth rate. But Warburg noticed something odd: the tumor cells broke glucose down without using oxygen – a process called fermentation that is a grindingly inefficient way of turning food into energy.

Cancer cells' preference for fermentation over oxygen-fueled reactions might seem a mere eccentricity, but it speaks to something profoundly divergent between cancer cells and normal cells. Cancer cells, it turns out, not only grow and divide more quickly than normal cells, not only invade healthy tissue and outlive other cells, but they also differ in the way they use nutrients for energy and building materials – that is, in their metabolism.

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Matthew Vander Heiden, MD, PhD

Metabolism is the collective name for all the chemical reactions involved in keeping a cell or an organism alive. Each cell is the site of hundreds, if not thousands of metabolic pathways – chains of chemical reactions that spawn other reactions – intersecting in a vast, layered web. Survival requires that these reactions be in balance. Whenever there's a change in a cell or organism's environment – when a particular nutrient becomes scarce, say – metabolic pathways are re-routed in response.

So striking was the discovery that cancer cells burn glucose by a different metabolic pathway than normal cells – known as the Warburg effect – it counts as one of the seminal events in cancer research. "It was the first molecular observation about cancer – the first indication that at the most basic level, tumor cells operate differently from normal cells," says Dana-Farber's Matthew Vander Heiden, MD, PhD, whose laboratory conducts metabolic research in cancer.

A sweet tooth for glucose is so fundamental to cancer cells' nature that it became the basis for positron emission tomography (PET) scanning, a major tool for diagnosing and evaluating cancer in patients. PET scans work by showing areas of the body where glucose is being consumed at ravenous rates, an indication that cancer cells are present.

Scientists have yet to solve the riddle of why the Warburg effect exists (Warburg himself believed it was because cancer cells are inherently incapable of using oxygen properly, and that this defect is the defining trait of cancer). But debate over the issue continued for decades after Warburg's discovery, until the discovery of the spiral structure of DNA in 1953 essentially brought the conversation to a halt. So powerful did the role of genetics in cell life appear to be, that scientists quickly embraced the view that cancer is primarily a disease of mutated genes, which underwrite cancer cells' unbridled growth and proliferation. The metabolic enzymes and processes that fascinated Warburg and his followers were soon dismissed as "housekeeping" elements; the real action – and the real opportunities for breakthroughs against cancer – lie in the genome.

Nevertheless, in certain corners of the cancer research world, study of the metabolic aspects of cancer continued, largely unheralded and parsimoniously funded. But in recent years, the field has begun to undergo a revival, thanks in part to new research showing that the metabolics of cancer are linked to the genomics of cancer in ways that few scientists imagined.

Master and Commander

The genome – the master set of DNA in each cell – is often portrayed as a hallowed catalog of commands and instructions, operating in austere aloofness from the rest of the cell. But as research is increasingly showing, the cell operates less like a top-down dictatorship than a participatory democracy. The genome is in fact exquisitely sensitive to input from inside as well as outside the cell. Such input doesn't alter the content of the genome itself, but does affect gene activity, the networks of genes that are switched on or off at any given time. And the agents spurring these changes are, in many cases, chemical substances produced in metabolic pathways.

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Julie-Aurore Losman, MD, PhD

"It's increasingly evident that the metabolism of a cell, which is normally thought of as involving energy use, is communicating in a very direct way with the structure of DNA," says Dana-Farber scientist Julie-Aurore Losman, MD, PhD. "There's a cross-talk between DNA structure and energy metabolism that plays an incredibly important role in cell function – affecting, among other things, when a cell grows and divides, and which genes are in use at a particular moment."

The range of this intracellular conversation is so broad, and so central to cell growth, that "it's ripe to be hijacked by cancer," Losman continues. "Many of the proteins that sense changes in a cell's environment are mutated in cancer. And even when they're not mutated, their activity can be upset by the abnormal metabolism of cancer cells."

The fact that metabolic changes are so deeply linked to cancer, and that research into cancer metabolics has been something of a niche interest until relatively recently, means the field is wide open for discovery. Researchers are exploring the metabolism-cancer nexus from a variety of perspectives – tracking how key metabolic pathways are re-routed in cancer cells, exploring whether metabolic pathways differ in different types of cancer, examining how the body's own metabolism affects cancer growth, and, critically, developing therapies that can exploit cancer's metabolic weaknesses.

"If we can understand how these abnormal metabolic pathways work, how they're regulated, we'll be better positioned to find ways of intervening in them with new drugs," Vander Heiden remarks. "The result will be more weapons for fighting cancer, and more ways to use them effectively while reducing the side effects of treatment."

The Cost of Growth

Cancer cells' ability to rewire their metabolism, to choose alternate sources of energy and alternate channels for using it, has undeniable advantages for cancer cell survival. It lets them maintain their extravagant growth rate, even if, as in the case of the Warburg effect, the path they've chosen is grindingly inefficient. But their proliferative advantage comes at a cost.

"Although cancers can be very adaptable, they pay a big price for it," Losman comments. "They become highly dependent on metabolic pathways and mechanisms of energy production that normal cells don't need as much. And that kind of dependency creates vulnerabilities." Depriving cancer cells of the pathways or chemical products they've come to rely on can damage them in ways that have little effect on normal cells. Such specificity – the ability to inflict harm on tumor cells while leaving normal cells relatively unscathed – is the essence of what cancer therapy seeks to achieve. At Dana-Farber, scientists are engaged in a variety of efforts to probe and prod cancer's metabolic weak points.

A Metabolic Approach to Drug Resistance

For Nika Danial, PhD, the metabolic dependencies of cancer cells may present a way to overcome the problem of drug resistance in a form of lymphoma.

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Nika Danial, PhD

Like plants that generate electricity by burning either coal, oil, natural gas, or biomass (plant material), cancer cells are picky about their source of energy. Some cancer types prefer to get their energy from sugars, some from fats, and some from protein. Danial and her colleagues have found that diffuse large B cell lymphoma (DLBCL) – the most common type of non-Hodgkin lymphoma – exists in two metabolic subtypes, one that favors sugar and one that favors fatty acids. The sugar-favoring type grows in response to signals from a cell protein called the B cell receptor. An array of potential chemotherapy agents are being tested that target the B cell receptor. By stifling the receptor, such drugs could potentially bring cell growth to a stop.

DLBCL cells, however, are a cagey bunch. "If you block the B cell receptor in the sugar-utilizing subtype, the cells can switch to using fat," Danial observes. "This gives them a survival pathway independent of the B cell receptor."

Clinically, this means that even if a drug successfully halts DLBCL growth by blocking the B cell receptor, the benefit may be short-lived. The cells may skirt the blockage by firing up the fatty acid-burning pathway and resuming their growth. The result would be drug resistance: tumor cells that no longer respond to a front-line treatment. Knowing that such DLBCL cells have a Plan B for fueling their growth, however, means scientists can seek ways of blocking the alternate pathway.

Danial and Dana-Farber colleague Margaret Shipp, MD, "are exploring how B cell receptor-targeting drugs affect other metabolic and fuel-utilization pathways in DLBCL," Danial says. "The hope is that by learning these, we'll be prepared for drug resistance when or before it emerges."

Targeting Metabolites in Metastatic Melanoma

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Pere Puigserver, PhD

Metabolic vulnerabilities are being uncovered in other types of cancer as well. In melanoma skin cancer, Pere Puigserver, PhD, is exploring how such susceptibilities play into the genetic circuitry of cancer cells. His focus is on metabolites, substances produced by metabolic reactions and often involved in such reactions. "We have identified certain metabolites that are important for the survival of melanoma cells," Puigserver states. "It turns out that some of these components also play a role in metastasis. So there is a connection between metabolic survival and the ability of melanoma cells to invade other tissue and spread throughout the body."

Like Danial's work, Puigserver's may offer an answer to the problem of drug resistance. "In becoming resistant to drugs known as BRAF inhibitors, melanoma cells often undergo a kind of metabolic reprogramming that enables them to survive the effects of the drugs," Puigserver explains. "Targeting these reprogramming components may provide a way to overcome drug resistance in these cells."

A Delicate Dance

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Massimo Loda, MD

The growing awareness that genomic and metabolic processes relate to each other more as dance partners than as master and servant is already influencing scientists' thinking about future approaches to cancer treatment. The revival of interest in cancer metabolism, combined with advances in technology, has birthed a new field called cancer metabolomics, which seeks to capture all the metabolic activity in a particular type of cell. Dana-Farber's Massimo Loda, MD, is combining metabolomic research with good old-fashioned genomic profiling – which can read the activity of thousands of genes at a time – to gain new insights into how cells function.

Although this research is at a relatively early stage, it's revealing how changes in gene activity occur in step with changes in metabolic pathways. The implications for cancer therapy are clear, Loda says: "The integration of gene activity profiling and metabolomics gives you a fuller picture of what's happening in the cell."

He offers an example: "Suppose a genetic event such as a mutation gives a cancer cell a proliferative advantage over other cells. In order to proliferate, the cell needs more food, and in order to create or process more food, it has to rewire its metabolism. Our concept is that if you target both the genetic events underlying cancer and the metabolic enzymes that support its growth, you achieve a very specific targeting of tumors."

Connecting Environmental Changes and Metabolism

Another example of how researchers are using technology to uncover once-hidden aspects of metabolism is work led by Edward Chouchani, PhD. His research explores how environmental changes, such as fluctuations in food availability, impact cells and tissues, and how they rewire their metabolism in response. Until recently, it was next to impossible to study these processes in living animals, but technology known as small molecule mass spectrometry has opened them up for scientific observation.

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Edward Chouchani, PhD

Much of Chouchani's work involves metabolites that traditionally garnered little attention from the biomedical establishment – enzymes and other chemical products that were viewed as mere cogs in metabolic processes. His research suggests that their reputation for drab utility is due for an upgrade.

One such metabolite is succinate, a member of what is probably the best-known metabolic pathway of all, the Krebs cycle, also known as the citric acid cycle. The cycle is a linked series of chemical reactions that ultimately produce energy via an organic "battery" that powers all living things. Chouchani and his associates tracked succinate's comings and goings throughout the body with a technology called small molecule mass spectrometry. They discovered that when some cells experience metabolic stress – if the cells are overworked, for example, – succinate tends to accumulate. That, in turn, spurs the production of free radicals – corrosive molecules notorious for their ability to damage cells, proteins, and DNA in ways that may contribute to cancer. (In recent years, free radicals' marauder image has undergone something of a rehabilitation. The same caustic qualities that make free radicals a potential threat to normal cells can also make them a threat to cancer cells.)

"The classical view has been that free radicals are an undesirable by-product of metabolism," Chouchani remarks. "What we've shown is that some cells are wired to produce free radicals under certain conditions and appear to use them as important signaling molecules.

"On a related point, it has long been thought that metabolites like succinate are used entirely within the cell where they are produced," he continues. "In our recent studies, we've found that certain metabolites can enter the circulation and help different types of tissues communicate with one another. For example, we've found that succinate helps muscle tissue 'talk' to fat tissue; and it's almost certainly going to be the case that metabolites play a role in how cancer metabolism interacts with the metabolism of the patient as a whole."

The Case of Lookalike Metabolites

Molecules involved in the Krebs cycle are so crucial to life that when a genetic blunder causes similar molecules to be created, the ripple effects can be severe. Consider Julie-Aurore Losman's investigation of what might be called the Case of the Lookalike Metabolites.

It begins with a metabolite called 2HG, which was one of the first abnormal metabolites to be linked to cancer, earning it dubious fame as an "oncometabolite." It bears a close structural resemblance to a Krebs cycle metabolite called α-ketoglutarate (AKG). The similarity essentially enables 2HG to impersonate AKG and react with many of the same proteins that AKG does. The consequences are not always benign.

"AKG is one of the central participants in energy metabolism and other pathways and interacts with a wide variety of enzymes. 2HG's similarity enables 2HG to interact with many of these enzymes as well, interfering with their normal functioning," Losman observes. "We're interested in understanding which of the enzymes that react with 2HG play a role in promoting cancer.

"We know that 2HG interacts with, and inhibits, TET2, an enzyme that is often mutated in leukemia. But 2HG targets many other molecules as well, and it isn't clear which of these targets actually matter – which contribute to cancer when they're inhibited."

To find out, she and her colleagues are examining the effects of 2HG's on a wide range of target enzymes. The results are apt to show that 2HG is far from a fringe player in cancer.

"There is a large class of enzymes that require AKG to function, and many of them have a role in switching genes on and off – helping to keep cell division under control," Losman explains. "All of these enzymes can potentially be undermined by 2HG. The cross-talk between metabolites like AKG and enzymes that influence gene activity is ripe to be hijacked by cancer. 2HG is likely to be one of many hijackers."

Body and Cell

The metabolic processes within a cell – the breaking down of food for energy and raw materials – mirror those within the body as a whole. The micro and macro are closely related: when a problem occurs in whole-body metabolism, cells in various tissues are certain to feel the effect. When cell metabolism goes awry, the body suffers.

One area of Matthew Vander Heiden's research deals with how cancer can lead to changes in whole-body metabolism. With Dana-Farber's Brian Wolpin, MD, MPH, he's exploring why patients with pancreatic cancer often experience sudden and sharp weight loss.

"The weight loss can occur very early in the development of pancreatic cancer, so we're looking at the earliest stages of the disease to understand how they affect the body," Vander Heiden remarks. "Pancreatic tumors can affect the way that even normal portions of the pancreas function. In mouse studies, we've found these changes can cause the body to enter a starvation-like state. We're hoping this work will lead to therapies or dietary approaches that can counteract the loss of weight."

Many people with advanced cancer, kidney disease, or heart disease experience drastic, uncontrolled weight loss as a result of a metabolic disorder known as cachexia. The loss, which results from a wasting away of muscle and fat tissue, is thought to affect more than half of patients with advanced cancers.

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Bruce Spiegelman, PhD

A key insight into cachexia's origins emerged from the laboratory of Dana-Farber's Bruce Spiegelman, PhD. "Cachexia is a state of increased metabolic activity," he relates. "Several years ago, we found that mice with advanced cancer had a sharp increase in energy expenditure in brown fat tissue. One of our research fellows, Sirkhan Kerr, [PhD], identified what was causing this hypermetabolic state: a little-understood hormone called parathyroid hormone-related peptide, or PTHrP."

"For reasons that aren't clear, tumor cells often, but not always, secrete PTHrP. We showed that blocking PTHrP production relieves most of the hypermetabolic state – at least in the model of lung cancer we were studying and, later, in a model of kidney failure. We also showed that PTHrP is associated with the cachectic state in humans with advanced cancer: patients whose tumors made the hormone were more likely to suffer fat and muscle loss as their disease progressed than were other patients."

While PTHrP almost certainly isn't the sole actor in cachexia, it clearly is involved in some cases of the condition, Spiegelman says. To help such patients, he and his colleagues are working to develop antibodies that can neutralize PTHrP. "One of the most unfortunate aspects of cachexia is that it can make patients too weak to receive life-sparing or life-extending therapies," Spiegelman remarks. "By finding ways to stop dramatic weight loss, we can hopefully help more patients be eligible for these therapies."

For all its potential, metabolic research at the whole-body and cellular level represents less a new branch of cancer science than the rediscovery of an already-proven one. As Vander Heiden notes, "some of the most successful cancer therapies, including some of the major chemotherapy drugs, work by targeting metabolic pathways – although that wasn't known at the time they were developed." The challenge of today's researchers is to use emerging science to extend that success for the next generation of patients.

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