Currently, no screening tests exist that can catch pancreatic cancer early, before symptoms develop. NCI is now funding several large research projects that are working to develop such an early-detection tool.

One known risk factor for developing pancreatic cancer is a new diagnosis of diabetes, sometimes called new-onset diabetes. About 1 in 100 people with new onset diabetes are diagnosed with pancreatic cancer within 3 years after learning they have diabetes. And 1 in 4 people who get pancreatic cancer had already been diagnosed with diabetes.

The NCI-funded New Onset Diabetes (NOD) Study, which is scheduled to run through 2025, is currently enrolling 10,000 people with new-onset diabetes or hyperglycemia (also known as prediabetes). The NOD researchers hope to develop a blood test that can identify the few individuals with a new diabetes diagnosis who may need further testing for pancreatic cancer.

Other NCI-funded teams, coordinated through the Pancreatic Cancer Detection Consortium (PCDC), are trying to create a blood test that could pick up early pancreatic cancer in the general population. PCDC researchers are also working to improve imaging of the pancreas, by developing methods that may be able to pick up tiny deposits of tumor cells.

Pancreatic cancer can be hard to treat surgically due to the location of the organ, and because the disease has often spread in the body by the time it is diagnosed.

Standard treatment for pancreatic cancer usually consists of surgery, chemotherapy, radiation, or combinations of each, depending on the cancer’s stage. Beyond these standard treatments, NCI scientists continue to look for ways to treat pancreatic cancer more effectively. Researchers are looking at the potential of new drugs, ways to combine standard drugs, and new modalities (such as immunotherapy) to give to patients.

Patients with pancreatic cancer are generally recommended to have both biomarker testing and testing for inherited genetic changes. Both types of testing can help suggest possible treatments and can indicate with a patient’s family members might have an increased risk for pancreatic cancer or other types of cancer.

Testing treatments for early-stage pancreatic cancer

Therapies for early-stage disease that are being tested in clinical trials right now include

• new adjuvant chemotherapy drug combinations
  Some of these postsurgical drug combinations are already known to extend the lives of patients with metastatic disease, but it's not clear if they are better at killing cancer cells left behind after surgery than standard treatments.
• neoadjuvant chemotherapy
  This form of chemotherapy is given before surgery, with the goal of improving outcomes by shrinking the tumor before it’s removed. Pre-surgical chemotherapy also may help by killing cancer cells that have escaped from the tumor that would continue to grow as the patient recovers from surgery.
• cancer treatment vaccines
  Cancer treatment vaccines help the body’s immune system recognize and destroy cancer cells. Cancer cells contain substances, called tumor-associated antigens, that are not present in normal cells or, if present, are at lower levels. Treatment vaccines can help the immune system learn to recognize and react to these antigens and destroy cancer cells that contain them.

Testing treatments for advanced pancreatic cancer

New treatments for metastatic pancreatic cancer that are being investigated in clinical trials include immunotherapy and targeted therapy. Immunotherapy uses substances to stimulate or suppress the immune system to help the body fight cancer. Targeted therapy uses drugs or other substances to target specific molecules that cancer cells need to survive and spread.

Drug Targets Common Mutation in Pancreatic Cancer

In mice, experimental drug MRTX1133 shrank pancreatic tumors with KRAS G12D mutations.

Targeted therapies

• Ras-directed therapies. The RAS genes makes proteins that take part in signaling pathways that control cell growth. Altered forms of these genes are found in more than 90% of pancreatic cancers. Drugs that target mutant forms of RAS are now being tested. One example is a drug that targets a form of RAS that has a mutation called G12C and another drug that targets a more common mutation, G12D.
• olaparib. Olaparib (Lynparza) is used as maintenance therapy in adults with metastatic cancer that has not progressed after platinum chemotherapy and has certain mutations in the BRCA1 or BRCA2 gene.

Immunotherapy

• pembrolizumab. In rare cases, people with pancreatic cancer have mutations in their tumor that cause high microsatellite instability (MSI). Pembrolizumab (Keytruda) is an immune checkpoint inhibitor approved for patients with pancreatic cancer that has high MSI.
• novel immune checkpoint inhibitors and combinations. Using one drug for immunotherapy treatment has not been effective for most people with pancreatic cancer. Therefore, researchers are combining several immunotherapies that can act on different parts of the immune system.
• combinations of immunotherapy drugs with other treatments. These include radiation therapy, stromal modifying agents, and other targeted drugs.
• cell therapies. Researchers are exploring the use of cell-based therapies for pancreatic cancer. These therapies use immune cells such as T cells and natural killer cells that are altered in the lab to kill cancer cells.

Stroma-modifying drugs

• the stroma is the fibrous tissue around a tumor that does not contain cancer cells. It is mostly made up of connective tissue, blood vessels, lymphatic vessels, and nerves. Some of these components can help to support cancer cells and/ or prevent the immune system from recognizing cancer cells.
• pancreatic cancers have much denser stroma than most tumors. Agents that help break down or remodel this stroma may help more chemotherapy drugs reach cancer cells. Or they may help reduce cancer cell resistance to killing by other agents.

June 22, 2023, by Carmen Phillips

A new study has revealed some important information about the behavior of one of the most notorious forms of cancer. Pancreatic cancer, the study found, can readily turn to an alternate source of energy to survive when its primary source, the sugar molecule glucose, is in short supply.

Tumors in the pancreas typically develop a dense, nest-like structure around them—an area often referred to as the tumor microenvironment—and they also often lack intact blood vessels. This unruly architecture surrounding these tumors creates conditions that decrease the supply of glucose, an essential fuel source for normal and cancer cells.

In the study, funded in part by NCI, an international research team showed that pancreatic cancer cells appear to have a potent strategy for overcoming this glucose deprivation: They use an alternative source of fuel, a molecule called uridine.

In experiments involving human pancreatic cancer cells grown in laboratory dishes, they showed that when glucose was lacking, uridine became the main energy source for the cells. And when pancreatic cancer cells that could not use uridine were implanted in mice, only small tumors could form, according to findings published May 17 in Nature.

A related study, published the same day in Nature Metabolism, provided strong confirmation of the finding. In that study, researchers reported that other types of cancer cells could also turn to uridine for energy when they lacked access to glucose.

More research is needed to see if there’s a way to use this information to develop new treatments for pancreatic cancer, acknowledged one of the Nature study’s lead investigators, Costas Lyssiotis, Ph.D., from the University of Michigan Medical School.

Blocking how cancer cells acquire and use energy, or their metabolism, as a treatment has been challenging, Dr. Lyssiotis explained. But a better understanding of how cancer cells adapt their metabolism in the often oxygen- and nutrient-deprived environments in which they exist, he said, may open other avenues for attacking them.

Identifying alternative sources of energy for cancer cells

Pancreatic cancer is one of the leading causes of death from cancer. Not only does its stark microenvironment thwart the entry of drugs designed to kill tumors, but numerous studies have shown that other residents in and around the tumors create an ecosystem that help the tumors thrive.

But this microenvironment also has a downside for tumors: it reduces the amount of oxygen that can flow to them. Pancreatic tumors, in particular, are “highly avascular,” Dr. Lyssiotis said. And not only do they often lack blood vessels, but those that do form are often leaky and mangled.

According to Konstantin Salnikow, Ph.D., of NCI’s Division of Cancer Biology, this abnormal vasculature limits the nutrients available to tumors and can cause “glucose starvation.”

Other studies have shown that pancreatic tumors can get energy from sources other than glucose. But Dr. Lyssiotis’ lab team, along with colleagues from the Institute for Cancer Research, London, wanted to go deeper and identify the specific nutrients that pancreatic tumor cells take in to support their energy needs.

Uridine: Not the typical fuel for cancer cells

The research team began by using an advanced testing platform specifically designed to analyze the nutrients in blood and other tissues. Using the tool, they assessed how readily more than 175 types of nutrients were taken up by about 20 different human pancreatic cancer cell lines (pancreatic cancer cells kept alive in lab dishes) when glucose wasn’t available.

The analysis turned up many of the “usual suspects” that cancer cells would be expected to use for fuel, Dr. Lyssiotis explained. But uridine stood out.

To begin with, uridine is a structural component of RNA, so it’s different than the typical energy sources cells rely on, including carbohydrates like glucose, Dr. Lyssiotis said. It was also readily used by all the pancreatic cancer cell lines they tested.

In addition, they found strong links between high activity of a gene called UPP1 and pancreatic cancer cells’ use of uridine. The latter finding is an important piece of the puzzle, Dr. Lyssiotis explained.

Like a sidecar on a motorcycle, a sugar molecule called ribose is attached to uridine. Ribose is also a component of ATP, the primary energy carrier in cells. UPP1, the protein created when UPP1 is active, interacts with uridine in cells to release ribose, which cells can then use to meet their energy needs.

Analyses of tumor samples from people with pancreatic cancer revealed a link between high levels of UPP1 and shorter survival. And other experiments involving cancer cell lines strongly suggested that UPP1 was stripping uridine of ribose, which the cells then used for energy.

Analyses in mice with pancreatic tumors confirmed what the researchers saw in the cell line experiments. And when they injected mice with pancreatic cancer cells that lacked a functional UPP1 gene—meaning the cells could not produce the UPP1 protein—the resulting tumors were much smaller and more sluggish than those that formed from cells that had an intact form of the gene.

“We were quite surprised by how potent an effect” having no UPP1 had on tumor growth, Dr. Lyssiotis said.

Where are cancer cells getting the uridine? RNA!

Findings from the Nature Metabolism study—funded in party by NCI and conducted by researchers from Harvard, MIT, and the University of Lausanne in Switzerland—largely aligned with those from the Nature study.

The study showed that some cancer cells, including skin and brain cancer, gobbled up uridine to fuel their energy needs when glucose wasn’t available. Other cell types, including immune cells, did as well. The researchers also reported that UPP1 (and a related gene, UPP2) were highly active in cells when glucose was restricted.

But a key question for both research teams was: Where were cells getting the uridine? Dr. Lyssiotis’ team’s analysis pointed to multiple sources in and around the tumor, including immune cells called macrophages. But the companion study pointed directly at RNA.

Indeed, when cancer cells deprived of glucose were given access to plentiful amounts of RNA, they grew just like they would if glucose were present.

“I remember telling my friends that I did a crazy experiment where I tried to feed cells with RNA,” said one of the study’s co-leaders, Alexis Jourdain, Ph.D., of the University of Lausanne, in a news release. “I did not think this was going to work. I was very surprised to see the cells grow.”

Dr. Lyssiotis agreed that RNA appears likely to be a primary source of uridine for cancer cells when glucose in limited.

That cancer cells are getting uridine from RNA “has important implications for cancer biology,” Dr. Salnikow said. “RNA is a very abundant molecule,” he continued, so tumor cells of all types may be relying on it to fuel their metabolism.

It’s also possible that RNA isn’t the sole uridine source for glucose-starved cancer cells, said Michael Pacold, M.D., Ph.D., a radiation oncologist at NYU Langone’s Perlmutter Cancer Center whose research focuses on cancer cell metabolism.

“There are most likely multiple sources,” Dr. Pacold said. When it comes to tumors getting the energy they need, he continued, they are “incredibly adaptable.”

Targeting metabolism as a cancer treatment

With few effective treatments for pancreatic cancer, an obvious question is whether any of these findings suggest possibilities for new therapies, Dr. Lyssiotis said.

Although there’s been tremendous progress in understanding cancer cell metabolism, there is still a lot of work to be done to find ways to exploit it for potential treatment, he explained. Pancreatic cancer, in particular, is challenging.

Pancreatic cancer cells “are professional scavengers,” he said. “If you shut off one fuel source, they will find another.”

Many long-used and highly effective chemotherapy drugs work by interfering with cell metabolism (they are often called antimetabolites), Dr. Pacold said, so there’s already a strong precedent for targeting specific aspects of cancer cell metabolism.

In fact, a host of experimental drugs that disrupt metabolism in different ways are being tested in clinical trials.

Dr. Pacold said he is hopeful that “identifying additional metabolism-related dependencies will be useful in developing improved treatments for cancer.”

January 12, 2023, by Elia Ben-Ari

Pancreatic cancer is an aggressive disease that is notoriously resistant to treatment. Many cancer types and most pancreatic cancers are driven by mutations in a gene called KRAS, so researchers have long sought drugs that block the actions of mutant KRAS proteins made from these altered genes.

But, until recently, efforts to develop drugs that block the cancer-fueling effects of mutant KRAS proteins have been unsuccessful.

Now, results from a new study in mice have identified a promising experimental drug that directly targets pancreatic tumors with a particular KRAS mutation known as G12D. The G12D mutation is the most common in pancreatic cancer, present in approximately 35% of people diagnosed with the disease.

The new drug, known as MRTX1133, shrank tumors or halted their growth in several mouse models of human pancreatic cancer with KRAS G12D mutations, including a genetically engineered mouse model known as KPC that closely mimics the human disease. Findings from the NCI-funded study were published December 5 in Cancer Discovery.

MRTX1133 is the first KRAS-blocking drug, and the first targeted therapy of any kind, to have such promising results in these mouse models of pancreatic cancer, said Ji Luo, Ph.D., of NCI’s Center for Cancer Research, who was not involved with the new study.

The findings in the KPC mice, which are “considered the most rigorous mouse model of pancreatic cancer,” Dr. Luo said, “make me cautiously optimistic” that the drug could shrink tumors in patients with KRAS G12D-mutated pancreatic cancer.

“The KPC mouse model of pancreatic cancer is highly resistant to every drug that has been tested, very much like the human disease,” said Ben Stanger, M.D., Ph.D., of the University of Pennsylvania Abramson Cancer Center, who co-led the new study.

With MRTX1133 treatment, Dr. Stanger said, “we saw shrinking of tumors greater than we have ever seen in our 10 years of testing multiple compounds” against pancreatic cancer in these mice.

Treatment helps immune cells penetrate pancreatic tumors

The KRAS protein normally acts like an on–off switch. In response to certain signals, it becomes activated and tells the cell to grow and divide. When the signals are no longer present, it turns off. However, some mutant forms of KRAS, such as KRAS G12D, remain active even in the absence of growth signals, leading to uncontrolled cell growth.

The KRAS G12D mutation is present in more than one in three pancreatic cancers, about one in ten colorectal cancers, and in several other cancer types.

Although developing compounds that bind effectively to KRAS G12D has proven challenging, researchers at Mirati Therapeutics, the company that developed MRTX1133, showed in a recent study that the drug specifically blocks the actions of the G12D mutant form of the KRAS protein. In that same study, the drug shrank tumors in mouse models created by transplanting human pancreatic cancer cells into mice with weakened immune systems.

Importantly, Dr. Luo said, the pancreatic cancer models used in the new study had intact immune systems, as most people do. These models included mice with tumors created by implanting lab-grown mouse pancreatic tumor cells under the skin or into the pancreas, as well as the KPC mice.

KPC mice are genetically engineered so that tumors develop from normal pancreas cells that become cancerous, “the way a tumor would naturally develop [in humans], as opposed to taking preexisting cancer cells and injecting them into a mouse,” Dr. Stanger explained.

In all these models, his team showed, MRTX1133 not only inhibited the growth of KRAS G12D-mutant pancreatic tumors but also, through indirect effects that are not fully understood, caused changes in the environment surrounding the cancer cells.

One of the things that makes pancreatic cancers so hard to treat, Dr. Stanger explained, is that the tumor cells create a dense web of proteins and noncancerous cells around them. This web, which is part of what is called the tumor microenvironment, helps the tumor cells grow and impairs the immune system’s ability to attack them.

When a treatment is highly effective in killing tumor cells, “you usually trigger some sort of remodeling of the tumor microenvironment as well as changes in the immune cells that are part of the microenvironment,” Dr. Luo said.

Indeed, Dr. Stanger’s team found that blocking KRAS G12D activity with MRTX1133 resulted in several changes in the tumor microenvironment. Most notably, he said, treatment with MRTX1133 “allowed cancer-fighting immune cells called T cells to come into the tumors.” This finding is encouraging, he explained, “because it means that the T cells can now begin to recognize the cancer cells.”

In addition, when the team eliminated T cells from the mice, they found that tumors did not shrink as much in response to the experimental drug and grew back faster after treatment was stopped.

Testing MRTX1133 with checkpoint inhibitors

These findings, Dr. Luo said, suggest that MRTX1133 helps enlist the immune system to attack tumors, enhancing the drug’s effects. That might mean that combining the drug with immune checkpoint inhibitors—which help T cells kill cancer cells—could make it more effective, he said.

And “that is exciting because checkpoint inhibitors generally don’t work well [by themselves] in pancreatic cancer,” Dr. Luo said. If MRTX1133 enables cancer-fighting T cells and other immune cells to move into the tumor, he said, “that creates an opportunity for a checkpoint inhibitor to come in and work better.”

In fact, Dr. Stanger said that he and his colleagues next plan to test combinations of MRTX1133 and immunotherapy drugs in their mouse models.

Studies in mice have shown promising results for a similar combination approach using drugs that block a different mutant form of KRAS, known as G12C. And clinical trials of combination therapy with KRAS G12C inhibitors and immune checkpoint inhibitors are already under way in patients with non-small cell lung cancer, Dr. Luo said.

Progress continues in targeting a hard-to-hit cancer protein

KRAS has been one of the most hard-to-hit targets in cancer research. But over the past 2 years, two new drugs, sotorasib (Lumakras) and adagrasib (Krazati), have been approved to treat people with non-small cell lung cancer that has the KRAS G12C mutation. This mutation occurs less frequently in other cancers and is only seen in about 1%–2% of pancreatic cancers. Even so, researchers have begun testing both drugs in small clinical trials of people with other cancers with KRAS G12C mutations.

In a trial involving 38 patients with advanced pancreatic cancer, for example, sotorasib shrank tumors in about 20% of participants. Similar results were seen with adagrasib in a trial involving people with advanced colorectal cancer.

Another potential advantage of combining KRAS inhibitors and checkpoint inhibitors is that these drugs “work through completely different mechanisms,” Dr. Luo said. “So, you are less likely to get resistance in the tumor that could evade both treatment strategies simultaneously.”

However, both he and Dr. Stanger emphasized, the next critical step for MRTX1133 will be testing it by itself in people with pancreatic cancer to make sure it’s safe.

“We’re optimistic that this and other drugs that target KRAS being developed by various companies will make their way into clinical trials in 2023,” Dr. Stanger said.

August 22, 2022, by Sharon Reynolds

A protein called collagen, which provides structure to tissues, is found almost everywhere in the human body, from the skin to the bones. Pancreatic cancer cells can also produce their own misshapen collagen, a new study has found.

And this abnormal collagen appears to have additional cancer-promoting functions. In experiments in mice, shutting down the production or effects of the abnormal collagen made treatments for pancreatic cancer more effective.

In the NCI-supported study, the research team found that the abnormal collagen ramped up activity in pancreatic cancer cells that increased tumor growth and survival.

But when the research team stopped cancer cells in mice from producing the abnormal collagen, everything changed. Perhaps most importantly, cancer-fighting immune cells started to move into the tumors. And when the researchers then treated the mice with a commonly used immunotherapy drug, their tumors shrank dramatically. The immunotherapy drugs were minimally effective in mice that had the abnormal collagen.

The study findings were published August 8 in Cancer Cell by Raghu Kalluri, M.D., Ph.D., of the University of Texas MD Anderson Cancer Center, and his colleagues.

“When the collagen is present around the cancer cells, it’s functioning like a cloaking device so that the immune cells aren’t able to recognize those cancer cells, or get to those cancer cells. So [they are] almost invisible to the immune system. But then when this collagen is removed, the immune cells are able to see and kill them," Dr. Kalluri said.

This abnormal collagen makes a potentially promising therapeutic target, he explained, because it’s only produced by cancer cells.

“This is what everyone wants to find: an abnormal protein that’s specific to cancer cells,” said Grace Ault, Ph.D., of NCI’s Division of Cancer Biology, who was not part of the study.

Any potential strategies to target this abnormal collagen are years away from clinical testing, Dr. Ault warned. But these early results suggest that such an approach may hold promise.

Different collagens, different functions

Pancreatic cancer is notoriously resistant to commonly used treatments. Among other roadblocks, pancreatic tumors become packed with stromal (supportive) cells and the molecules they produce, including collagen. “Sometimes, the [cancer] cells are actually a minority of the cells in a pancreatic tumor,” explained Dr. Ault.

Normal tissues rely on collagen to perform many of their functions. A protein with a branched, fiber-like structure made up of chains called α1 and α2, it gives tissues both strength and flexibility.

“It’s the most abundant protein in the human body. It’s present in our bones, ligaments, and cartilage—it’s everywhere,” said Dr. Kalluri.

Collagen is normally produced by cells called fibroblasts. Past work from Dr. Kalluri and his team using mice found that the presence of normal collagen may actually help suppress pancreatic cancer growth.

But other research had suggested that pancreatic cancer cells can produce their own collagen. Whether this collagen is different—and whether it helps tumors survive and grow—wasn’t well understood.

When Dr. Kalluri and his colleagues reviewed a database that captures the molecular makeup of human cancer cell lines used for research, they noticed that the collagen produced by pancreatic cancer cells had a different structure. Rather than two α1 chains and one α2 chain, called a heterotrimer, it only contained α1 chains, producing an abnormal structure called a homotrimer.

This abnormal collagen didn’t appear to be the result of any gene changes (mutations) in the cancer cells. Instead, its production was driven by a difference in how the genes responsible for collagen production were expressed, through a process called methylation. This action, known as an epigenetic change, turned off the gene that normally produces the α2 chain.

When they looked at mice engineered to develop pancreatic tumors, they found that the abnormal collagen appeared to be promoting rather than suppressing tumor growth.

When the researchers engineered mice to develop pancreatic cancer that couldn’t produce the abnormal collagen, tumors grew more slowly, and the mice lived longer. Their tumors also had more of the tumor-suppressing collagen normally produced by fibroblasts.

Cancer cells isolated from the mice lacking the abnormal collagen and grown in the lab were slower to divide and more sensitive to the chemotherapy drug gemcitabine (Gemzar), a standard treatment for pancreatic cancer, than cancer cells that could still produce the abnormal collagen. The cells lacking the abnormal collagen were also slower to form tumors when implanted into other mice.

Uncloaking a tumor

How does the abnormal collagen promote tumor growth? Further work in pancreatic cancer cells isolated from mice found that the homotrimers were somehow boosting a communication pathway that can drive runaway cell growth. In contrast, normal collagen suppressed this pathway.

The researchers then zeroed in on a receptor on the surface of pancreatic cancer cells called α3β1 integrin, which seemed to be turning on this signaling pathway when the abnormal collagen bound to it. When the researchers shut down this receptor in pancreatic cancer cells, the cells stopped growing and dividing, even those that still produced the abnormal collagen.

When the research team looked for α3β1 integrin in tumor samples taken from 130 people with pancreatic cancer, they found that almost all expressed high amounts of the receptor.

Tumor samples with the highest levels of the receptor had fewer immune cells called T cells than tumors that had proportionally lower levels of the receptor. And people with tumors containing the highest levels of the receptor died sooner.

Looping back to mice, several good things appeared to happen in pancreatic tumors engineered to lack the abnormal collagen. Among other things, it changed the microbiome of the tumor: the microorganisms and viruses that live in the tumor tissue.

The fact that tumors deep in the body can have resident microbes is a relatively recent discovery in cancer biology, explained Dr. Ault.

“It used to be thought that bacteria were mostly found in places [in the body] that were 'open,' like the mouth or the colon,” said Dr. Ault. “And people thought that inside, in contained tissues [like the pancreas] you didn't have all these bacteria. But it turns out they're all over.”

In tumors in mice that were engineered to lack the abnormal collagen, the populations of bacteria that lived in the tumors shifted compared with those found in nonengineered mice. These microbial changes were associated with the presence of more immune cells, such as T cells, in the tumor.

But the bacteria weren’t the only things linked to these immune cell changes in the tumors. Shutting down the aberrant collagen, they showed, also blocked signaling by the cancer cells that directly impeded immune cells, allowing T cells to flood into the now-friendlier tumor microenvironment.

As a result, mice with tumors that couldn’t produce the abnormal collagen lived longer when treated with an immune checkpoint inhibitor, a type of immunotherapy, than mice with tumors that could produce the homotrimer.

Harnessing a potential vulnerability

“Making this homotrimer [may be] a very early event in a cancer cell's journey,” said Dr. Kalluri. “But more work needs to be done to connect the dots [as to how this happens],” he added.

Mutations in a cancer-causing gene called KRAS, which are present in almost all pancreatic tumors, may be causing the initial shutdown of normal α2 collagen chain production, he explained, but further study is needed to tease out if this is the case.

Regardless of the initial events that lead to a buildup of this abnormal collagen, Dr. Kalluri and his team are now looking at whether it could be a target for new cancer treatments in people.

One strategy they’re exploring is developing drugs that can shut down α3β1 integrin, which could potentially block abnormal growth signaling even in the presence of the collagen homotrimer.

Combining such a strategy with other treatments has potential, explained Dr. Ault. While blocking the activity of the abnormal collagen might not kill cancer cells, it could make them more sensitive to chemotherapy or immunotherapy, she explained.

The researchers would also like to engineer CAR T cells that can bind to the abnormal collagen. Since this collagen is only found in and around cancer cells, “that could direct [such T cells] to go to the cancer cells, not anywhere else,” Dr. Kalluri explained.

“We'd also like to understand if this [collagen] is unique to pancreatic cancer, or if it’s found in other cancers as well,” he added. Early results from his lab suggest that the homotrimer might also be found in lung, colon, and head and neck cancer cells, he explained, expanding the potential pool of cancer types that might be targeted with such an approach.

“But to understand how widespread this [collagen] is, we still need to do more work,” he said.

July 7, 2021, by Sharon Reynolds

Bob Aronson was only 54 years old and, in the words of his son Tom, “extremely healthy.”

“So it was really surprising to everyone when he went in for an annual routine eye exam and his eye doctor suspected diabetes,” Tom recalled.

With his diabetes diagnosis confirmed, Bob got back to his normal routine, with the addition of daily blood sugar checks. But only a year after that trip to the eye doctor, he received a diagnosis of metastatic pancreatic cancer. He died 9 months later.

Around the time of Bob’s cancer diagnosis, in 2005, Tom overheard some of his doctors mention a growing suspicion of a possible link between a new diagnosis of diabetes, sometimes called new-onset diabetes, and pancreatic cancer. In other words, in rare cases, diabetes may actually be caused by a tumor in the pancreas.

Though the Aronson family can’t know if Bob’s diabetes was caused by his tumor, “we’ll always wonder what would have happened if he could have been tested [for pancreatic cancer] the second he presented with diabetes?” Tom asked.

Over the last several years, evidence has mounted to support a link between new-onset diabetes and pancreatic cancer. And the Aronson family’s hope has been inching closer to reality: Several large NCI-supported studies are testing ways to pick out those people whose diabetes might be a sign of a much deadlier problem. The research is part of larger ongoing efforts aimed at finding ways to detect pancreatic cancer early, when treatments may be more effective.

“There’s been a lot of progress over the last 5 years or so,” said Brian Wolpin, M.D., M.P.H., who leads a pancreatic cancer early detection program at the Dana-Farber Cancer Institute. “We’re not quite to the point where there’s a test in the clinic that you can order, but we’re getting progressively closer.”

Risk as a Two-Way Street

Although pancreatic cancer is only the 11th most common cancer in the United States, it’s the 3rd leading cause of death from cancer. Unlike breast, colorectal, and lung cancer, no screening test exists to catch it early.

More than 80% of the time, people are not diagnosed with pancreatic cancer until after it’s invaded nearby tissues or spread to other organs. And, overall, only about 10% of people with pancreatic cancer will be alive 5 years after their diagnosis. But about 40% of people diagnosed before their cancer has spread outside the pancreas will be alive after 5 years, highlighting the importance of early detection.

An important job of the pancreas is to produce insulin. This hormone controls the amount of sugar in the blood by moving it into cells, where it can be used by the body for energy. In type 1 diabetes, which is relatively uncommon, the immune system attacks and destroys the cells in the pancreas that make insulin.

Type 2 diabetes, which affects almost 10% of the US population, is usually the result of the body not being able to properly use the insulin it makes. Being age 45 or older, having a family history of diabetes, or being overweight are risk factors for developing type 2 diabetes.

Physical inactivity, race, and certain health problems such as high blood pressure also affect the likelihood of developing type 2 diabetes.

And living with diabetes for a long time “is a known risk factor for pancreatic cancer,” said V. Wendy Setiawan, Ph.D., of the University of Southern California, who’s led long-term studies of pancreatic cancer risk in diverse populations. The reasons why aren’t totally clear, but some of the proposed mechanisms include higher-than-normal levels of insulin circulating in the blood, high blood sugar, and long-term inflammation caused by type 2 diabetes, she explained.

But in some people, diabetes can rapidly develop because of a problem in the pancreas, instead of the diabetes causing damage to the pancreas in the long run. These problems can include chronic inflammation of the pancreas, cystic fibrosis, and pancreatic cancer.

“Anything that damages your pancreas can [cause it to] not make enough insulin,” said Dr. Setiawan. The result of this damage can be a rare kind of diabetes sometimes called pancreatogenic diabetes or type 3c diabetes.

This type of diabetes is very uncommon, explained Anirban Maitra, M.B.B.S., of the University of Texas MD Anderson Cancer Center. “In the overwhelming majority—more than 99%—of new cases of diabetes, it’s just run-of-the-mill type 2 diabetes,” Dr. Maitra explained. But the other 1% with pancreatogenic diabetes have a risk that their diabetes is driven by pancreatic cancer.

While frightening, this last scenario is rare—the estimates are that fewer than 1 in 100 cases of new-onset diabetes are caused by cancer. And about 1 in 4 people diagnosed with pancreatic cancer were first diagnosed with diabetes.

“So how do we pick out that small, small subset of people with pancreatogenic diabetes, which in some cases may be caused by cancer?” asked Dr. Maitra.

Finding Those at Highest Risk

At the moment, there’s no good answer to that question. Sending every person with new-onset diabetes to get imaging tests of the pancreas would result in too many unnecessary follow-up surgical procedures—when abnormalities seen on scans turn out not to be cancer—potentially doing more harm than good, explained Suresh Chari, M.D., also of MD Anderson.

To help find these rare patients with pancreatogenic diabetes while limiting harms, including unnecessary surgeries and the fear caused by undergoing diagnostic procedures, Drs. Chari and Maitra are leading a nationwide project, funded by NCI and the National Institute of Diabetes and Digestive and Kidney Diseases, called the New Onset Diabetes (NOD) Study.

The project, which is in the process of enrolling 10,000 people with new-onset diabetes or hyperglycemia (also known as prediabetes), hopes to develop a blood test that can identify the few individuals who may need further testing for pancreatic cancer, Dr. Maitra explained.

“Can we identify biomarkers in the blood that will tell us, in a room of 100 patients with new-onset diabetes, there may be someone who we need to send for more workup and imaging studies?” he asked.

Out of 10,000 participants, Drs. Chari and Maitra estimate that about 85 will develop pancreatic cancer during the study.

Participants will donate blood samples periodically for up to 3 years. The NOD researchers will look for proteins and other biomarkers found in samples that differ substantially between people who later develop pancreatic cancer and those who don’t. Their hope is to find a specific group of markers in the blood that can be used in the future to detect those people with new-onset diabetes who are at highest risk for pancreatic cancer.

Such markers could then potentially be used as the basis of a test that, “when a patient walks in with new-onset diabetes, can raise a red flag that they should go and get some additional tests” for pancreatic cancer, said Dr. Maitra. And ideally, such a test would help identify the cancer long before it has spread beyond the pancreas.

“The longer you have to wait, the closer you’re getting to the clinical diagnosis of pancreatic cancer and losing that window of opportunity” for early detection, Dr. Maitra said.

A Trial for People at Highest Risk

Since Bob Aronson’s diagnosis more than 15 years ago, researchers have come to recognize that several clinical factors can also be used to identify a subset of people with new-onset diabetes who have an especially high risk of pancreatic cancer.

Three key differences that tend to be found together distinguish these people from others with new-onset diabetes, said Dr. Maitra. “One is their age,” he explained. People who develop diabetes as a consequence of pancreatic cancer tend to be older, he explained.

The second is that blood sugar levels tend to rise more rapidly in people whose diabetes is driven by a tumor. “And the third is weight loss,” Dr. Maitra explained. “Normally with type 2 diabetes, people gain weight when they become diabetic.” People whose diabetes is caused by pancreatic cancer can instead experience unexpected weight loss around the time of a diabetes diagnosis.

In 2018, Dr. Chari and his colleagues proposed that these three clinical risk factors, which they called the Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC) score, may be useful for identifying people who need additional testing now, before a blood test has been developed.

Not long after, they found some groups willing to take them up on testing that idea.
If people with new-onset diabetes who have a high ENDPAC score are indeed more likely to have pancreatic cancer, said Lynn Matrisian, Ph.D., chief science officer at the Pancreatic Cancer Action Network (PanCAN), “as an advocacy group, our interest is: Can we help these people now?”

PanCAN recently launched the Early Detection Initiative (EDI) for Pancreatic Cancer, a collaboration with NCI and the Fred Hutchinson Cancer Research Center in Seattle. The initiative is testing whether referring people to get a CT scan of the abdomen based on a high ENDPAC score alone can find early-stage pancreatic cancer while minimizing unnecessary follow-up procedures, anxiety, and overdiagnosis. (Overdiagnosis is when a cancer that will never cause any symptoms is found, potentially leading unnecessary diagnostic procedures and treatments.)

As part of the EDI, CT scans will be stored in a repository. This resource could potentially be used for future studies using artificial intelligence-based approaches to improving pancreatic cancer imaging, explained Eva Shrader, PanCAN’s director of scientific initiatives.

The EDI is also contributing samples of blood from participants to the NOD study, “But we mainly want to answer the clinical question: Will imaging work for early detection for people with a high ENDPAC score?” said Dr. Matrisian.

Beyond Diabetes

In addition to diabetes, there are other established risk factors for pancreatic cancer, including a family history of pancreatic cancer or having a pancreatic cyst, explained Dr. Wolpin. However, most of the approximately 60,000 people in the United States who develop pancreatic cancer every year don’t have known risk factors for the disease.

“[Studies] suggest that survival for pancreatic cancer could be improved many-fold if we could detect it at early stages,” said Sudhir Srivastava, Ph.D., of NCI’s Division of Cancer Prevention (DCP). Since 2016, DCP’s Pancreatic Cancer Detection Consortium (PCDC) has been funding research teams to develop something that has proven elusive: a test that can detect pancreatic cancer early in people not already known to be at high risk.

Creating a blood test that could pick up early pancreatic cancer in the general population faces many hurdles, Dr. Wolpin explained. One is that, since about 80% of people with pancreatic cancer are diagnosed at a late stage, blood samples taken from people with pancreatic cancer largely reflect the biology of advanced disease.

Blood samples from people with early-stage pancreatic cancer are rare, Dr. Wolpin added. So he and his team are collaborating with cancer centers across the country to collect blood from people newly diagnosed with early-stage pancreatic cancer.

“This way we’ll be better able to capture a larger number of those patients,” he said. “Part of the benefit of the structure of the PCDC is that it helps us all collaborate to do that.”

They’re also following a large group of people at high risk of pancreatic cancer—those with a family history or with pancreatic cysts—over time. That includes periodically collecting blood and tissue samples.

“Unfortunately, some of these people will be diagnosed with pancreatic cancer,” said Dr. Wolpin. “When this occurs, we will have samples in the bank that are actually from before their diagnosis, before they got symptoms,” he continued.

Such samples may allow them to identify markers that can form the basis of a pancreatic cancer screening test for the general population.

There’s already some evidence to support that possibility. Recent work on a related project found that changes in levels of a protein called CA19-9, which is commonly used to track responses to pancreatic cancer treatment, can be found before diagnosis in blood samples from people who later developed pancreatic cancer.

However, on its own, CA19-9 was not sensitive enough to identify everyone who went on to develop pancreatic cancer. His team is now looking for other markers in the blood that show similar changes before a pancreatic cancer diagnosis.

Eventually, he explained, any blood-based markers to detect pancreatic cancer may be incorporated into what are called pan-cancer screening tests: those that screen for many cancer types at the same time.

Other PCDC teams are looking at different sets of proteins and other markers in the blood that may help with early detection, and ways to improve imaging of the pancreas. If doctors end up searching for smaller and smaller tumors, they get harder and harder to see on conventional CT scans, Dr. Chari explained.

Researchers are studying alternative methods that may be able to pick up tiny deposits of tumor cells, including ultrasound techniques that can visualize tumors as small as a millimeter, and PET imaging that homes in on proteins expressed specifically by pancreatic cancer cells. All these projects involve multidisciplinary teams that are committed to working together across institutions.

Early detection of pancreatic cancer “is very much an area where collaboration is necessary,” said Dr. Wolpin. “People sometimes believe that scientists work alone in their own labs and don’t talk to each other. That really is not true, particularly in this area. The PCDC, the NOD cohort, and the Early Detection Research Network are great examples of large consortia really working together to try to solve this difficult problem.”

“Pancreatic cancer is so deadly because there’s no early detection,” Tom Aronson said. “That’s why I’m so excited about all the work that’s happening now. Hopefully, in the future, many people who get pancreatic cancer won’t [be diagnosed] at stage 4, and there will be some hope for them and their families.”

April 28, 2020, by NCI Staff

Scientists may have found an important clue as to why immunotherapies—treatments that stimulate the immune system to fight off cancer—tend to work for people with lung cancer but not for those with pancreatic cancer. In part, the answer may lie in the number of special immune cells, called dendritic cells, in the two types of tumors.

Dendritic cells are part of the immune system’s first line of defense against cancer and infections. They patrol the body, searching for abnormal or infected cells. If they find one, they eat the offender and show pieces of it to an army of immune cells, like holding up a “wanted” poster. The army then hunts down and attacks the cancer or infection.

In mouse models, pancreatic tumors had far fewer and less active dendritic cells than lung tumors, the scientists found. Without dendritic cells, other immune cells in the pancreatic tumors didn’t recognize cancer cells as a threat, they found.

But treating the mice with drugs that boost the number and activity of dendritic cells triggered an immune response that slowed the growth of pancreatic tumors, the researchers discovered. Combining the drug treatment with radiation therapy was even more effective, causing pancreatic tumors in the mice to shrink.

Findings from the NCI-supported study, led by David DeNardo, Ph.D., of the Washington University School of Medicine in St. Louis, were reported March 16 in Cancer Cell.

These findings “have a strong potential to be rapidly translated into novel treatment strategies for pancreatic cancer, a highly lethal malignancy,” said Serguei Kozlov, Ph.D., of the Frederick National Laboratory for Cancer Research, an expert on the interplay between the immune system and pancreatic cancer who was not involved in the study.

Further studies are needed to closely examine the safety of the dendritic cell–directed treatment, as well as its efficacy against cancer that has spread beyond the pancreas, Dr. Kozlov added.

Neoantigens Accelerate Pancreatic Cancer Growth

The immune system has a remarkable ability to kill abnormal or infected cells while leaving healthy cells alone. It tells healthy and diseased cells apart by scanning proteins called antigens on the surface of cells.

If the antigens on a cell’s surface appear normal, the immune system recognizes the cell as part of the body and leaves it alone. But if the antigens are unfamiliar or abnormal (what are called neoantigens), the immune system is more likely to attack.

Scientists think that immunotherapies work best for people whose tumors contain many neoantigens and cancer-killing immune cells. Pancreatic tumors have neoantigens—although not as many as lung or skin cancer—and some have cancer-killing immune cells in them, Dr. DeNardo explained.

So why don’t immunotherapies work for people with pancreatic cancer? One theory is that something in the environment around pancreatic cancer cells prevents the immune system from attacking.

To find out whether that might be the case, Dr. DeNardo’s team modified two well-established mouse models of pancreatic and lung cancer. Both models closely mimic how these cancers are thought to develop in humans, but they don’t have enough neoantigens for the immune system to spring into action.

To address this, the scientists engineered the cancer cells of both models to express an artificial neoantigen, a widely studied protein from chicken eggs called ovalbumin.

This “elegant genetic approach … enables more accurate examination of antigen-specific immune responses in pancreatic cancer and how such responses affect cancer growth,” Dr. Kozlov said.

Dr. DeNardo's team expected the neoantigen to trigger an immune response that slows tumor growth, which is exactly what they saw in the lung cancer model. But, in the pancreatic cancer model, tumors that had the neoantigen grew and spread faster than tumors that did not have the neoantigen.

Further experiments revealed that pancreatic tumors with neoantigen expression had more immune cells that help cancer cells survive and grow. These “pro-cancer” immune cells were present starting from the early stages of pancreatic cancer development, the researchers found.

Pancreatic Tumors Have Fewer, Less Active Dendritic Cells

Next, the team looked at the various types of immune cells in pancreatic and lung tumors with the neoantigen and found a glaring difference.

Pancreatic tumors had far fewer dendritic cells than lung tumors—almost 80 times less. Dendritic cells were also sparse in samples of pancreatic tumors from people, they discovered.

An important role for dendritic cells is teaching cancer-killing T cells what neoantigens to look for in a process called T-cell licensing. In lab studies, the researchers found that dendritic cells from pancreatic tumors were less able to present antigens. As a result, far fewer T cells from mice with pancreatic cancer recognized the artificial neoantigen.

If cancer-fighting T cells are inside the tumor but don’t recognize the tumor’s neoantigens, “then that might be a problem” and might explain why the immune response against pancreatic cancer is ineffective, Dr. DeNardo said.

One possible explanation for why there are fewer dendritic cells in pancreatic tumors is that a healthy pancreas may not have many dendritic cells patrolling through it in the first place, Dr. DeNardo said. Unlike the lungs or skin, the pancreas isn’t a “barrier” organ that encounters a lot of invaders, he explained, so it might not need a lot of dendritic cells.

Another possibility is that dense scar tissue, which typically surrounds pancreatic cancer cells, might prevent dendritic cells from reaching or surviving in the tumor, he added.

Boosting Dendritic Cells in Pancreatic Tumors

Based on these findings, the team reasoned that luring dendritic cells into pancreatic tumors might jump-start an immune response against the cancer. They turned to two drugs, one that mobilizes dendritic cells (called a Flt3 ligand) and another that enhances the function and survival of dendritic cells (called a CD40 agonist).

Treating mice with pancreatic cancer with the drug combination caused dendritic cells to flood into tumors. Compared with mice that were not treated or were treated with only one of the drugs, mice that were treated with the combination had many more cancer-killing T cells—including T cells that recognize the neoantigen—in their tumors. The combination treatment also slowed tumor growth.

Encouraged by these results, the researchers considered ways to enhance the effects of the drug combination. They turned to radiation therapy because studies have shown that it can trigger an anticancer immune response by killing cancer cells and releasing neoantigens.

Although radiation alone or the drug treatment alone had a small effect on tumor growth, treatment with the drug combination followed by radiation shrank pancreatic tumors in mice. And mice treated with the triple therapy lived longer than mice treated with radiation alone.

The team is exploring the effects of the dendritic cell-directed treatment in combination with an immune checkpoint inhibitor (a type of immunotherapy) in follow-up studies, Dr. DeNardo said.

Targeting the Innate Immune System

Dendritic cells are part of the “innate” immune system, the body’s initial response to infection or disease. After that, the “adaptive” immune system—which includes T cells and antibodies—kicks in.

Most immunotherapies in current use target components of the adaptive immune system. This study, on the other hand, is in line with a recent shift toward developing cancer treatments that target cellular components of the innate immune system that have a role in cancer, Dr. Kozlov said.

“These findings identify dendritic cells as yet another component of the innate immune system that, if targeted therapeutically, may improve cancer outcomes,” he noted.

And it’s possible that “targeting parts of the innate and adaptive immune systems at the same time … could lead to additional advances in cancer treatment,” Dr. Kozlov added.

The study also sparks hope that treatments targeting dendritic cells might be effective against other types of cancer that don’t typically respond to existing immunotherapies, he said.