Drawing on several lines of ongoing research, David A. Tuveson, MD, PhD, has created a theoretical framework to consider while developing clinical trials in pancreatic cancer. In his keynote lecture at the 2020 American Association for Cancer Research (AACR) Special Conference on Pancreatic Cancer, “Overcoming the Seven Deadly Hallmarks of Pancreatic Cancer,” he provided a road map for tackling the disease.1
“There are seven major challenges for every patient with pancreatic cancer that we need to address in order to provide them with the most help. The design and conduct of clinical trials of pancreatic cancer have to change [to accommodate these factors], and I plan to spend the rest of my career inspiring others to make this happen,” said Dr. Tuveson, President-Elect of the AACR and Director of the Cancer Center at the Cold Spring Harbor Laboratory, in an interview with The ASCO Post.
Some of the “deadly hallmarks” are part of the disease process, he continued. Others suggest limitations in current approaches to diagnosis and treatment. Herewith, we break down Dr. Tuveson’s seven challenges to the management of pancreatic cancer.
David A. Tuveson, MD, PhD
Inflammation
The inflammatory response manifesting as pancreatitis is the first deadly hallmark of pancreatic cancer. “I predict that everyone who develops pancreatic cancer will have developed pancreatitis at some point, either clinically or subclinically. There are more than 250,000 cases of pancreatitis in the United States each year and 50,000 cases of pancreatic cancer per year,” he said.
Inflammation [ie, pancreatitis] initiates the disease process, keeps it going, and makes pancreatic cancer worse. The link between pancreatitis and pancreatic cancer was discovered by geneticists. Several genes (eg, PRSS1, NR5A2) that put people at risk for pancreatitis and pancreatic cancer promote inflammation of the pancreas.
“In our lab, former Postdoctoral Research Fellow Dr. Dannielle Engle developed a mouse model that can generate CA19-9, which, surprisingly, caused pancreatitis and stimulated pancreatic cancer. We have developed an approach using an antibody molecule called 5B1 that can block pancreatitis in mice that is caused by CA19-9. Dannie’s lab at the Salk Institute and my lab are trying to get this investigational drug off the ground and study it in patients with pancreatitis, but our attempts to study it have been slowed by the COVID-19 pandemic,” he said.
“We have to take the inflammation hallmark of pancreatitis seriously and study blocking and dampening it in patients with pancreatic cancer. 5B1 is also being studied as a potential therapeutic for patients with pancreatic cancer in early-phase clinical trials,” he said.
Other features related to pancreatic cancer may also stimulate inflammation in pancreatitis, including obesity, smoking, and the gut microbiome. These topics are areas for further research.
Desmoplastic Stroma
“If you think of inflammation as the [initial] flame that causes pancreatic cancer, desmoplastic stroma would be the [resulting] fire,” Dr. Tuveson told listeners.
Desmoplasia is a scar-like structure in the stroma around cancer cells unique to pancreatic cancer. Efforts to target desmoplasia focus on modifying the fibroblasts—cells that produce the stroma—and blocking the ability of fibroblasts to create desmoplasia and other cells that promote cancer cells and immune evasion, leading to cachexia.
One of these approaches is to block the function of interleukin (IL)-6. Another approach is to use synthetic vitamin D to modify fibroblast activation. Yet another is AMD3100, a compound that blocks CXCL12’s ability to bind to its receptor. This is important because CXCL12 is a chemokine made by fibroblasts that prevents T lymphocytes from attacking the tumor, a discovery originally made by Dr. Douglas Fearon when he was in Cambridge in the United Kingdom.
Dysregulated Metabolism
In keeping with the metaphors of flame and fire, Dr. Tuveson continued, “dysregulated metabolism is the pot on the stove making food to feed the hungry pancreatic cancer cells.”
Pancreatic tumors have few blood vessels, and tumor blood flow is sluggish. Dr. Dafna Bar-Sagi discovered that the surviving pancreatic cancer cells eat the stromal proteins surrounding it, and this protein breaks down inside the cell into amino acids that fuel cell division. There are several approaches to blocking the pancreatic cancer cells’ ability to eat the protein.
“In our lab, we are studying a process by which pancreatic cancer cells lower the amount of oxygen, producing reactive oxygen species,” Dr. Tuveson said. Moderate levels of reactive oxygen species facilitate carcinogenesis, but excessive levels are damaging to cancer cells. “Causing reactive oxidation makes the cancer cells ‘unhappy’…. Giving high doses of oxidized vitamin C, called deoxyascorbic acid, is a potential treatment strategy for pancreatic cancer discovered by Lewis Cantley, PhD, and Douglas Spitz, PhD. Investigational trials are studying this approach,” he said.
“The metabolic milieu of pancreatic cancer is very complex. We have much more work to do,” he commented.
Metastasis
Returning to his metaphor, Dr. Tuveson explained: “Metastasis can be conceptualized as what comes out of the pot [ie, dysregulated metabolism].” From its inception, pancreatic cancer cells rapidly spread far and wide, trying to escape a hostile environment. When cancer metastasizes, it is difficult to help patients…. An important concept is to study ways to prevent metastasis in pancreatic cancer.”
New understanding of the molecular pathway by which pancreatic cancer cells transit from low grade to high grade has elucidated a major part of the metastatic process. According to Dr. Tuveson, a better appreciation of disease subtypes may help us figure out how to block that process with novel treatment approaches. Two general subtypes of pancreatic cancer have been defined: the classical subtype, with which patients live longer, and the basal-like subtype, where they die more quickly.
Undruggable KRAS
“Ninety percent of patients with pancreatic cancer have mutated KRAS…. This is the Gordian knot of pancreatic cancer…. Learning how to target KRAS is extremely important. Although there is now a drug that targets the KRAS G12C mutation in non–small lung cancer [ie, sotorasib], only 1% of patients with pancreatic cancer have this mutation. We don’t have drugs like this in pancreatic cancer yet,” Dr. Tuveson explained.
“We need to discover ways to target KRAS. Lowering KRAS levels could really help patients with pancreatic cancer. If we had a drug to target KRAS and could attack one of the other hallmarks of this disease, we could potentially have a winning combination. If we could go after two or more hallmarks, we might see significant benefits in our patients,” he said.
“KRAS is the best Achilles’ heel we have, and we need to make better arrows,” he added.
“If we could go after two or more [disease] hallmarks, we might see significant benefits in our patients.”
Rapid Deconditioning
Another hallmark, rapid deconditioning, is a patient factor. Patients with pancreatic cancer can become sick very quickly, out of proportion to the amount of cancer harbored in their bodies.
We have to take the inflammation hallmark of pancreatitis seriously and study blocking and dampening it in patients with pancreatic cancer.— David A. Tuveson, MD, PhD
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“At first, they don’t feel well, but they can talk and eat and perform activities of daily living, but suddenly they get super sick. They develop cachexia, become very thin, develop blood clots, and run out of steam. This makes it very hard to treat them with chemotherapy. They are also too sick to go on clinical trials,” Dr. Tuveson noted.
Thus, patients with pancreatic cancer tend to be undertreated. Most patients are too sick after first-line chemotherapy to get second-line therapy. Only one drug is approved in the second-line setting for this disease.
“We need to think about the patient with pancreatic cancer differently from those with other types of cancer. We need to administer medications differently and follow the patient more closely. These patients have no physiologic reserve. We have to do better as medical practitioners,” he stated.
One approach is to go after the cause of cachexia. IL-6 is being studied in this regard. Also, proper nutrition is important.
“We need to think about the patient with pancreatic cancer differently from those with other types of cancer. We need to administer medications differently and follow the patient more closely.”
Diagnostic Deficiency
The seventh deadly hallmark of pancreatic cancer is diagnostic deficiency, said Dr. Tuveson. “There is a deficiency of good diagnostics in pancreatic cancer. In lung cancer, x-rays, [magnetic resonance imaging], and [computed tomography] scans can measure tumors, but in pancreatic cancer, it is difficult to visualize the tumor. We need better radiographic methods to detect pancreatic cancer earlier and better methods of measuring responses to medications,” he continued.
Without such tools, patients may be treated for too long before therapy is modified. “We need more specific measures for this disease that can help us take care of the patient today, so he or she can get better tomorrow. Diagnostics is a major problem for pancreatic cancer,” he said.
One approach being studied is the use of artificial intelligence with computer-generated deep-learning algorithms to study scans for earlier detection of pancreatic cancer.
Conclusion
“Addressing the seven deadly hallmarks of pancreatic cancer is a contextual framework I have developed. This is a hypothesis, a starting point for us in the field to think about why our patients are not getting better. Typically, oncologists don’t think about inflammation, desmoplasia, or dysfunctional metabolism. They focus on whether the chemotherapy they are giving will work,” he said.
“Researchers in the field could consider an approach where we evaluate these seven hallmarks in each patient and think about what is going on. With this approach, I believe we would actually help our patients,” he added.
DISCLOSURE: Dr. Tuveson has served as a consultant or advisor for Leap Therapeutics, Surface Oncology, Cygnal Therapeutics, and Mestag Therapeutics; holds stock in Leap Therapeutics and Surface Oncology; is a scientific cofounder of Mestag Therapeutics; has received honoraria from Ono Pharmaceutical, Chugai, and Merck; and has received research support or other funding from Ono Pharmaceutical, FibroGen, Mestag, Thompson FF, Lustgarten Foundation, and the National Cancer Institute.
REFERENCE
1. Tuveson D: The seven deadly hallmarks of pancreatic cancer. AACR Virtual Special Conference: Pancreatic Cancer. Presented September 29, 2020.
