Pancreatic Cancer: Emerging Breakthroughs and Clinical Strategies

Pancreatic cancer is one of the most fatal malignancies, with one of the lowest cancer survival rates.¹ The most common type of pancreatic cancer—called pancreatic ductal adenocarcinoma (PDAC)—starts in the cells lining the ducts that carry digestive enzymes out of the pancreas. A minority of pancreatic cancers also emerge within hormone-producing cells of the pancreas.

Pancreatic cancer often causes symptoms only after it has spread to other organs, leading to diagnoses in advanced stages and its high mortality rate. Another challenge that contributes to the low pancreatic cancer survival rate is the development of resistance to chemotherapy.² The heterogeneity of the tumor microenvironment and its dense protective stroma promote its chemoresistance.

However, researchers are increasingly understanding more about pancreatic cancer, contributing to advances in vaccines against the condition and more effective treatment options including those in combination with chemotherapy. Read on to learn about breakthroughs and clinical findings that offer strategies to overcome the barriers posed by pancreatic cancer tumors.

Redefining Success in Pancreatic Cancer Therapy

When developing and testing pancreatic cancer therapies, researchers at the biotechnology company Immuneering reconsidered their goals. They shifted their aim from shrinking tumors rapidly to “outlasting the disease” and prioritizing patient survival, ultimately leading to the creation of a new category of cancer drugs called deep cyclic inhibitors. The first of these drugs called atebimetinib suppresses an important cell survival pathway in a pulsed manner, giving time for healthy cells to recover when the inhibition is released. However, cancer cells need constant signaling for survival, leading to atebimetinib selectively targeting cell survival in tumor cells. In a Phase 2a clinical trial, the researchers observed that atebimetinib treatment in combination with chemotherapy in 34 patients with pancreatic cancer led to a 94 percent six-month survival, far surpassing conventional chemotherapy benchmarks.

Pancreatic Cancer Clinical Trial Reveals a Drug that Doubles Survival Rate

Results from a Phase 3 pancreatic cancer clinical trial demonstrated that the drug daraxonrasib extended the survival rate of people with pancreatic cancer by more than 13 months on average. In comparison, those treated with another chemotherapeutic drug lived 6.7 months. Daraxonrasib blocks the RAS signaling pathway—which controls cell growth, division, and survival—that has long been implicated in driving pancreatic cancer, with more than 90 percent of tumors showing mutations in a RAS gene. People who received the drug also showed slower disease progression compared to those who received standard chemotherapy. With experts not associated with the trial lauding the results as significant and promising, the findings could represent a milestone in the approach to treating pancreatic cancer.

Pancreatic Cancer Vaccine Trial Shows Promise

Elizabeth Jaffee, an oncologist at Johns Hopkins University, and her team examined the potential of a vaccine targeting the most common mutations in PDAC in a Phase 1 clinical trial. They administered the peptide-based vaccine, which they had previously shown was safe, to people at a high risk for PDAC who had pancreatic lesions that had not developed into cancer. Their results demonstrated that the vaccine triggered specific immune responses and slowed the growth of pancreatic lesions, offering a proof-of-concept supporting the use of vaccines as interventions for pancreatic cancer.

Pancreatic Cancer Chemotherapy and Sunshine

Pancreatic cancer cells envelop themselves in a dense mesh of extracellular matrix containing cells like fibroblasts, which creates a barrier against chemotherapeutic drugs. More than a decade ago, Ronald Evans, a molecular biologist at the Salk Institute for Biological Studies, found that activating the vitamin D receptor in pancreatic fibroblasts in mice along with chemotherapy could prevent fibrosis, extending survival. Building up on this, Evans and his team tested a vitamin D agonist, called paricalcitol, in combination with chemotherapy in people with metastatic pancreatic cancer. They found that this treatment was generally safe, and that those who expressed vitamin D receptors at greater levels showed better outcomes, indicating that a section of the population may benefit more from the treatment.

Immunotherapy for Pancreatic Cancer Exposes Cancer Cells to Macrophage Attack

Northwestern University glycobiologist Mohamed Abdel-Mohsen and his team investigated if complex sugars, or glycans—which regulate the immune system—could help pancreatic cancer cells evade the body’s defenses. Single-cell RNA sequencing from human PDAC tumors revealed that immune cells within the tumor microenvironment expressed genes encoding a glycoprotein. This is normally found on healthy cells, where it signals immune cells not to attack them. Abdel-Mohsen and his team developed an antibody to block the binding between the glycoprotein and immune cell receptor, rendering tumor cells sensitive to macrophage attack, potentially guiding the development of immunotherapy for pancreatic cancer.

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Next Frontiers in Cancer Immunotherapy

Experts will discuss emerging approaches for profiling the tumor microenvironment, identifying neoantigens, developing cell therapies, and addressing challenges in preclinical immunotherapy research.

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Diet for Pancreatic Cancer? Mouse Study Offers Clues

University of California, San Francisco cancer biologist Davide Ruggero and his team had been studying the molecular mechanisms behind the benefits of fasting and a ketogenic diet consisting of high-fat and low-carbohydrate meals. They found that mice on these diets showed increased phosphorylation of a protein called eukaryotic translation initiation factor (eIF4E), resulting in the formation of ketone bodies—compounds produced from fatty acid breakdown. Since pancreatic cancer cells can use ketone bodies as an energy source, Ruggero and his team wondered whether under a ketogenic diet, these tumors rely on phosphorylated eIF4E-mediated translational reprogramming for survival. Treating mice with a drug that inhibits phosphorylated eIF4E in combination with a ketogenic diet showed reduced pancreatic cancer growth. However, the drug had no effect on mice that received a normal diet, indicating that personalized drug-diet combinations could potentially be used for cancer therapies.