Dana-Farber investigators are at the forefront of a new era in RAS therapeutics for pancreatic cancer research
July 1, 2026
By Elizabeth Dougherty
Brian Wolpin, MD, MPH, has been treating patients with pancreatic cancer for 20 years. Over those years, he's often witnessed one of the hallmarks of the disease – abdominal and back pain that slowly, and only sometimes, goes away with chemotherapy.
A few years ago, however, in the early stages of a clinical trial of a new drug, a few of Wolpin's patients told him their pain had vanished within weeks of starting treatment.
"The dose of the new medicine that we had given was relatively low and yet the patient's pain had rapidly improved," says Wolpin, who is the Robert T. and Judith B. Hale Chair in Pancreatic Cancer and director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber. "Something was happening here that was different."
Recently, the results of a global phase 3 trial of that same drug have made headlines, reporting a doubling of median survival times and improved quality of life for patients with previously treated metastatic pancreatic cancer compared with earlier therapies. The drug, daraxonrasib, targets the RAS family of proteins, which are known to be mutated and cancer-driving in more than 90% of patients with pancreatic cancer. Daraxonrasib is the first RAS inhibitor to show encouraging signs of efficacy in a large phase 3 trial of patients with metastatic pancreatic cancer, and fortunately for patients, many other RAS-targeted therapies – from small-molecule inhibitors and degraders to cell therapies and vaccines – are being tested in the clinic or are coming soon.
From left, Brandon Huffman, MD, Brian Wolpin, MD, MPH, Andrew Aguirre, MD, PhD, and Stephanie Dougan, PhD.
A little more than a decade ago, a targeted RAS inhibitor was unthinkable. RAS proteins were deemed "undruggable" because they don’t have the deep pockets needed to jam up their machinery with small molecule drugs. Two developments changed the course of history. One was an advancement in medicinal chemistry that made it possible to inhibit RAS.
The other was the galvanizing work, over many decades, of a community of investigators devoted to improving the lives of patients with pancreatic cancer. Researchers at Dana-Farber's Hale Family Center for Pancreatic Cancer Research, for example, are committed to laboratory, translational, and clinical research focused specifically on pancreatic cancer. They have built trusted research partnerships with patients. When the moment arrived to develop new approaches to treat pancreatic cancer, Dana-Farber's team of experts was ready to work with pharmaceutical and biotechnology companies, patients, and other researchers to make that possibility a reality.
"We have a nucleus of expertise at the Hale Center that has been completely committed to pancreas cancer research," says Andrew Aguirre, MD, PhD, associate director of the Hale Family Center and co-director of the Center for RAS Therapeutics at Dana-Farber. "This is the right place and the right time, and we have had the support to jump on this opportunity and move it forward as quickly as possible."
KRAS and Pancreatic Cancer
In 2003, it was already known that mutations in a RAS family gene called KRAS occur in many patients with pancreatic cancer. At that time, while working as a graduate student in the lab of former Dana-Farber scientist Ronald DePinho, MD, PhD, Aguirre studied how the KRAS mutation can initiate pancreatic cancer and drive its growth.
Aguirre's research also established an animal model of pancreatic cancer that could be used to test potential therapeutics and learn more about the biology of the disease.
"That was among the first models that really allowed us to study pancreatic cancer in a thorough way in the laboratory," says Wolpin.
At that time, however, RAS was still thought to be undruggable, so there were no RAS inhibitors to test using this model. But Aguirre remained hopeful and continued working toward discoveries that could eventually unlock better outcomes for patients. He joined the lab of Dana-Farber’s William Hahn, MD, PhD, who is known for developing so-called “wiring diagrams” for cancer. Hahn, Aguirre, and Dana-Farber scientist Srivatsan Raghavan, MD, PhD, teamed up to use genetic screening tools to detail how RAS drives cell growth and to expose new therapeutic vulnerabilities in pancreatic cancers.
Then, in 2013, while Aguirre was still a postdoc, a scientific paper suggested it was possible to inhibit RAS. He and Wolpin were captivated by the report of small molecules that bound to RAS, though many years of work remained to refine this concept into safe and effective human medicines.
The agents weren’t even drugs yet, but the chemistry was there. My first thought was, holy smokes, maybe this could lead to therapies that would benefit our patients with pancreatic cancer.
"The agents weren’t even drugs yet, but the chemistry was there," recalls Wolpin. "My first thought was, holy smokes, maybe this could lead to therapies that would benefit our patients with pancreatic cancer."
By 2018, pharmaceutical companies had turned these concepts into medicines targeting mutant RAS proteins in other cancers, and Aguirre and Wolpin had begun working with them to develop drug candidates relevant to pancreatic cancer. Aguirre, who by then had started his own lab and clinical practice at Dana-Farber, began testing the agents in patient-derived tumor models and animal models, including the model he had developed as a student. He and Wolpin also shared their deep knowledge of patients with pancreatic cancer to help design clinical trials.
"Based on those efforts, today Dana-Farber is a key center for running these trials," says Aguirre. "The companies developing the drugs and sponsoring the trials could come to one place, Dana-Farber, where there are experts in preclinical work, translational work, clinical trial development, and where there is a critical mass of clinicians and scientists who are completely focused on pancreas cancer."
The pancreas (yellow), which is responsible for creating enzymes and hormones that regulate digestion and blood sugar, is a six-inch long gland that sits deep inside the abdomen. Its location makes screening for pancreatic cancer challenging. Dana-Farber investigators are exploring innovative approaches to early detection so that more patients can be diagnosed earlier, when a cure is more likely.
RAS Inhibitor Research
Now, one of these trials, led by Wolpin, is transforming the landscape of pancreatic cancer treatment. The trial evaluated daraxonrasib as second-line treatment for patients with metastatic pancreatic cancer and found that nine out of 10 patients taking the drug saw their cancer shrink or stop growing. Many are living longer and experiencing fewer side effects compared to what has been observed with chemotherapy. The study results were presented by Wolpin at the ASCO annual meeting on May 31, 2026, and simultaneously published in the New England Journal of Medicine.
While some patients have experienced side effects, such as painful mouth sores or rashes, “compared to chemotherapy, the side effects of this oral medicine seem to be much more manageable,” says Brandon Huffman, MD, an expert in pancreatic cancer treatment at Dana-Farber who leads several RAS inhibitor clinical trials.
The results are so promising that follow-on trials are already underway to test the drug as an earlier line of therapy and in combination with chemotherapy in patients with advanced disease. Studies will also determine if the drug can stave off recurrence after surgery in patients with localized disease.
A mutant protein in the RAS-family (dark blue) drives 90% of pancreatic cancer cases. RAS inhibitors that block nearly all forms of RAS work by using a molecular glue (light blue) and another protein (cyclophilin A in yellow) to form a shield that blocks RAS proteins from signaling the cell to grow. RAS inhibitors are poised to dramatically shift the way pancreatic cancer is treated.
Other promising RAS inhibitors are also being tested. One such inhibitor targets one specific mutation, KRAS G12D, which is seen in about 40% of patients with pancreatic cancer. (By contrast, daraxonrasib targets a wide range of RAS mutations.) Huffman, who is principal investigator for a phase 3 randomized, placebo-controlled trial of chemotherapy with or without a KRAS G12D inhibitor, is excited to provide this option to patients.
"As a single agent in an earlier trial, this drug was highly active, which is really remarkable," says Huffman. "It is very promising."
Patients taking RAS inhibitors alone do relapse, suggesting that some tumor cells can evade the treatment and resurge. Combining these drugs with chemotherapy aims to boost the killing of those escapees without adding too many side effects beyond those of standard chemotherapy.
"It is really early days in terms of understanding how we will use these oral KRAS inhibitors in the long run," says Huffman.
RAS Therapeutics Across Cancer Types
A few years ago, when RAS inhibitors began to gain traction for pancreatic cancer, Aguirre and Wolpin recognized a need to collaborate not only across the pancreatic cancer research community, but also beyond it. RAS mutations also occur in approximately 25% of non-small cell lung cancer cases, half of colorectal cancer cases, and in other cancers, including ovarian and biliary cancers.
The types of RAS mutations differ across diseases, requiring different inhibitor designs. In addition, drug developers began adding to the arsenal of small molecule inhibitors by devising degraders and cellular therapies that target RAS.
Alice Shaw, MD, PhD (left), and Andrew Aguirre, MD, PhD, co-direct Dana-Farber's Center for RAS Therapeutics.
"The drug development landscape for RAS inhibitors was getting so complicated that we needed a cross-disease center that could help us learn from one another and work efficiently with companies to vet novel medicines in our models and test them in clinical trials," says Aguirre, who in 2024 co-founded and now co-directs Dana-Farber's Center for RAS Therapeutics with Alice Shaw, MD, PhD, chair of Medical Oncology, chief of Strategic Partnerships, and a thoracic oncologist at Dana-Farber. "We want to figure out which are the best therapies to put Dana-Farber resources behind, and which are most likely to benefit the patients who opt to join our clinical trials."
For example, Dana-Farber investigator Rishi Surana, MD, PhD, a gastrointestinal cancer expert, is collaborating with Jennifer Marks, MD, a thoracic oncologist, to lead a clinical trial of a T-cell receptor (TCR) therapy that targets KRAS and is open to certain patients with metastatic solid tumors with KRAS mutations.
In addition to vetting novel therapies and testing them in the clinic, pancreatic cancer researchers at Dana-Farber are also developing novel approaches to treatment in the laboratory.
For instance, one project underway aims to discover more RAS antigens, which are fragments of RAS-mutant proteins that might appear as a flag on a cancer cell. These antigens can be targeted by TCR therapy and other immunotherapies. This work is being done by researcher William Freed-Pastor, MD, PhD, using a novel antigen discovery tool called immunopeptidomics.
Early Detection and Prevention in Pancreatic Cancer
As promising as RAS therapeutics are, they are still mostly being used to treat advanced cancer. Approximately 80% of patients with pancreatic cancer discover the disease late, when it has already spread and cannot be surgically removed.
Currently, there is no recommended screening test for pancreatic cancer, but Wolpin is exploring a few different approaches. In a collaboration with MIT, he is working on developing a stool test to detect the disease. In other research, he and his colleagues are using AI to examine millions of medical records to see if they contain hints of changes that could point to the early development of pancreatic cancer.
It is known that pancreatic cancer begins with precancerous lesions, and based on research at Dana-Farber and elsewhere, it is known that these lesions depend on RAS-mutant proteins to drive them. That means there is potential, with advances in screening methods, for RAS inhibitors to be used to treat the very earliest stages of disease and possibly even eradicate it before it begins. This could be particularly promising for patients with a strong family history of pancreatic cancer, or with inherited mutations that increase the risk of the disease.
"Could we treat these patients before they have cancer and clear out those early lesions, wiping the slate clean, so to speak?" says Aguirre.
Aguirre, Wolpin, Huffman, and Dana-Farber molecular pathologist Jonathan Nowak, MD, PhD, recently received support from the Mark Foundation and Lustgarten Foundation for a series of studies, both preclinical and clinical, to begin testing some of these ideas. It’s all part of their quest to harness the power of the clinical and research engine within the Dana-Farber community. That engine brings together scientists who are primed with decades of knowledge and expertise, a supportive environment for clinical trial patients, and collaborative relationships across cancer centers and industry, to transform the lives of patients with pancreatic cancer everywhere.
Stephanie Dougan, PhD
A Fresh Look at Immunotherapy for Pancreatic Cancer
In the past, pancreatic cancers have not responded to immunotherapy, in part because RAS suppresses and blocks the immune system. But Dana-Farber immunologist Stephanie Dougan, PhD, thinks that RAS inhibitors might create a window of opportunity for the immune system to be successful against the disease.
"The early success of RAS inhibitors rejuvenates some of our ideas about immunotherapy," says Dougan. "If a RAS inhibitor can shrink a tumor, for example, can we get a T-cell response to come in and clear out the rest? Can it eliminate every last tumor cell?"
One way to generate such a T-cell response might be through AI-generated cytokines. Natural cytokines are immune signaling molecules that can activate T cells. AI-generated cytokines have been designed using artificial intelligence to mimic a natural cytokine and be both highly stable and more specific to the tumor to reduce side effects. Dougan has tested such a cytokine mimic in models of other forms of cancer and is exploring its potential as a companion treatment with RAS inhibitors in models of pancreatic cancer.
"We're going back to what we've learned about how a RAS-mutant tumor is wired, what changes when we block RAS, and what's meaningful to think about for new therapies," says Aguirre. "Our best scientists and clinicians are thinking about pancreatic cancer every day and bringing their best ideas. It's an inspiring time."
