Pancreatic Cancer
Pancreatic ductal adenocarcinoma, PDAC, is recognized as one of the deadliest cancers, with a 5 year survival rate of less than 15%. It is an aggressive cancer, commonly asymptomatic for extended periods and with no reliable biomarkers that would suggest earlier disease presence. As a result, disease is commonly advanced or metastatic at the time of diagnosis.
It is a disease primarily of older adults, usually over the age of 65. It is rare in people under 40 but it is starting to become more prominent in 40-64 year old age groups. It accounts for 3% of cancers in America but it is an aggressive disease. To achieve long term survival, early diagnosis is necessary, sometimes occurring serendipitously due to radiology imaging of the abdomen for other concerns. Advancements in diagnosis and treatment are becoming more promising, raising optimism for new approaches to impact the disease.
Factors Associated with Obstacles to PDAC Treatment
There are genetic mutations seen in PDAC that change the normal actions of genes and allow uncontrolled cancer growth that contribute to the aggressiveness of disease. These abnormal mutations occur in
TP53, a gene that makes p53, a tumor suppressor that regulates replication of cells and normally prevents uncontrolled cell growth
KRAS gene is the template to create K-Ras which controls cell signaling to regulate growth
SMAD4 is a gene that makes a protein that allows cell signals to go from the surface to the nucleus and is essential in the TGF-B signaling pathway that regulates the synthesis of DNA and RNA, a tumor suppressor acting to limit uncontrolled cell growth
CDKN2A is a gene that produces tumor suppressor proteins, helping to control cell growth.
Mutations in these genes negates their suppressive actions and are associated with cancer proliferation.
Desmoplastic Stroma
Another significant impediment to pancreatic cancer treatment is the presence of a dense fibrous connective tissue, collagen and extracellular matrix substances, called Desmoplastic stroma, surrounding the tumor. Due to this thick protective structure it creates a barrier that is less permeable to immune cells entering, and penetration by chemotherapy drugs, producing a terrain supportive of aggressive invasive cancer.
Autophagy is a response in which damaged cellular components, or unneeded materials are broken down to be reused as nutritional components for metabolic pathways or structural intracellular reconstruction. It is tightly regulated in the body and normally subject to cellular regulation but has been shown to be enhanced in pancreatic cancer, to allow sustained tumor growth when limited resources are available. It is currently a target of research therapies in mouse models to inhibit its effect in PDAC.
Treatment for Pancreatic Ductal Adenocarcinoma (PDAC)
People with PDAC require chemotherapy regardless of their status when diagnosed.
Resectable Tumors
Surgery for resectable pancreatic adenocarcinoma is called the Whipple Procedure. It is a MAJOR surgery, a pancreaticoduodectomy or the removal of the head of the pancreas ,the duodenum, the gallbladder and part of the bile duct. The tumor is removed, and the digestive system is refigured and reconnected. Recovery is slow, often requiring many months.
In patients with an initial diagnosis of a primary tumor that can be removed surgically, which is the only potentially curative treatment, the recurrence rates are still high, occurring in almost half the patients.Therefore, adjuvant chemotherapy is given, therapy after the initial surgical procedure, to prevent the formation of new tumors. And in some situations intraoperative radiation is also utilized.
The current standard with the longest overall survival, in this situation, is mFOLFIRINOX consisting of the chemotherapies, Leucovorin, Fluorouracil, Irinotecan and Oxaliplatin. Using this combination cancer specific survival was 4 1/2 years with metastasis free survival of approximately 3 years.
While many other types of cancer are now showing improved survival with immunotherapy, treatment in PDAC is often ineffective due to the terrain around the cancer. This is because of the dense fibrotic tissue and low oxygen levels in the tumor microenvironment making it difficult for immune cells and drugs to penetrate this protection. In addition, the cancer is also able to suppress the immune system function.
Locally Advanced PDA
Requires neoadjuvant chemotherapy prior to exploratory surgery, and the FOLFIRINOX regime is currently the standard used.There are multiple studies using different neoadjuvant combinations which appear to allow approximately two thirds of the people to undergo surgical removal of visual tumor and experience better survival at 1 year.
However, neoadjuvant therapy does have an increased risk of hematologic side effects and there is debate about indications for its use.
Also, at diagnosis, 30% of cases of locally advanced disease, with no spread distantly, cannot be surgically removed due to the vascular interlacing within the tumor but. This makes complete surgical exclusion of tumors very difficult and survival is poor.
Chemo/Radiation Therapy
A multicenter study randomized trial, from 2004 with Drs Neoptolemos and Beger, assigned 73 patients with resected pancreatic cancer to treatment with chemo and radiation therapy or 75 patients to chemotherapy alone, and 69 patients for observation.
In patients receiving the chemoradiation treatment , the 5 year survival was 10% and in those that did not receive any chemoradiotherapy it was 20%. Those receiving chemotherapy had a 5 year survival of 21% and 8% in those that did not receive chemotherapy.
The conclusion was patients receiving chemotherapy had a survival benefit while those that received chemoradiotherapy had an adverse effect.
Metastatic Disease
In metastatic pancreatic cancer, treatment is with multiple chemotherapies in combination, and FOLFIRINOX is again the standard used currently. Survival with chemotherapy was 11 months versus 7 months in a control group but the time to progression free survival was < 7 months with chemotherapy and it was associated with significant toxicity in almost half of the treated patients.Immunotherapy for pancreatic cancer has uniformly had poor results.
The Changing Approach to Pancreatic Ductal Cell Carcinoma
As can be seen from the limited effect of chemotherapy and even surgery, investigators and scientists are seeking to develop new innovative treatments to improve survival in this aggressive deadly disease.
mRNA Based CancerVaccine
The initial information from 2023 involved a Phase 1 trial where an individually synthesized adjuvant neoantigen vaccine was created from patients with resectable surgically removed pancreatic ductal adenocarcinoma, PDAC. Neoantigens are new proteins that form on cancer cells due to the mutations of those cells. Based on these new antigen expressions, the hypothesis suggested that the potential exists for the immune system, if primed correctly, to stimulate the production of CD8 T lymphocytes, and attack the pancreatic cancer cells and kill them.
The study design protocol was, surgery and preparation of the vaccine from an individual's PDAC tissue, followed sequentially by an immune checkpoint inhibitor drug to allow the immune system to be unrestrained in activity. The vaccine was introduced and then the FOLFIRINOX chemotherapy combination was given.
The study looked at whether increased immune attacking CD8 T cells were generated by the vaccine and whether it would produce longer disease free survival. There were 16 patients, and half developed high levels of T cells to the neoantigens.
The results at 18 months showed that those who had vaccines had increased T cells compared to those without vaccine treatment and they had a longer median recurrence free survival of 13.4 months.
FOLLOW UP 3.2 years later
The goal of the follow up was to assess delayed PDAC recurrence but also to evaluate if the T cells induce an immune memory, and if so were they still effective. In the data analysis, these T cells showed they had excellent functionality at 3.6 years that correlated with delayed recurrence.
KRAS Targeted Drugs Against Pancreatic Ductal Adenocarcinoma
Many types of cancer are promoted by the RAS gene mutation, commonly K-RAS, including colorectal,and non-small cell lung cancer. Pancreatic ductal adenocarcinoma can be driven by this pathway which when aberrant allows uncontrolled cancer growth. Treatment goals are to turn off the mutated gene’s signals and stop growth.
A mouse study,from 2023, identified an experimental drug that targeted pancreatic cancers with a specific KRAS G12C mutation which occurs in 1-2% of pancreatic cancers . The drug stopped growth or decreased tumor size in the KRAS mutations. It also altered the tumor microenvironment and allowed T cells into the tumor terain, allowing the immune system to recognize the cancer.
A phase 1-2 trial study, from 2022, evaluated the safety and effect of the oral drug Sotorasib, (Lumakras), on 38 patients with advanced pancreatic cancer that had been treated with a previous chemotherapy. It was effective in decreasing tumor size in 20% of the people with this mutation.
A new study, published May 6,2026 in the New England Journal of Medicine by Wolpin,Park,Punekar and others was a phase 1-2 trial that evaluated Daraxonrasib in the treatment of advanced PDAC with RAS mutations. Its mode of action targets a mutation called guanosine triphosphate bound -mutant and wild type RAS. Doses used varied and the ultimate goal at this early study juncture was to evaluate the safety of the drug and included 168 treated patients. Side effects of any type occurred in 96% and severe ones in 30%.
In the specific RAS G12 group of 26 patients a measured response occurred in 35%. The median duration of response was 8.2 months, with median progression free survival of 8.5 months and 13.1 months of overall survival.
In other RAS mutations,G12,G13 or Q61 mutations, 29% had an objective response; with 8.2 months median duration of response and 8.1 months median progression free survival and 15.6 months for overall survival.
Pancreatic Cancer Invasion and Spread
Epithelial cell cancers are called carcinomas and line the airways and alveoli of the lungs, the entire GI tract, and act as a protective barrier of body cavities. They also line the interior of blood vessels and compose glandular tissues.
Metastasis
Epithelial lining cells of an organ or tissue are fixed and normally are unable to migrate. To do this requires that they become mobile so they can enter the vasculature and travel to a new site and adapt to the new microenvironment and commence growth.
Normally epithelial cells adhere and contact other cells, and are oriented in a specific direction and are anchored to a basement membrane. In embryologic development and wound healing the body enlists the epithelial-mesenchymal transition,EMT, program which allows the epithelial cells to loosen their bonds, change position, become mobile and travel to other areas. During embryonic development EMT allows these cells that have the plasticity to differentiate into other tissues. For example neural crest cells in the developing fetus can migrate and become peripheral nerves,facial cartilage and adrenal tissue. However, to prevent abnormal migration, cells that become detached eventually undergo anoikis or attachment induced apoptosis cell death. To prevent cell death and allow migration when needed the body upregulates Netrin-1, a protein encoded by the NTN1 gene in humans which is crucial for cellular migration by preventing this attachment apoptosis.
In pancreatic cancer, and breast, lung and colorectal cancers, the tumor itself is capable of producing Netrin-1, in the tumor microenvironment under certain conditions stimulating pathways that create persistent inflammation which stimulates the IL-1/Inflammosome pathway that requires cells to migrate for healing the damage. In this situation the tumor and its microenvironment stimulate EMT development signals that allow metastasis by producing Netrin-1 to allow cancer spread.
Chemoresistance
With the cancer promoting EMT and the production of Netrin -1 it also recognized that there is an increase in resistance to chemotherapy drugs and a reduction of their effectiveness.
A study published in Nature,April 2026, by Drs Roth, Artu, Mehlen and multiple other contributors showed the creation of a Netrin-1 antibody (NP137) in preclinical and clinical situations inhibits tumor EMT.
A phase 1 study assessed the combination of NP137 with modified FOLFIRNOX in the initial treatment of 43 patients with advanced pancreatic cancer. Median progression free survival was almost 11 months, and median overall survival was sixteen months. 23% were also able to then have surgery and their surgical specimens showed that the therapeutic combination down regulated the EMT. Also patients that had high levels of Netrin-1 receptors had longer survival.
The conclusion was that Netrin-1, by inhibiting EMT, reduced chemotherapy resistance.
Treatment With an Electric Field Device
An Electric Field Device In February, 2026 was approved by the FDA, a first of its kind device for treating locally advanced pancreatic cancer. It is called Optune Pax, a portable non-invasive device that delivers alternating electrical fields, called tumor treating fields(TTFields) to the abdomen. It is designed to physically disrupt the cancer cell accelerated replication, while creating minimal damage to healthy tissue.
It is administered through electrically insulated adhesive patches placed on the skin and connected to an electric field generator. It is a continuous treatment and the generator is carried in a specifically designed bag with preset, unchangeable parameters that can only be adjusted by the manufacturer.
The basis of premarket approval is based on clinical study with locally advanced pancreatic cancer for up to five years which was used with two standard of care chemotherapies, gemcitabine and nab-paclitaxel and improved survival by 2 months compared to chemotherapy alone.
Landmark Artificial Intelligence Application In Early Pancreatic Cancer Diagnosis
The Mayo Clinic and MD Anderson Cancer Center have developed an AI model called the Radiomics -based early detection model REDMOND. It is based on the analysis of nearly 2000 CT scans, including scans from patients later diagnosed with pancreatic cancer to allow the AI model to learn subtle tissue texture and changes in pancreatic structure that were unlikely to be identified with human eyes.
AI was able to successfully recognize PDAC, pancreatic ductal adenocarcinoma approximately 16 months before diagnosis and it was double the detection rate when compared to radiology specialists reviewing the same scans without AI.
It also identified suspicious patterns suggestive of PDAC 2 years before diagnosis.
While still in the research stage, there is optimism that it may revolutionize diagnosis of early stage PDAC and help patients be diagnosed and treated at much earlier stages of disease when curative treatment might be possible.