Advances in Pancreatic Cancer Research

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

Patients with pancreatic cancer are generally recommended to have genetic testing for inherited mutations and, if they have advanced or metastatic disease, biomarker testing of their tumor. Both types of testing can help suggest possible treatments and can indicate whether a patient’s family members might have an increased risk for pancreatic cancer or other types of cancer.

Chemotherapy

For people who have pancreatic cancer that can be removed surgically, chemotherapy is often given, sometimes along with radiation, before surgery (called neoadjuvant chemotherapy) or after surgery (adjuvant chemotherapy). Neoadjuvant chemotherapy can help shrink the tumor before it's removed, and adjuvant chemotherapy can kill cancer cells that may remain in the body after surgery.

Researchers are investigating whether chemotherapy regimens that have been found to extend the lives of people with metastatic disease are more effective than standard treatments when used as neoadjuvant treatment for people with operable pancreatic cancer.

Combination chemotherapy is the mainstay of treatment for metastatic pancreatic cancer. A newly approved first-line chemotherapy drug combination is NALIRIFOX, which is similar to the older standard FOLFIRINOX and is more effective than another standard chemotherapy combination, gemcitabine (Gemzar) plus nab-paclitaxel (Abraxane).

Targeted Therapy

Researchers are excited about the possibility that targeted therapies may be effective treatments for pancreatic cancer. These treatments that block several other key targets are in development and testing.

• Targeted therapies that block altered KRAS proteins are a major focus for drug development in pancreatic cancer because more than 90% of pancreatic cancers have KRAS gene mutations. 
• Drugs that block mutant forms of KRAS proteins are now being tested. 
• Combining KRAS inhibitors with chemotherapy has shown promise in recent trials. Using both may reduce tumor growth and spread because they affect different cellular pathways that can drive pancreatic cancer cell growth.
• PT886 is a new therapy that marks cells with a protein called claudin 18.2 for destruction by the immune system. It was fast-tracked in 2024 by the FDA to be studied in advanced and metastatic cancers, including pancreatic cancers, that express high levels of claudin 18.2. 

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 found in normal cells or are found at lower levels. These treatment vaccines can help the immune system learn to recognize and react to these antigens and destroy cancer cells that contain them.

Several cancer treatment vaccines are being tested in early-phase trials involving patients with pancreatic cancer. One recent study showed that using a patient’s own tumor DNA and RNA may allow for personalizing vaccines to treat pancreatic tumors. Another study showed that boosting a special type of immune cell (dendritic cell) in pancreatic tumors may increase immune responses by stimulating cancer-killing T cells.

Immunotherapy

People with pancreatic cancer whose tumors have microsatellite instability (MSI), which make up about 1% to 3% of pancreatic cancers, can be treated with immunotherapies. Researchers are investigating possible ways to improve the effectiveness of immunotherapies in people with pancreatic cancer that does not have MSI. These approaches include:

• Novel immune checkpoint inhibitors and combinations. Using a single immunotherapy drug on its own has not been effective for most people with pancreatic cancer. Therefore, researchers are studying whether combining several immunotherapies that can act on different parts of the immune system is more effective.
• Combinations of immunotherapy drugs with other treatments. These include radiation therapy, stromal modifying agents, and other targeted drugs. Some researchers are even developing targeted therapies that not only block the activity of mutant KRAS but also flag the cell for destruction by the immune system.
• 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 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.

An oncolytic virus is a type of virus that infects and breaks down cancer cells but not normal cells. The VIRAGE trial is studying whether combining chemotherapy with the oncolytic virus VCN-01 is effective in patients with metastatic pancreatic cancer. VCN-01 replicates in tumor cells and helps break down the stroma, potentially allowing treatment to be more effective.