Targeted Treatment for Pancreatic Cancer

myTomorrows Team 16 Aug 2022

10 mins read

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Pancreatic ductal adenocarcinoma (PDAC) is pancreatic cancer that originates in exocrine cells and has a poor prognosis. Targeted therapies target specific features on cancer cells and can be used in combination with chemotherapy. Targeted therapies are personalized treatments based on genetic and biomarker testing.

Pancreatic ductal adenocarcinoma (PDAC) is pancreatic cancer that grows from exocrine cells located in the small tubes or ducts of the pancreas. This is where approximately 9 out of 10 pancreatic cancers begin. PDAC has a poor prognosis due to late-stage diagnosis, metastasis and resistance to conventional chemotherapies and radiotherapies. Surgery, which can be curative, is an option for only 10-15% of patients. Targeted therapies are drugs or substances that target specific features of cancer cells, which can differ between cancer types.

Genetic testing for personalized medicine

The National Comprehensive Cancer Network (NCCN) guidelines recommend that patients with confirmed pancreatic cancer have genetic testing, sometimes called germline testing. This means testing for DNA changes that are inherited from parents and that may be passed on to children. Genetic or germline mutations are found in all cells in the body and can be detected in blood or saliva. It is helpful to know if these mutations are present because they can predict the development of certain types of cancer. Since different types of cancer respond differently to treatments, genetic testing can help inform treatment decisions.

Biomarker testing for personalized medicine

Different types of tumors can be distinguished from each other by differences at a molecular level. These differences are called biomarkers. Biomarker testing can help oncologists decide which targeted treatments are most likely to be effective. Tumor-specific biomarkers in genes or DNA are detected by PCR and next-generation sequencing (NGS). Tumor-specific biomarkers in proteins are determined by immunohistochemistry.

Tumor biomarkers can give information about the type of cell from which the tumor first grew, which can impact how the tumor responds to therapy. Additional changes, to DNA and proteins, that occur as the cancer progresses can also be identified with biomarker screening. Different types of tumors can be more resistant to some therapies and more vulnerable to others.

In cancer, DNA changes commonly occur in the genes BRAF, BRCA1, BRCA2, HER2, KRAS, and PALB2, which give tumors growth or survival advantages. Certain cancer cells have a deficiency in a type of DNA repair called mismatch repair which makes them more vulnerable to some treatment types. The biomarker, called MSI-H/dMMR, identifies cancers with this DNA repair deficiency.

Two genes may become abnormally joined together and some of these genetic rearrangements cause increased growth or survival of cancer cells. Tumor biomarker testing commonly finds the genes ALK, NRG1, NTRK, and ROS1 in genetic rearrangements. Clinical trials are evaluating targeted therapies directed at other gene fusions.

When targeted therapies are recommended

In locally advanced pancreatic cancer after first-line therapy, targeted therapies may be recommended as second-line therapy. Targeted therapy may be a first-line treatment option for metastatic pancreatic cancer or part of palliative care when performance status, a measure of the ability to perform activities of daily living, is poor. Since targeted therapies are directed at specific types of tumors, the recommendation of targeted therapy will depend on the results of genetic testing and tumor biomarker testing.

Clinical trial treatments for pancreatic cancer include many targeted therapies. For patients who did not receive neoadjuvant therapy (systemic treatment before surgery), NCCN guidelines recommend a clinical trial treatment after surgery to help prevent tumor recurrence. In certain scenarios, the guidelines recommend clinical trials as the next step if cancer returns after surgery or after primary therapy. In locally advanced and metastatic pancreatic cancer, clinical trials are the recommended first-line treatment when there is a good performance status.

Targeted therapy for pancreatic cancer

Targeted therapies include drugs and antibody-based therapeutics, which can be grouped together based on their similar types of targets. Blood vessel growth, DNA repair, tumor microenvironment, and key regulators of cell growth are targets for these therapies. The targeted therapies described below are either in clinical trials or in preclinical research stages.

Antiangiogenic therapies

Angiogenesis is the formation of new blood vessels. Tumor angiogenesis creates networks of blood vessels to supply oxygen and nutrients to the tumor. Antiangiogenic therapies are targeted therapies that aim to thwart tumors by blocking angiogenesis. Unfortunately, tumors can develop resistance to the lower oxygen condition, called hypoxia, created by antiangiogenic therapies. Another potential downside to reducing the blood supply to the tumor is it can make anti-tumor drugs less able to get to the tumor. Biomarker testing may help identify which patients may most benefit from antiangiogenic therapies.

VEGF is one of the key molecules that signals and promotes the formation of blood vessels. Antibodies are special molecules created by our immune systems that are able to stick to and target pathogens. Antibody therapies use this concept, but they are designed in the laboratory to stick to molecules on cancer cells.

DNA repair targeted therapy

Cells will self-destruct when too damaged, which is a kind of quality control mechanism. Some cancer therapeutic agents such as gemcitabine, induce DNA damage as a way to induce this death response. However, some cancer cells are still able to block and repair the damage caused by these therapeutic agents. DNA repair targeted therapy aims to inhibit these repair mechanisms to make DNA-damaging cancer therapeutics more effective.

There are two main approaches to blocking DNA damage repair. One approach is to directly stop the process of DNA repair. The other is by not allowing the cell enough time to check for and repair damage. The latter approach inhibits regulators of the cycle of cell division that normally put the cell on pause and checks to make sure DNA is repaired before progressing. Inhibiting these cell cycle regulators results in cell division continuing with DNA damage.

DNA damage repair inhibitors can also make cancer cells more vulnerable to radiotherapy. Patients with operable and inoperable PDAC have demonstrated improvements in survival outcomes when treated with radiation or chemoradiation. Clinical trials are investigating the combination of radiotherapy and DNA damage repair inhibitors for PDAC.

KRAS pathway inhibitors

The most common mutation in PDAC, which occurs in more than 95% of cases, is a mutation in the KRAS gene. The KRAS gene codes for the KRAS protein which acts as a switch that controls cell behavior and cell division. KRAS gene mutations cause KRAS switches to be stuck in the “on” position and promote cancerous behavior. KRAS mutations differ in prevalence in different cancer types. The mutations G12D, G12V, and G12R are more common in PDAC and the G12C mutation is more common in non-small cell lung cancer (NSCLC).

PDAC is said to be addicted to KRAS mutation, meaning this type of cancer relies on the dysregulated KRAS switch for survival. Because of this reliance, KRAS mutations, are a potential target for PDAC therapeutics. Some KRAS inhibitors target specific KRAS mutations, while others broadly target a range of KRAS mutations.

A class of KRAS inhibitors prevents KRAS from going where it needs to function, on the inside of the cell membrane. Farnesyltransferase inhibitors (FTIs) prevent a chemical modification to KRAS that helps it attach to the cell membrane and perform its job. Various treatments that prevent KRAS from attaching to the cell membrane are under investigation for PDAC.

KRAS itself has proven difficult to inhibit. Other molecules in the KRAS pathway, meaning molecules that regulate KRAS or that KRAS regulates, are therapeutic targets. MEK and RAF are downstream molecules that are regulated by KRAS and promote tumor survival and growth. The MEK inhibitor, trametinib has been shown to improve overall survival in clinical trials in combination with gemcitabine compared with gemcitabine alone. Tumors have been shown to develop resistance to RAF inhibition.

Anti-stromal therapies

PDAC cells stimulate the stroma, which is connective tissue that forms around the tumor and creates a favorable environment. Stimulation of the stroma by PDAC cells leads to a tumor microenvironment that has low oxygen and plenty of growth factors. This environment is favorable to tumor invasion and resistant to cancer therapies. Anti-stromal therapies target the PDAC environment to make it less protective of PDAC and make these tumors more vulnerable to treatment.

Key players in PDAC stroma construction are pancreatic stellate cells (PSCs) that have become activated. Vitamin A analogs have been shown to reduce the activity of PSCs, leading to reduced PDAC cell proliferation in preclinical research. In animal models, the vitamin D analog calcipotriol in combination with gemcitabine was shown to improve both survival and delivery of chemotherapy drugs.

MicroRNA (miRNA) is a class of RNA molecules that regulate the expression of their target genes. The miRNA called miR-21 is known to promote fibrosis, an abnormal scar-forming process in connective tissue, that tends to occur around tumors. In PDAC, miR-21 is elevated. miR-21 and another miRNA called miR-29 have the potential to be used for diagnostics and as anti-stromal therapeutic targets.


Nanoparticles, tiny particles engineered to carry drugs into target tissues, can provide a method to get therapeutic agents past the barrier created by the PDAC stroma. Nanoparticles that target the protein EGFR on the cell surface of cancer cells have been shown to make the delivery of gemcitabine more efficient. By delivering it more specifically to tumors it can be used at lower concentrations.

Stuck switches and multikinase inhibitors

Kinases are like “on/off” switches that control cell processes like cell growth and cell migration at the right time and place. In cancer, stuck “on” kinase switches lead to uncontrolled cell growth and metastasis. MK2461 is a therapeutic agent that targets multiple kinases and multiple mechanisms of oncogenesis. Preclinical research has shown that MK2461 interferes with the communication between PSCs and PDAC cells by targeting the kinase proteins MET and PDGFRβ. High levels of MET are associated with more invasive PDAC.

Other targeted therapies

The mitochondria, the power source of cells, are targeted by the therapy CPI-613. CP-613 is a metabolic inhibitor used in combination with other drugs in PDAC. BEY-1107, targeting cell cycle regulation through cyclin-dependent kinase, is in clinical studies for PDAC.

There is a wide range of targeted therapies in various stages of research for pancreatic cancer. Genetic testing and tumor biomarker analysis will help you and your healthcare team decide which targeted therapy is right for you. In addition to targeted therapies approved for pancreatic cancer, clinical trials can offer more targeted therapy options. Depending on the stage of pancreatic cancer, clinical trials may be recommended as first- or second-line treatment options.

myTomorrows is dedicated to helping patients with pancreatic cancer find and access pancreatic cancer clinical trials and other potential treatment options.

The information in this blog is not intended as a substitute for a medical consultation. Always consult a doctor before receiving a diagnosis or treatment.

The myTomorrows team
Anthony Fokkerweg 61-2
1059CP Amsterdam
The Netherlands

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KnowledgePancreatic CancerGenetic TestingTargeted TherapiesPDAC

myTomorrows Team 16 Aug 2022

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