Overview

Targeted therapy is an innovative treatment method that attacks specific cancer cells while doing less harm to normal cells.¹ This is good compared to other treatments like radiotherapy as it reduces the risk of damage to healthy cells. The treatment targets proteins that control how cancer cells grow, divide, and spread. Targeted therapy prevents the transition of normal cells to cancer cells.¹ The treatment prevents pancreatic cancer from growing and spreading to other areas. This treatment method can be used in certain circumstances where the chemotherapy does not work.²

The pancreas is a gland in the abdomen that produces digestive juice, which helps with food digestion. Pancreatic cancer is a type of cancer that grows in the pancreas. Due to several reasons, it is very unlikely to diagnose pancreatic cancer at an early stage, and most cases reach an advanced stage. Pancreatic cancer does not always show symptoms in its early stage of development.³ Pancreatic cancer is a fatal disease. The five-year survival for patients with all stages of this cancer type is less than 10%, with a majority of patients dying from the disease.⁴ This is because of the late diagnosis at the advanced stage after the cancer has metastasised.⁵

The main existing treatments for pancreatic cancer are surgery, chemotherapy, radiotherapy, and supportive care. Recent clinical trials have been evolving in 

proving that targeted therapy is showing improvement in clinical outcomes.⁶ Immunotherapy is another evolving area that helps the body's natural immune system to find and destroy pancreatic cancer cells. However, more knowledge about the genetic makeup of individual cancers is leading to research into targeted and immunotherapy drugs for pancreatic cancer. Genomic sequencing helps to determine which pancreatic cancer patients could benefit from treatments designed for their specific cancer.⁷

Mechanism of targeted therapy

The body constantly produces cells that help to grow and heal injuries, and these cells die in an orderly way. However, cancer cells have a change in their genes, multiplying and growing faster, harming normal cells, preventing their growth and disrupting cellular function. The cancer cells keep growing, forming a lump (tumour) that grows in size.⁸ All cancer cells are not the same.

In targeted therapy, the drugs are used to identify and attack certain types of cancer cells. Research has already been conducted about the environment in which different cancers start, grow and thrive. Targeted therapies can attack specific areas in cancer cells, or can detect and block certain types of messages sent inside a cancer cell that tell it to grow.⁹ 

Some of the substances in cancer cells that become the "targets" of targeted therapies are:⁹

• Concentration of protein on a cancer cell
• A protein on a cancer cell which is different from a normal cell
• A protein that is mutated or (changed) 
• Gene (DNA) changes that are absent in a normal cell

Different ways targeted therapy treats cancer

• Help the immune system destroy cancer cells¹⁰
• Stop cancer cell growth
• Stop signals that help form blood vessels
• Deliver cell-killing substances to cancer cells
• Killing cancer cells
• Stop making hormones for cancer cells to grow
• Blocks hormones needed for cancer cell growth

Comparison with Conventional Therapies

• Surgery is used when it is possible to remove the cancer¹¹
• Radiation therapy uses high-energy X-rays (or particles) to kill cancer cells. It is given after the surgery to lower the chance of cancer returning
• Chemotherapy is a method of injecting drugs into a vein or taken by mouth
• Immunotherapy is the use of medicines to stimulate the immune system to destroy cancer cells 

Types of targeted therapy for pancreatic cancer

Targeted therapies are mostly in the form of small molecular drugs or monoclonal antibodies, which is a type of protein that is made in the laboratory. Owing to the size of the small molecule drugs, they can be used for ‘targets’ inside the cell. Like the antibodies in our immune system, monoclonal antibodies are designed to interact and target cancer cells.

Key targeted therapies for pancreatic cance

There are different types of targeted therapy drugs approved for pancreatic cancer by the FDA, which are listed below.¹²

Belzutifan

Belzutifan can be used in adults with certain types of pancreatic cancer that do not require surgery right away. It can be taken as a tablet. A research study showed belzutifan continued to demonstrate robust activity and manageable safety in Von Hippel-Lindau (VHL) disease associated with pancreatic neuroendocrine tumours.¹³

Eerlotinib hydrochloride

Erlotinib blocks the epidermal growth factor receptor (EGFR) tyrosine kinase that helps cancer cells grow. It is used in the treatment of non-small cell lung cancer, pancreatic cancer and other types of cancer.¹²

Everolimus

Everolimus is approved to treat Pancreatic neuroendocrine tumours that are progressive. Everolimus showed robust anti-tumour activity with side effects manageable by patients, across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract.¹⁴

Olaparib

Olaparib is used as maintenance therapy in adults with metastatic cancer that has not progressed after first-line therapy with platinum chemotherapy and has certain hereditary mutations in the BRCA1 or BRCA2 gene which help in DNA repair. Olaparib is known as a PARP inhibitor. PARP enzymes are also involved in a pathway that helps repair DNA cells. The POLO clinical trial results showed patients with metastatic pancreatic cancer whose cancer responded to initial chemotherapy, taking olaparib as a maintenance therapy extended the time their cancer remained stable.¹⁵

Sunitinib malate

Sunitinib malate is approved to treat adults with Pancreatic neuroendocrine tumor. It is a tumour that is formed in hormone-making cells of the pancreas. It is used in patients with progressive neuroendocrine tumours that cannot be removed by surgery or have spread. A clinical trial result suggested that continuous daily administration of sunitinib showed that pancreatic cancer took longer to start growing or spreading again, overall survival, patients lived longer and the tumours shrank or stopped growing in more patients.¹⁶ 

Zenocutuzumab-zbco

This is an intravenous injection used to treat non-small cell lung cancer and pancreatic cancer. It is approved to treat adults with cancer that has an NRG1 gene fusion. NRG1 gene fusions are mutations that foster cancer cell growth. These fusions are found in pancreatic cancer. Zenocutuzumab is a treatment that is being tested to see if it can stop cancer. Tumors with NRG1 gene fusions do not respond well to standard care.¹⁷

Accessing targeted therapies for pancreatic cancer

Targeted therapies are available in two ways:

• Clinical trials
• After changes identified through Genomic testing or Biomarker testing

Genetic testing looks for inherited changes in genes. Anybody can be born with inherited changes even in the absence of a family history of cancer. Genetic testing looks for if there is any inherited mutation. For example, the presence of an Inherited BRCA mutation. Patients with advanced pancreatic cancer can undergo genomic testing to determine their eligibility for clinical trials focusing on Targeted therapy for Pancreatic cancer.¹⁸Biomarker testing involves collecting a tissue sample from the tumour via biopsy and analysing it to identify changes in genes, molecules, or proteins. This test is done using blood or saliva.

Is targeted therapy always successful?

Targeted therapies are effective treatments, but they have limitations in practice.¹⁹

• The tumour does not always have the target or receptor that corresponds to the treatment
• The tumour doesn’t show a response to the therapy as projected 
• The tumour cells continue to mutate. The targeted therapy becomes ineffective
• The side effects vary depending upon the patient's response to treatment

Combination therapies and future directions

Promising research indicates that targeted therapies may be effective in treating pancreatic cancer. The treatments are still evolving and are currently under testing through trials.²⁰

• Targeted therapies for altered KRAS proteins that control cell growth and division are a major focus for drug development in pancreatic cancer 
• Using KRAS inhibitors and chemotherapy may reduce cancer growth and spread. And are currently under trials
• PT886, a novel laboratory-generated antibody, targets and treats pancreatic cancers 
• A new drug called BIZENGRI targeting a tumour alteration called NRG1 gene fusion found in patients with Pancreatic cancer marks another treatment option for patients²¹ 

Summary 

According to Cancer Research UK, Pancreatic cancer is the 5th most common cause of cancer death in the UK (2017-19). Due to the advancement of medical research in genomic sequencing, we are now able to find exact causes for genetic changes in cancer cells, which opened new doors for advanced Targeted therapy treatment for pancreatic cancers. Every patient is different, targeted treatment will be based on the biology of the cancer or tumour, giving more information on proteins and genes. Targeted therapies based on molecular profiles improve overall survival. However, it is an evolving treatment area with the possibility of making pancreatic cancer treatment effective.