Targeted Therapy

Targeted therapy is a type of cancer treatment that uses drugs to precisely identify and attack certain types of cancer cells. Cancer starts when certain genes in healthy cells change and become abnormal due to mutations. Genes tell cells how to make proteins. If certain genes become mutated, the corresponding proteins change as well, making them dysfunctional. As a result of these protein dysfunctions, cancer cells divide too much, too quickly, or live longer than normal. This results in the formation of a tumoral mass, or an excess of malignant cells in the blood, or bone marrow.

To develop targeted therapies, researchers work to identify the specific genetic changes that helps cancer cells to grow, divide and survive (the drug target). Ideally, such a drug target is only present in cancer cells and not in healthy cells. Once researchers have identified such a target, drugs can be developed that specifically attack it.

Given their targeted mode of action, targeted drugs are generally less toxic than chemotherapy. However, these agents still have side effects. The nature and severity of side effects vary from person to person and depend on the drug that is given. Some people don’t have any side effects, while others may experience a significant toxicity burden

An important group of targeted therapies consists of tyrosine kinase inhibitors (TKIs). This type of drugs interrupts the process that manages how cells grow and divide. This process involves enzymes (tyrosine kinases) that can be switched on or off by the binding of growth factors. Normal tyrosine kinases turn on and off in a controlled fashion. However, due to certain mutations this mechanism can be disturbed leading to the constant activation of a tyrosine kinase. A prime example of this consists of the BCR-ABL fusion protein which is formed in patients with chronic myeloid leukemia. To specifically block this fusion protein, several TKIs have been developed (e.g., imatinib, dasatinib, nilotinib, ponatinib, bosutinib).

Another example of TKIs with an important role in hematological malignancies consists of inhibitors of the Bruton’s tyrosine kinase (BTK) (e.g., ibrutinib, zanubrutinib, acalabrutinib). B-lymphocytes are an important part of the immune system and form the cell of origin for a wide range of hematological malignancies. When an antigen binds to a receptor on a B-lymphocyte, the B-cell receptor (BCR) signaling pathway is activated. BTK is an enzyme with a critical role in the activation of this signaling pathway. By blocking BTK, the BCR signaling can be disturbed, blocking the growth and proliferation of cancerous B-cells.

Apoptosis refers to the orchestrated process of cell death in response to certain triggers. It is an important process to maintain cell populations in tissues and allows the elimination of damaged, or defective cells. In cancer, proteins involved in this process can become dysfunctional, taking away the trigger to die. A prime example of such a protein is BCL-2, which inhibits apoptosis. Insights into the role of this protein formed the basis for researchers to develop targeted drugs that interfere with BCL-2 (e.g., venetoclax). By inhibiting BCL-2, the break on the apoptotic process is lifted, inducing cell death in cancer cells.

Other forms of ‘targeted therapies’ include monoclonal antibodies, immunomodulatory agents, immune checkpoint inhibitors, proteasome inhibitors, antibody-drug conjugates (ADC), and bispecific antibodies. These treatments are discussed in more detailed on separate pages.