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Targeted Cancer Therapies

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Traditional cancer therapies, such as chemotherapy and radiotherapy, are not highly selective in targeting cancer cells and, therefore, have various side effects on normal cells of the body as well.

In contrast, targeted cancer therapies use drugs designed to target specific molecular structures that are present only in the cancer cells, and are absent in normal cells.

For example, healthy cells have two separate genes, BCR and ABL1. In chronic myeloid leukemia, chromosomal translocation fuses a part of the BCR gene with the ABL1 gene, leading to the synthesis of fusion protein BCR/ABL1.

This abnormal fusion protein drives uncontrolled cell proliferation and results in an excessive number of white blood cells in the bloodstream.

Imatinib mesylate is a small molecule kinase inhibitor that can specifically target the BCR/ABL1 fusion protein, preventing its activity and the downstream signaling pathways that control cell proliferation.

The drug also inhibits the ABL1 protein in the healthy cells, but additional redundant tyrosine kinases in such cells cover up for the loss of function of the ABL protein.

Imatinib mesylate is an example of a successful targeted molecular therapy against cancer with a response rate as high as 90%.

Targeted therapy is also used in some cases of breast and ovarian cancer that have inactive tumor suppressor genes, BRCA1 and BRCA2.

Cancer cells with inactive BRCA1 and BRCA2 proteins rely on poly (ADP-ribose) polymerase or PARP enzyme for DNA repair and survival.

This means that drugs which can selectively inhibit PARP enzyme activity can permanently block DNA repair in BRCA1 and BRCA2 deficient cancer cells. In contrast, healthy cells remain unaffected because of the active BRCA1 and BRCA2 DNA repair pathway.

Monoclonal antibodies directed against tumor-specific proteins can also be used for targeted therapy. For example, the trastuzumab antibody is used to inhibit the activity of overexpressing human epidermal growth factor receptor two or HER2, a receptor tyrosine kinase protein in some breast cancer patients.

However, since normal cells also express HER2 protein, HER2 targeted therapy can also affect normal cells and cause side effects.

Overview

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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.

There are several types of targeted therapies against specific molecular targets to treat different kinds of cancers.

Angiogenesis inhibitors

Angiogenesis plays a huge role in the tumor microenvironment by providing necessary oxygen and nutrients to the growing tumor cells. Therefore, the use of specific inhibitors, such as bevacizumab that can bind circulating vascular endothelial growth factors and block the formation of new blood vessels, can help to restrict the growth of tumor cells.

Monoclonal antibodies

Another commonly used strategy against cancer is the use of monoclonal antibodies, such as alemtuzumab, trastuzumab, and cetuximab, that can directly target tumor cells. While some of these antibodies target a specific marker on the cancer cells, others just improve the immune response in the body.

Proteasome inhibitors

The ubiquitin-proteasome pathway plays a crucial role in apoptosis, cell survival, cell-cycle progression, DNA repair, and antigen presentation in eukaryotic cells. Inhibitors of this pathway, such as bortezomib, carfilzomib, and ixazomib, are successfully used to treat myeloma and mantle-cell lymphoma (MCL).

Signal transduction inhibitors

Most cancer cells have abnormal signal transduction pathways that lead to their uncontrolled cell growth, proliferation, and survival. The development of drugs that can inhibit the aberrant signal transduction elements in the cancer cells, such as the surface receptors or the downstream effectors, such as kinases, is a promising avenue for targeted therapy. For example, epidermal growth factor receptor or EGFR is a transmembrane receptor tyrosine kinase that is abnormally expressed in some cases of cancer. Gefitinib, an FDA-approved drug, is an EGFR inhibitor that is successfully used for the treatment of non-small cell lung cancer.

Transcript

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Traditional cancer therapies, such as chemotherapy and radiotherapy, are not highly selective in targeting cancer cells and, therefore, have various side effects on normal cells of the body as well.

In contrast, targeted cancer therapies use drugs designed to target specific molecular structures that are present only in the cancer cells, and are absent in normal cells.

For example, healthy cells have two separate genes, BCR and ABL1. In chronic myeloid leukemia, chromosomal translocation fuses a part of the BCR gene with the ABL1 gene, leading to the synthesis of fusion protein BCR/ABL1.

This abnormal fusion protein drives uncontrolled cell proliferation and results in an excessive number of white blood cells in the bloodstream.

Imatinib mesylate is a small molecule kinase inhibitor that can specifically target the BCR/ABL1 fusion protein, preventing its activity and the downstream signaling pathways that control cell proliferation.

The drug also inhibits the ABL1 protein in the healthy cells, but additional redundant tyrosine kinases in such cells cover up for the loss of function of the ABL protein.

Imatinib mesylate is an example of a successful targeted molecular therapy against cancer with a response rate as high as 90%.

Targeted therapy is also used in some cases of breast and ovarian cancer that have inactive tumor suppressor genes, BRCA1 and BRCA2.

Cancer cells with inactive BRCA1 and BRCA2 proteins rely on poly (ADP-ribose) polymerase or PARP enzyme for DNA repair and survival.

This means that drugs which can selectively inhibit PARP enzyme activity can permanently block DNA repair in BRCA1 and BRCA2 deficient cancer cells. In contrast, healthy cells remain unaffected because of the active BRCA1 and BRCA2 DNA repair pathway.

Monoclonal antibodies directed against tumor-specific proteins can also be used for targeted therapy. For example, the trastuzumab antibody is used to inhibit the activity of overexpressing human epidermal growth factor receptor two or HER2, a receptor tyrosine kinase protein in some breast cancer patients.

However, since normal cells also express HER2 protein, HER2 targeted therapy can also affect normal cells and cause side effects.

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