Targeted Therapy

What is Targeted Therapy in Cancer

For cancer treatment, the initial method of chemotherapeutic agents has been cytotoxic drugs. Their action of mitotic inhibition is not limited to cancer cells, particularly profound effects being seen on the haematopoietic system, often with resulting neutropenia or pancytopenia. Targeted therapy conversely seeks to selectively affect cancer cells based on specific molecular characteristics. Targets for therapy are diverse but involve cellular growth, proliferation and, more recently, immune evasion. What is targeted therapy? Targeted therapy is a newer type of cancer treatment that uses drugs or other substances to more precisely identify and attack cancer cells, usually while doing little damage to normal cells.It has been validated to be a curative treatment for cancer, with many clinical trials and approved by FDA.

Types of Targeted Therapy

Tyrosine kinase inhibitors, such as erlotinib, gefitinib and afatinib, are orally active small molecules that act intracellularly to prevent downstream signal transduction from activated growth factor receptors. They have demonstrable efficacy in non-small cell lung cancers (NSCLCs) harbouring activating EGFR mutations.

Monoclonal antibodies utilize the specificity of the fragment antigen-binding region of the antibody to target specific therapeutic epitopes. Modern antibodies are either chimeric mouse ehuman or fully human, with the latter felt to be less immunogenic. They target either extracellular ligands (the compounds that activate the receptor), for example bevacizumab on vascular endothelial growth factor (VEGF), or the cell surface receptors themselves, for instance cetuximab on EGFR. Bevacizumab and cetuximab have demonstrated efficacy in colorectal cancers. Similarly to chemotherapy, they are usually delivered by intravenous infusion.

Antibody drug conjugates combine a monoclonal antibody with a cytotoxic to deliver the cytotoxic directly to the targeted cells. The antibody targets and binds to a specific extracellular receptor, leading to internalization of the complex, thus delivering the cytotoxic payload only to those cells expressing the targeted receptor. TDM-1 is a conjugate of trastuzumab and the cytotoxic emtansine and has been shown to improve survival in patients with metastatic human epidermal growth factor 2 receptor (HER2) positive breast cancer.

Immune checkpoint inhibitors are monoclonal antibodies that target key regulatory points in the cellular immune system such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). As with growth factor-targeting antibodies, they target either the receptor (e.g. the anti-CTLA-4 monoclonal antibody ipilimumab or the anti-PD-1 antibody nivolumab) or the ligand (e.g. programmed cell death ligand 1 (PD-L1). They facilitate immune recognition and destruction of cancer cells, and have proven efficacy in malignant melanoma and NSCLC.

Hormonal agents used for breast and prostate cancer comprise a variety of agents that target ligand synthesis or binding with intracellular hormonal receptors. Agents include peptides (gonadotropin-releasing hormone (GnRH)antagonists and agonists), steroidal antiandrogens (e.g. abiraterone acetate) and non-steroidal antiandrogens (e.g. enzalutamide).

How does Targeted Therapy Work

Targeted cancer therapies are drugs designed to interfere with specific molecules necessary for tumor growth and progression. Traditional cytotoxic chemotherapies usually kill rapidly dividing cells in the body by interfering with cell division. A primary goal of targeted therapies is to fight cancer cells with more precision and potentially fewer side effects.

Therapeutic monoclonal antibodies target specific antigens found on the cell surface, such as transmembrane receptors or extracellular growth factors. In some cases, monoclonal antibodies are conjugated to radio-isotopes or toxins to allow specific delivery of these cytotoxic agents to the intended cancer cell target. Some examples are bevacizumab, humanized monoclonal antibody targeting VEGF-A; cetuximab, chimeric monoclonal antibody targeting EGFR; and ipilimumab, fully human antibody with an immune system target CTLA-4.

Small molecules can penetrate the cell membrane to interact with targets inside a cell. Small molecules are usually designed to interfere with the enzymatic activity of the target protein. Some examples are bortezomib, a small molecule proteasome inhibitor; imatinib, a small molecule tyrosine kinase inhibitor, and seliciclib, small molecule cyclin-dependent kinase inhibitor.

The FDA has approved multiple targeted drug cancer therapies, and many more are being studied in clinical trials either alone or in combination with other treatments.

References

Charlton P, Spicer J. Targeted therapy in cancer[J]. Medicine, 2016, 44(1): 34-38.