Subchapter list

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13.1 Introduction

Targeted therapy in oncology represents a newer group of drugs developed based on a deeper understanding of the processes of carcinogenesis and the regulatory pathways of cancer cells. Thanks to the rapid development and wider availability of molecular biology methods in the last decades, the complex processes that take place in the cancer cell have been described in great detail and are conditioned by multiple genetic changes in the cell that lead to the production of aberrant and fusion RNA molecules and their encoded proteins. These distinguish cancer cells from healthy cells. Based on this knowledge, the search was launched for new drugs to affect these signaling pathways. Targeted anti-cancer therapy focuses on these pathways and represents a new generation of drugs that, unlike cytostatics, do not interfere with or damage the genetic information of cells but rather intervene several levels down in the area of proteins with regulatory and signaling effects. This differentiates them from standard cytostatics, which damage the DNA of cancer cells non-selectively, unfortunately also the DNA of healthy cells. For this reason, the nature, frequency, and intensity of adverse effects of cytostatics and targeted therapy also differ (see below). It is essential to say that targeted drugs have not displaced but rather complemented cytostatic treatment – combination regimens of cytostatics and targeted drugs are pretty often administered (e.g., paclitaxel, doxorubicin, and trastuzumab in the treatment of metastatic breast cancer, or 5-fluorouracil, leucovorin, oxaliplatin, and cetuximab or panitumumab in the treatment of metastatic colorectal cancer). However, if a molecular alteration is a strong „driver“ of cancer biology, which means that the survival of the cancer cell depends highly on the oncogenic pathways encoded by a specific pathogenic mutation, targeted monotherapy can also be highly effective (e.g., imatinib in bcr/abl-fusion positive chronic myeloid leukemia, or erlotinib, gefitinib, afatinib, osimertinib in EGFR-mutant non-small-cell lung cancer).

To think about

Try to think about and characterize the mechanism of action of the cytostatics paclitaxel and docetaxel. Based on your knowledge of basic pharmacology, state the target structure of the monoclonal antibody trastuzumab.

In addition to pharmacological targeting of structures located on the surface of tumor cells or pharmacological influence on intracellular signaling pathways of tumor cells, monoclonal antibodies that affect the target structures of immunocompetent cells, especially T-lymphocytes, have been significantly applied in cancer treatment in recent years. Pharmacological interference with "silencing" receptors, especially programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4), also known as immune checkpoints, has been successfully applied in clinical practice. Tumor cells can activate these checkpoints with the help of specific ligands, thereby stopping the immune response. Checkpoint inhibitors (PD-L1/PD-1 or CTLA-4 inhibitors) focus on these target structures, and by inhibiting them, the immunological response of cytotoxic T-lymphocytes against tumor antigens is restored. You will learn more about this so-called "immunotherapy" of tumors in the lecture