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Targeted therapy

The global project to study the human genome has helped streamline knowledge about human DNA and led to the development of technologies that can detect genomic, transcriptional, proteomic, and epigenetic changes in the DNA code. These molecular technologies, combined with the development of the pharmaceutical industry, have accelerated the introduction of personalized medicine.

Personalized medicine is a form of medicine that uses information about human genes and proteins to prevent, diagnose, and treat many diseases, including cancer. The cornerstone of personalized medicine was the creation of antitumor drugs of molecular-targeted action, called targeted drugs (from the English "target" – target).

Targeted drugs are substances that block the growth and spread of a tumor by affecting certain molecules in the tumor cells ("molecular targets"), which are responsible for their growth, progression and spread. In contrast to "classical" chemotherapy, targeted drugs have their effect only on those cells in which specific molecular targets are present, whereas most chemotherapy drugs act on all rapidly dividing cells, regardless of whether they are tumor or normal. For the most part, targeted drugs are cytostatic (which means that they block the proliferation of tumor cells and act directly on molecules involved in carcinogenesis), while standard chemotherapeutic drugs are cytotoxic (that is, they kill existing tumor cells).

 

To create an effective targeted drug, it is necessary to find exactly the target that plays a key role in the growth and survival of tumor cells.

 

One approach to identifying potential targets is to compare the amount of certain proteins in tumor and normal cells. Proteins that are present in tumor cells in an amount that exceeds the values for normal cells, or are not present at all in normal cells, can become potential targets, especially if they are involved in the growth or survival of tumor cells. An example is the epidermal growth factor receptor (HER2/neu). High levels of HER2/neu expression are found on the surface of tumor cells in some types of breast cancer and stomach cancer. For the treatment of these types of cancer, several targeted drugs have been created, among which the most famous is trastuzumab (Herceptin).

 

Another approach to finding suitable targets is to identify mutant forms of common proteins that produce tumor cells. For example, the BRAF protein is normally one of the proteins of the main signaling pathway that activates growth and is responsible for the preservation of cellular elements. With the development of a mutation (for example, in melanoma), an altered form of this protein (BRAF V600E) triggers the mechanism of excessive signal transfer to growth factors, which as a result leads to several times accelerated proliferation of tumor cells and the growth of neoplasms. The drug vemurafenib (Zelboraf) targets this mutant form of the BRAF protein and is approved for the treatment of patients with inoperable or metastatic melanoma containing an altered form of the BRAF protein.

 

Chromosomal abnormalities can also lead to the development of a malignant tumor. Sometimes they lead to the creation of a hybrid (chimeric) gene (a gene that includes parts of two different genes). The protein encoded by the hybrid gene is also called hybrid and can contribute to the development of a tumor. Such hybrid proteins can be targets for targeted therapy, as in the case of the hybrid protein BCR-ABL, which is the result of the fusion of two genes and the cause of some forms of leukemia. For their treatment, the targeted drug imatinib (Glivec) was developed.

 

To date, dozens of targeted drugs have been created for the treatment of various malignancies, such as breast cancer, stomach cancer, lung cancer, and many others. Even more drugs are at different stages of clinical trials. New perspectives have opened up for patients with breast cancer (breast cancer), gastro-intestinal stromal tumors (GIST), colorectal cancer, light cell kidney cancer, squamous cell head and neck cancers, liver cancer, and other tumors.

The effectiveness of targeted therapy varies depending on the drug – from a radical change in the prognosis (imatinib for gastro-intestinal stromal tumors) to a not very encouraging increase in the median survival rate by 9 days (erlotinib for pancreatic cancer). However, the" exam " in the treatment of solid tumors with metastatic spread, targeted therapy was generally successful – the possibility of achieving an antitumor effect and prolonging the life of patients for this class of drugs is convincingly proven.

Most modern targeted drugs have the most pronounced antitumor effect as part of drug combinations with classic antitumor drugs. The development of combined chemotherapy regimens with simultaneous use of molecular targeted and classical anticancer drugs operating at the supramolecular level is relevant.

The toxicity of targeted drugs and the associated side effects are peculiar and differ from the toxicity of most classical chemotherapeutic drugs in less severity and greater tolerability. The most common side effects are diarrhea, allergic reactions in the form of rashes, dry skin, fatigue, nail changes and loss of hair color, the appearance of ulcers in the oral cavity. Less often, there is an increase in blood pressure, blood clotting disorders, liver problems and perforation of the wall of the esophagus, stomach, small or large intestine.

The toxicity of each targeted drug has its own characteristics. For example, trastuzumab (Herceptin), in addition to tumor cells in breast or stomach cancer, can affect cardiomyocytes and cause cardiomyopathy, since there are similar receptors on their surface that are sensitive to the effects of this drug.

There are medications for many of these side effects. They can be prescribed both to prevent the occurrence of side effects, and immediately after their appearance. Most of the side effects of targeted therapy disappear after the end of treatment.

However, targeted therapy is not suitable for all patients with malignant tumors, but only for those whose tumor cells contain the necessary "targets"for treatment. To determine the need to prescribe targeted drugs to the patient, it is necessary to conduct special studies, which include immunohistochemical research and various molecular genetic studies, for example, fluorescent in situ hybridization (FISH-study).

To perform any of these studies, a tissue sample of the tumor itself is required, which is obtained either by biopsy or during surgery. This sample is delivered to the pathomorphological laboratory, where, after special preparation and processing, paraffin blocks are made from it, and glass blocks are made from the blocks, on which thin tissue sections are located. These sections are colored with special dyes and studied under a microscope.

The method of immunohistochemical research is based on the detection of antigens specific to a particular type of cell in the analyzed tissue sample, which allows us to distinguish between tumor and non – tumor processes, distinguish one type of tumor from another, specify the degree of malignancy of the tumor, and also identify markers responsible for the drug sensitivity of the tumor tissue-including sensitivity to targeted drugs.

For some cancers, this method of determining sensitivity to targeted therapy has become a routine practice – such as the determination of Her2 / neu status in breast cancer, which is carried out for each patient. The assessment of the tumor status is carried out by the intensity of staining of the cytoplasmic membrane of tumor cells and can be negative, uncertain and positive. Patients with a positive Her2/neu status will be prescribed Herceptin therapy.

 

The uncertain status of the tumor requires further investigation. To clarify the presence of sensitivity to the targeted drug in this case, an additional FISH-study is conducted.

In contrast to the immunohistochemical study, which determines the level of the Her2/neu protein in each tumor cell, the FISH method allows you to determine the presence of the gene encoding this protein in the tumor tissue.

The FISH test is widely used in the differential diagnosis of malignant diseases, primarily in oncohematology. Chromosomal abnormalities in combination with the clinical picture and immunohistochemical data are the basis for the classification, determination of treatment tactics and prognosis of lympho - and myeloproliferative diseases. In the diagnosis of solid tumors, in addition to breast cancer, the most commonly used FISH-study is used in the diagnosis of cancer of the bladder, colon, neuroblastoma, retinoblastoma and others.

Today, targeted drugs are included in the treatment regimens for a large number of malignant neoplasms, fundamentally changing the possibilities of therapy and prognosis. In addition to chemo-and hormone therapy, targeted drugs in some cases can significantly increase the effectiveness of treatment without seriously exacerbating toxicity. Every year, hopes are growing for a significant increase in the survival time of patients with advanced metastatic tumors, a complete cure of patients with locally advanced malignant tumors, as well as the appearance of targeted drugs for cancer prevention. 

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