NEW Molecular oncology. Molecular profiling of the tumor is a step towards personalized cancer treatment. B. Checking for a mutation in the K-RAS-Test is suitable for patients with metastatic colon and rectal cancer

Molecular medicine in cancer treatment

The creation of drugs based on marker genes and marker proteins makes it possible, acting only on them, to selectively destroy their carriers without giving side effects. This is molecular or genetic medicine.

In the coming years of the 21st century, this medicine should replace the existing one, which is now called "old". Indeed, with the "old" medicine, the medicine is created by the method of "trial and error", therefore they often cause severe side effects in patients. In this sense, standard cancer chemotherapy is in a difficult position today.
The main reasons for this are: 1) a cancer cell is a eukaryote among the normal cells of the human body, also eukaryotes; 2) backlog of science before recent years about the sources of carcinogenesis and its molecular causes.

Standard chemotherapy drugs alone cannot distinguish between a cancer cell and normal cells, and aim to kill the too-rapidly dividing cells that each cancer cell was assigned to.

It has recently been found that carcinogenesis comes from two sources: 1) from a normal tissue cell that has become a stem cell, or 2) from a tissue stem cell.

It also turned out that in the composition of cancer cells, the cells are not the same:

The bulk of the cells are non-cancerous cells: they rapidly divide and, after performing the functions of the tissue, they themselves die through apoptosis; it is these cells that are targets for standard chemotherapy drugs;
- a much smaller part is made up of cancer cells: these are cancer stem cells that copy themselves by asymmetric division and generate non-cancerous cells as part of cancer cells.

At the same time, cancer stem cells divide rarely and slowly. This is the reason why conventional chemotherapy drugs are ineffective against cancer stem cells (J.E. Trosko et al., 2005).
Until now, patients with symptoms of cancer predominate in clinical practice, and patients with cancer are extremely rare - "in situ", i.e. in place.

It is already too late to start treatment for cancer with symptoms. After all, cancer cells begin to spread throughout the body when the size of cancer in the tissue of any organ is only 2 mm in diameter, i.e. with the onset of angiogenesis and lymphangiogenesis in the nodule.

Now, when eramolecular medicine has come, the patient will be treated even before the first symptoms of the disease, including cancer, appear: at the very beginning - at the level of the first cancer cell and its first descendants, and even before its beginning - at the level of precancerous cells.

Having determined the marker gene of the disease, it is possible to determine which protein causes it, which means that it is necessary to create a medicine against this protein or its gene - this is the “magic bullet” that P. Ehrlich so dreamed of. This is what the pharmacology of the future will be based on.
New drugs and drugs based on marker genes and marker proteins for a specific disease will target only defective cells, destroying them without damaging healthy cells. Hence - there will be no side effects from drugs in the patient.

Cancer stem cell arises from a normal cell or tissue stem cell due to derepression of fetal protein genes in it and simultaneous repression of suppressor genes by methylation of the CpG dinucleotides of the promoter of these genes or mutations in the genes. At the same time, it becomes more tenacious than a normal cell of the same type.
A cancer cell carries a number of tricks that make it invulnerable and capable of independent existence in the patient's body. Those. this defective cell is not just a cell, but a whole unicellular organism.

1. Predisease.

Any disease begins with a pathology of a cell or cells. Changes in a particular gene or genes of a cell are not a diagnosis of a disease, but only an establishment of a probable predisposition to it.
With such changes in the germ cell, the term is used - a predisposition to the disease, and in the somatic cell, they often say - predisease.
In pre-illness, such a gene does not yet manifest itself, since there is no synthesis of the gene product, proteins, in the cell yet. When such changes in genes occur in a normal cell, this is a precancerous cell.
"Repair" of such a gene or genes, or its replacement in a cell with a normal gene, "switching off" the genes of the properties of a cancer cell eliminate the predisease.

2. Illness.

When in a cell under the control of a gene or genes there is already a synthesis of its product - proteins, then this is a sign that the gene has already begun destructive work in the cell, leading to disease.
Here, changes in the gene or genes are the root cause of the disease of the cell, and changes in the properties of the cell are caused by the product of the gene, i.e. its proteins. These properties then form the symptoms of a particular disease.
The cause gene in the cell is the marker gene, and its protein is the marker protein. Inhibition of the causative gene and its products, the proteins in the cell, can stop the disease.

3. Early diagnosis of the disease.

Until now, many diseases, including severe ones, including cancer, are diagnosed at the stage of their symptoms. Treatment of many diseases at this stage is extremely difficult in terms of cure or even impossible.
Now the diagnosis of any disease, including the most dangerous disease- cancer, will become possible in the presymptomatic period.

"Before the beginning". This will be done by detecting in a cell or cells in a patient a marker gene for a specific disease. In relation to cancer, this would be the diagnosis of a pre-cancerous cell or cells.

"From the very beginning". This will be done by detecting in a cell or cells not only a marker gene, but also a marker protein for a specific disease. In relation to cancer, this will be the detection in the patient's body of the first cancer cell and its close descendants.
Materials for these studies can be: tissue samples of the background process of the corresponding organ - a biopsy, as well as blood and other biological fluids from the patient.

At any localization of cancer in a patient, due to the mosaicity of the capillaries of the cancer nodule, both cancer cells themselves and their markers can be detected in the blood: marker genes in blood plasma, and marker proteins from cancer stem cells in blood serum.
There may be marker genes from precancerous cells in blood plasma, as well as marker genes from cancer cells, but it is almost impossible to distinguish between them.
Theoretically, these differences can be found using MS-PCR and PCR-MMC and protein microarrays.

If marker genes characteristic of a cancer cell are found in the blood plasma from a patient, and the corresponding marker proteins are absent in the serum of the same blood sample, this could indicate the presence of precancerous cells.
Detection in the blood plasma from a patient of marker genes from a cancer cell could be referred to as level I early diagnosis cancer, since gene disorders are the root cause of the transformation of a normal cell into a cancer cell. Then the detection of marker proteins from cancer cells in the patient's blood serum is the II level of early cancer diagnosis, since the marker protein is a gene product.

4. Treatment of the disease.

To do this, marker genes and cell marker proteins for each disease will be used as targets for drugs and drugs.
These are new drugs and agents that will target only defective cells, and for cancer, these are cancer stem cells, while not affecting normal stem cells. That is, these medicines and drugs will be selective and individual for a particular patient (A.I. Archakov, 2000).

5. Criteria for curing the disease and control.

Marker genes and marker proteins will make it possible to detect defective cells in any disease when they cannot yet be detected in the patient's body by any other methods.
They will make it possible to detect cancer in a patient with a size of a nodule of cancer cells in tissue with a diameter of 2 mm (A.S. Belokhvostov, 2000).
The amount or titer of marker genes and marker proteins in the blood from defective cells of a particular disease or from cancer stem cells will allow monitoring the process of treating a disease and the result of a patient's treatment.
If the titer of markers does not decrease during treatment, the treatment tactics should be changed. Complete absence markers two to three weeks after the end of treatment - a sign of the patient's recovery from the disease.

It will be very convenient to carry out such control using biochips: DNA chips for marker genes, and protein chips for marker proteins of defective cells of a particular disease and cancer stem cells.

Molecular pathology lung cancer studies the totality of morphological and molecular genetic features of a given tumor. At the same time, the most important aspects problems are the determination of biomolecular and histogenetic markers of cancer, as well as the pathology of apoptosis in lung cancer.

Biomolecular markers of lung cancer are diverse, apparently coincide with markers of non-radiation lung cancer and are represented by various genes, proteins, hormones and other molecules.

Cellular oncogenes in lung cancer. In the pathogenesis of lung cancer highest value have cellular oncogenes of four families: myc, ras, bcl, erb-B.

The myc family of cellular oncogenes - c-myc, L-myc, N-myc - is represented by immediately reacting genes and encodes cellular regulatory proteins that induce proliferation and suppress differentiation. It was found that in the absence of growth factors, an increase in c-myc expression does not lead to cell division, but to apoptosis, which can be inhibited by bcl-2. Amplification of c-myc is found in 10-25% of lung cancers, while L-myc and N-myc are found only in neuroendocrine lung tumors (10-30%). Determination of increased expression of myc oncoproteinins is recorded much more often.

L-myc expression is found only in the group of neuroendocrine lung tumors, and c-myc expression in both the group of small cell and non-small cell lung cancer. In the group of small cell lung cancer, a significant correlation of L-myc and c-myc expression with the presence of metastases and tumor size was established.

The ras family of cellular oncogenes often undergoes changes during tumor growth. The genes encode the synthesis of p21 proteins, which have GTPase activity and bind to GTP and thereby affect the transmission of the growth signal to the cell. Mutations that activate the ras genes and are localized in codons 12, 13, and 61 are described. Most often, K-ras mutations are found in lung cancer, which are inherent only in non-small cell lung cancer, in contrast to small cell lung cancer. The frequency of K-ras mutations in lung adenocarcinomas is up to 30%, and in squamous cell lung cancer only 3%. Communication shown K-ras mutations with smoking.

K-ras mutations were found in lung precancer - atypical hyperplasia of the alveolar epithelium. Expression of p53 has been described in the same foci. Correlations were found between higher expression of this oncoprotein with glandular differentiation of lung cancer. High expression of ras protein products was also recorded in foci of lung adenomatosis and in oval and slit-like epithelial structures in scars.

The bcl-2 family consists of bcl-2, bax, bak, bclXL, bclXS, protein products which are able to form homo- and heterodimers, which sometimes have a diametrically opposite effect on the proliferation and apoptosis of tumor cells. The most studied of this family, bcl-2, is localized on the inner membrane of mitochondria, as well as in the nucleus, stimulates cell proliferation and inhibits apoptosis, probably due to antioxidant activity. On the contrary, bax proteins, whose transcription and synthesis is regulated by p53, block proliferation and stimulate apoptosis of tumor cells. BclXL inhibits apoptosis and stimulates proliferation, while bclXS, on the contrary, induces apoptosis. Thus, the balance between the protein products bcl-2 - bax, bclXL-bclXS and determine the shift of the balance towards proliferation or apoptosis in the tumor.

Suppressor genes in lung cancer. The role of suppressor genes in the development of tumors is reduced to blocking apoptosis and removing their suppressive effect on cellular oncogenes, which ultimately ends with the activation of proliferation. To realize the effect of damage to suppressor genes, the changes must affect both alleles of the gene, since a mutated suppressor gene is always treated as intact as recessive to dominant. For example, a mutation or deletion of one of the alleles of a suppressor gene must be accompanied by a loss or change in the other allele.

Suppressor genes in lung cancer are relatively well understood. The most common chromosome deletions are known, affecting the following regions: 3p21-24, 17p13, 13q14, 9p21-22 and 5q21. The 3p21-24 deletion occurs most frequently: in small cell cancer - in 100% and in non-small cell - in 85% of cases. But not a single suppressor gene is localized in this zone. Other sites correspond to known suppressor genes. So, for example, p53 is localized in 17p13, the retinoblastoma gene is located in 13q14, p16 INK4B(MTS1) and p15 INK4B(MTS2) - 9p21-22. The functions of most of these genes are well known and are associated with the control of the G1 phase of the mitotic cycle and/or apoptosis. Their inactivation causes the development of apoptosis. The detection of genome damage in the area of ​​localization of suppressor genes at the stage of precancerous changes indicates the involvement of these genes in the early stages of tumor growth. Currently, a number of new suppressor genes have been described that appear to be important for the development of lung cancer and are localized on chromosomes 1 and 16.

The p53 gene undergoes the most frequent changes during tumor growth. Wild-type p53 (natural) is a transcription factor with multiple functions, including regulation of cell transition from G1 to S-phase, DNA repair, and apoptosis following genome damage. A deletion of one of the alleles (17p13) in combination with a point mutation in the other allele is a genetic rearrangement observed in most malignant tumors. The mutated p53 actually acts as a cellular oncogene, stimulates the proliferation of tumor cells and induces the formation of antibodies that are detected in the blood of patients. The latter served as the basis for the development of immunodiagnosis and immunotherapy for lung cancer.

The mutation causes conformational changes in the p53 protein, and it accumulates in the cell nuclei, which makes it possible to determine it by immunohistochemical methods. On the contrary, wild-type p53 is considered to have a very short half-life (20 min) and therefore cannot be determined immunohistochemically. Inactivation of p53 in lung cancer occurs in about 70% of cases. Studies on the correlation of p53 expression with survival are controversial. In general, if such an action exists, it is very insignificant. The association of p53 with malignant transformation is also unclear. At the same time, experimental data show that upon activation of wild-type p53, growth slows down and apoptosis develops, which can lead to reversal of the malignant phenotype.

There is evidence for the significance of the p53 mutation in the early stages of lung carcinogenesis. Mutant forms of p53 are never detected in reserve basal cell hyperplasia or squamous metaplasia no signs of dysplasia. In p53 dysplasia, mutations are detected in 12-53% of cases, and in cancer in situ, in 60-90% of cases in studies of tissue surrounding lung cancer. Detection of p53 in more than 20% of cells in dysplasia foci is a marker of irreversible precancerous changes. However, p53 mutation is not a necessary phenomenon in lung cancer, and therefore the absence of p53 is not a favorable prognostic factor. Moreover, neither the accumulation of p53 nor its mutation exhaust the molecular mechanisms through which p53 can be inactivated in tumors. Disruption of p53 function occurs when it interacts with other proteins that regulate the mitotic cycle - p21, Mdm2, bax.

The Rb gene is localized at the 13q14 site, which is deleted in 80% of small cell lung cancer cases (as often as in retinoblastoma), encodes a 110 kDa nuclear phosphoprotein, and controls the exit of the cell from the G1 phase. Hypophosphorylation of Rb leads to cell blockade at the G1 stage and apoptosis. Rb inactivation in tumors is achieved by loss of one of the alleles and mutation of the second allele of the gene.

Thus, inactivation of the p53 and Rb suppressor genes is more important for the development and progression of small cell lung cancer.

Growth factors, growth factor receptors and binding proteins in lung cancer. In the progression of cancer lung factors growth play important role, providing tumor growth with the help of autocrine and paracrine stimulation.

Adhesive molecules and extracellular matrix in lung cancer. Adhesive molecules, integrin receptors and the extracellular matrix of lung cancer have a modulating effect on tumor cells and ensure the growth, invasion and metastasis of the tumor, as discussed in the previous sections of the lecture.

The first phase of tumor invasion is characterized by a weakening of contacts between cells, as evidenced by a decrease in the number of intercellular contacts, a decrease in the concentration of some adhesive molecules from the CD44 family, etc., and, conversely, an increase in the expression of others that ensure the mobility of tumor cells and their contact with the extracellular matrix. On the cell surface, the concentration of calcium ions decreases, which leads to an increase in the negative charge of tumor cells. The expression of integrin receptors, which provide attachment of the cell to the components of the extracellular matrix - laminin, fibronectin, and collagens, is enhanced. In the second phase, the tumor cell secretes proteolytic enzymes and their activators, which ensure the degradation of the extracellular matrix, thereby clearing the way for invasion. At the same time, the degradation products of fibronectin and laminin are chemoattractants for tumor cells that migrate to the degradation zone during the third phase of invasion, and then the process is repeated again.

Histogenetic markers various types lung cancer. Lung cancer is represented by tumors of various histogenesis. In recent years, all histological types of lung cancer are divided into small cell and non-small cell, which differ not only in morphological manifestations, but also clinically, response to chemotherapy and life prognosis of patients.

Small cell lung cancer is also characterized by specific biomolecular markers from the group of cellular oncogenes, suppressor genes, and growth factors. In addition, small cell carcinoma is also distinguished by signs of neuroendocrine differentiation. In more than 90% of cases, tumor cells express both chromogranin and pancytokeratins. Chromogranin is found in the form of granules in the cytoplasm of tumor cells. The number of chromogranin-positive cells and the level of expression varies depending on the degree of tumor maturity.

Non-small cell lung cancer is a heterogeneous group of tumors belonging to different histogenetic groups: squamous cell carcinoma (markers are cytokeratins and keratohyalin), adenocarcinoma (mucus cytokeratins, surfactant), as well as large cell carcinoma, which can be represented by both low-grade adenocarcinoma and low-grade squamous cell carcinoma. cancer.

Lecture equipment

Gross preparations: bronchiectasis and pneumosclerosis, chronic obstructive pulmonary emphysema, cor pulmonale, honeycomb lung in idiopathic fibrosing alveolitis, lung silicosis, central lung cancer, lung cancer metastases to the adrenal glands.

Micropreparations: chronic obstructive bronchitis, bronchiectasis and pneumosclerosis, chronic obstructive pulmonary emphysema, cor pulmonale, restructuring lung vessels with secondary pulmonary hypertension, idiopathic fibrosing alveolitis, sarcoidosis, lung silicosis, peripheral lung cancer, squamous cell lung cancer, lung adenocarcinoma, small cell lung cancer.

Electronograms: chronic obstructive pulmonary emphysema (obliteration of alveolar capillaries), lung adenocarcinoma, small cell lung cancer.

We are completing a series of articles on oncological diseases.
Today I will tell you in detail what molecular testing is and how it affects the diagnosis.

In the photo: Vladislav Mileiko, head of the department,
biomedical holding "Atlas".

To understand how molecular diagnostics works and what place it occupies in oncology, one must first understand the mechanisms that occur in a tumor.

Molecular processes in a tumor

Mutations in proto-oncogenes and suppressor genes responsible for cell division and death cause the cell to stop following instructions and synthesize proteins and enzymes incorrectly. Molecular processes are out of control: the cell is constantly dividing, refusing to die, and accumulating genetic and epigenetic mutations. Therefore, malignant neoplasms are often called a disease of the genome.

Hundreds of thousands of mutations can occur in tumor cells, but only a few contribute to tumor growth, genetic diversity, and development. They are called drivers. The remaining mutations, "passenger" (passenger), in themselves do not make the cell malignant.

Driver mutations create different populations of cells, which provides tumor diversity. These populations or clones respond differently to treatment: some are resistant and relapse. In addition, the different sensitivity of clones to therapy can lead to a radical change in the molecular profile during treatment: even cells that are insignificant at the beginning of the population can gain an advantage and become dominant at the end of treatment, which will lead to resistance and tumor development.

Molecular Diagnostics

Driver mutations, changes in the number or structure of proteins are used as biomarkers - targets for which treatment is selected. The more targets are known, the more accurate the choice can be from potentially efficient schemes treatment.

It is not easy to separate driver mutations from the rest and determine the molecular profile of the tumor. For this, the technology of sequencing, fluorescence in situ hybridization (FISH), microsatellite analysis and immunohistochemistry is used.

Next-generation sequencing methods can identify driver mutations, including those that make a tumor sensitive to targeted therapy.

With the help of FISH technology, sections of chromosomes on which a certain gene is located are tinted. Two connected multi-colored dots are a chimeric or fused gene: when, as a result of rearrangement of chromosomes, sections of different genes are joined together. This can lead to the fact that the oncogene will fall under the influence of the regulation of another more active gene. For example, the fusion of the EML4 and ALK genes is of key importance in the case of lung cancer. The proto-oncogene ALK is activated under the influence of its rearrangement partner, which leads to uncontrolled cell division. The oncologist, given the rearrangement, may administer a drug that targets the activated ALK gene product (crizotinib).

Fluorescent in situ hybridization (FISH).

Microsatellite analysis shows the degree of damage to the DNA repair system, and immunohistochemistry - protein biomarkers located on the surface, in the cytoplasm and nuclei of tumor cells.

All of these studies are included in New Product biomedical holding "Atlas" - Solo test. With the help of such a test, the oncologist obtains information about the molecular profile of the tumor and how it affects the potential efficiency. a wide range anticancer drugs.

Solo examines up to 450 genes and biomarkers to evaluate how a tumor might respond to more targeted treatments oncological diseases. For some of them, biomarker analysis is dictated by the manufacturer. For others use data clinical research and recommendations of international communities of oncologists.

In addition to selecting targets for targeted therapy, molecular profiling helps to detect mutations that, on the contrary, make a tumor resistant to a particular treatment, or genetic features that are associated with increased toxicity and require an individual selection of a drug dose.

For research, biopsy material or paraffinized blocks of postoperative material are used.

Molecular profiling provides additional information about the disease, but it is not always applicable to the choice of treatment. For example, in situations where standard therapy is sufficiently effective or indicated surgery. It is possible to identify clinical situations where such a study may be most useful:

• A rare type of tumor;
• Tumors with unidentified primary focus(it is not known where the tumor that metastasized originally appeared);
• Those cases where a choice of several options for the use of targeted therapy is required;
• The possibilities of standard therapy have been exhausted and it is required experimental treatment or inclusion of the patient in clinical trials.

Solo project specialists consult oncologists or patients and suggest whether a test is needed in this case.

Precision Medicine and Clinical Research

Usually in medical practice apply general strategies to treat patients with a specific diagnosis. For small cell lung cancer, one strategy is used, for non-small cell lung cancer, another. For oncological diseases, this method is not always suitable. Due to differences at the molecular level, even with the same type of tumor, patients may receive ineffective or unnecessary treatment.

With the increase in research and the invention of targeted drugs, the approach to cancer treatment has begun to change. To increase the relapse-free period and life expectancy of the patient, it is necessary to take into account the molecular profile of the tumor, the body's response to drugs and chemotherapy (pharmacogenomics), and to know the main biomarkers.

Precision medicine can significantly improve the prognosis of a particular patient, avoid serious side effects of oncological drugs and significantly improve the patient's quality of life. But this method also has disadvantages.

Targeted drugs are on the rise and have two main limitations: most molecularly targeted agents provide only partial suppression of signaling pathways, and many are too toxic to be used in combination.

Imagine that you are an architect of Moscow. Standing in front of you not an easy task- Solve the problem of traffic jams during rush hour by building one bridge. Molecular mechanisms can be compared to the movement of machines, and the bridge is the main drug that should solve the main problem. It seems that several drugs (a series of bridges) targeting the major molecular disturbances may solve this problem. But the toxicity of drugs increases and can be unpredictable.

We have gained a better understanding of the molecular processes of malignant tumors, but the current methods of introducing precision oncology into clinical practice are far behind. To speed up the study of targeted therapy, scientists have developed two new approaches - Basket and Umbrella.

The essence of the Basket method is that patients with a certain biomarker are selected for the study, regardless of the location and name of the tumor. In May 2017, the FDA approved such a treatment for a biomarker called high microsatellite instability (MSI-H) or mismatch repair defect (dMMR).

Molecular disorders differ not only in different patients but also within the same tumor. Heterogeneity - a big problem in oncology, for which the Umbrella study design was developed. For the Umbrella method, patients are first selected by type malignant neoplasms, and then take into account genetic mutations.

Such studies help not only to collect information about the effect of targeted drugs - sometimes it the only possibility for patients who do not respond to standard treatment with registered drugs.

Clinical example

We decided to give an illustrative example of what the use of advanced molecular profiling might look like.

A patient with skin melanoma and liver metastases consulted an oncologist. The doctor and the patient decided to do molecular profiling in order to get more full information about the disease. The patient was biopsied and tissue samples sent for analysis. As a result of diagnostics, several important genetic disorders were found in the tumor:

• Mutation in the BRAF gene. Indicates activation of the RAS-RAF-MEK oncogene signaling pathway, which is involved in cell differentiation and survival.
• Mutation in the NRAS gene. Indicates additional activation of the RAS-RAF-MEK signaling cascade.
• An inherited variant of the TPMT gene. Indicates the features of metabolism anticancer drug"Cisplatin".

Based on the results of clinical studies and recommendations, we can come to the following conclusions:

• Drugs of the BRAF inhibitor class (Vemurafenib) can be potentially effective, moreover, the presence of an NRAS mutation can serve as an additional reason for prescribing a double blockade of the signaling cascade - a combination with MEK inhibitors (Trametinib).
• Although there is no approved therapy that directly targets the NRAS oncogene, mutations in it are known to increase the likelihood of successful treatment when prescribing immunotherapy (Ipilimumab and Pembrolizumab).
• The hereditary genetic variant in the TPMT gene indicates an increased individual toxicity of Cisplatin, which requires dose adjustment when prescribing platinum-containing therapy regimens.

Thus, the doctor gets the opportunity to navigate among options treatment based not only on the clinical parameters of the patient, but also taking into account the molecular features of the tumor.

Molecular diagnostics is not a panacea for all cancers. But this is an important tool for the oncologist, which allows you to approach the treatment of malignant tumors from a new perspective.

Thank you for reading and commenting on our materials on oncology. Here full list articles.

As a result of the progress of new scientific areas of molecular biology, molecular genetics and genetic engineering a huge step forward has been made, which now allows us to ask nature questions that were previously impossible to ask. It is about understanding the most fundamental foundations of such phenomena as cell division and differentiation, as well as the causes of the mechanism of their violations.

In a specific application to one of the most topical and exciting problems facing humanity - the problem of malignant tumors - we can talk about the appearance new science- molecular oncology. Her striking success in the field of studying the molecular mechanisms of oncogenesis and the molecular basis of the cancer phenotype is associated with the use of unique research methods inherent in her.

The book published and offered to readers " Molecular Oncology” is dedicated to summing up the first results and presenting the achievements of this young science. It clearly traces the continuity of the basic principles and postulates of classical theoretical oncology, primarily in the main issues: the polyetiology of the onset of tumors and the multi-stage nature of this process.

However, solutions are already given at another level of organization of living matter - the molecular one. This book- the first and only so far in our country. It was written by authors who are directly and actively working in this field, which predetermined the depth of understanding of the given specific facts and the constructiveness of generalizations. The idea of ​​the universality of the molecular mechanisms of oncogenesis runs throughout the book.

This idea follows naturally from the analysis carried out by the authors latest research the main types of carcinogenesis: chemical, physical, biological, the basis of which, as the authors convincingly show, is one and can be expressed in fundamentally general molecular terms.

Separate chapters are devoted to each of these types of oncogenesis. Chapter 1 turns the reader to the origins of theoretical oncology, to its classic studies of the beginning of this century. Chapters 2 and 3 are devoted to the molecular mechanisms of chemical and viral carcinogenesis, respectively.

The first three chapters mentioned logically precede the final chapters 4 and 5, the true core of the book.

It is in these chapters that facts and ideas are presented in a concentrated form, symbolizing the essence and spirit of modern theoretical oncology - molecular oncology. Her achievements inspire confidence in the final victory of the human mind over a serious illness.

"Molecular Oncology"
I.F. Seitz, P.G. Knyazev

To a critically thinking observer, modern theoretical oncology may appear to be a flowering tree, but not a fruitful one. Such an impression is to some extent justified and is due to a clear imbalance of huge intellectual efforts and material investments, on the one hand, and modest practical outputs, on the other. Still remain unclear both the nature of malignant neoplasms and the primary stimulus that initiates the inevitable chain ...

Over time, the identification of the carcinogenic properties of chemical agents has become only a matter of technology, and there has been a clear shift in research focus from routine testing for carcinogenicity to the study of the mechanism of oncogenic action. In this case, along with significant successes, considerable difficulties were revealed. Successes concerned the purely chemical side of the problem: the need for activation of the original carcinogens was established, metabolism, interactions were studied ...

How does the invasion of fragments of chemical carcinogens into DNA result in uncontrolled growth and transformation of cells? The theory of chemical carcinogenesis, in order to take a new and decisive step forward, needs some kind of scientific event, similar in significance to the discovery of reverse transcriptase in oncovirology. In the theory of chemical carcinogenesis, such an event has not yet occurred. However, you can expect…

The main success of oncovirology today should be considered the discovery of oncogenes - discrete material genetic elements in the DNA structure of cells responsible for the induction of malignant tumors in humans and animals. This line of research is the most promising in modern theoretical oncology. Oncogenes have been found in the genomic DNA of not only animals, but also humans, and the likelihood of their involvement in tumor induction…

Even I. M. Sechenov in 1860, in the theses of his doctoral dissertation, wrote that in the present state of the natural sciences, the only possible principle of pathology is molecular. Now one can only marvel at this providence. Today, molecular oncology stands at the threshold of the mysteries of cancer. It is she who owns the most outstanding successes in the field of theoretical oncology in recent years. These include the following…

If molecular biology in the most concise interpretation can be characterized as a science that expresses and explains complex general biological phenomena in terms of the properties and interactions of molecules, then molecular oncology, of course, is designed to reveal the molecular mechanisms of the process of carcinogenesis and the characteristics of tumors. This book attempts to summarize the progress of this young science. All the greatness of progress in the knowledge of tumors in our ...

The use of gene transfer and molecular cloning techniques has made it possible to establish some of the most important, central determinants of the cancer process. These determinants are oncogenes and their products are oncoproteins that act both on the structure and functions of cells and affect the regulatory mechanisms of biochemical reactions. Many of these functions of oncogenes and oncoproteins are still unknown, however, with the current level of knowledge, they ...

The oncoprotein p21cras, during cell transformation, apparently significantly affects the bioenergetics of the cell and the transmission of the regulatory signal from cell membrane into the core. There is also no doubt that the p2jcras oncoprotein in its multifunctional action in the process of malignancy of the target cell, it cooperates with the functions of other activated proto-oncogenes. For some steroid hormones, such as glucocorticoids, a mechanism has been established for transmitting their information from a specific ...

One of the most modern and high-tech methods for diagnosing cancer is genetic (molecular) tests. These studies make it possible not only to determine the hereditary predisposition to certain oncological diseases, but also to assess the feasibility of prescribing chemotherapy and determine the degree of cancer aggressiveness.

The Tel Aviv First Medical Center conducts the most effective and proven genetic research of more than 900 existing in the world. this moment. At the same time, a remote testing service is provided when the patient does not need to fly to Israel. It is enough to send a sample of the material by mail (after a puncture or operation), following some rules, and wait for the results of the study.

Oncotype DX

This molecular study is applied in breast cancer. Depending on the objectives of the study, the type of tumor and the individual characteristics of the patient, there are several types of Oncotype DX.

Oncotype DX Breast

The test is used to determine the degree of differentiation of breast cancer tumor cells (the probability of recurrence is determined accordingly). It is used after surgery to remove the tumor to determine the advisability of prescribing chemotherapy. The study is suitable for estrogen-positive tumors (ER+), invasive breast cancer without metastasis to regional lymph nodes.

Standard signs for the choice of treatment tactics after surgery are:

Before the advent genetic tests, these three signs were the only source information, on the basis of which the tactics for the further appointment of chemotherapy was determined. However, the aggressiveness of cancer cells and, accordingly, the likelihood of a distant recurrence does not always correlate with the size of the tumor and the presence of metastases in the lymph nodes.

Today, in world medicine, the Oncotype DX genetic test is the gold standard and the leading criterion for choosing treatment tactics for breast cancer. It allows both to prevent the recurrence of the disease, and to avoid unnecessary prescription of chemotherapy and all the side effects associated with it.

Fish test for Herceptin receptors

It is an immunohistochemical study that detects specific receptors (HER-2, PR, ER) on cancer cells, which make it sensitive to targeted drugs. Such, in particular, is the drug Herceptin, belonging to the class of monoclonal antibodies. It has long been successfully used in the treatment of breast cancer in Israel and has shown nice results to prolong life and prevent recurrence, even in advanced stage and the presence of metastases.

In about 1 out of 4 cases of breast cancer, the tumor is sensitive to Herceptin therapy and this can be determined by a molecular test for specific receptors. Treatment advantage biological preparations compared to standard methods(radio and chemotherapy) is the absence of harmful side effects.

Molecular test of the CYP2D6 gene

It is used exclusively in cases of hormone-dependent breast tumors. These cancer cells have receptors for the hormones estrogen and progesterone, making them sensitive to the effects of hormone therapy(especially in women during menopause).

Studies have shown that the hormone replacement drugs used are converted in the liver into active active substance thanks to a special enzyme CYP2D6, encoded by the gene of the same name. On average, up to 10% of people have a mutation of this gene, due to which a full transformation of hormones is impossible.

A genetic test makes it possible to identify this mutation and thus determine whether treatment with hormonal drugs will be effective and assess the risk of relapse. At the First Medical Center in Tel Aviv, this study is carried out with material from the patient's saliva.

Oncotype DX Colon

A molecular study that is used in colon cancer to comprehensively weigh the risk of recurrence and the degree of tumor progression. The essence of the test lies in the analysis of complex software 12 cancer cell DNA genes that are responsible for the degree of differentiation, atypicality and gene aberrations. The result of the analysis is converted into a numeric form and has a value from 0 to 100.

The Oncotype DX Colon study is indicated for patients with malignant tumors colon of the 2nd stage after the operation of removal of the primary tumor and in the absence of metastases in the regional lymph nodes. About 15% of patients with colon cancer have a non-aggressive form of the tumor that is not prone to recurrence. The test allows you to assess this risk and avoid unnecessary chemotherapy.

Duration genetic testing Oncotype DX Colon in Israel is about two weeks, and the material is taken directly from the primary tumor. The assessment is made on a 100-point scale, a comprehensive conclusion is made and further treatment tactics are selected.

K-RAS test

A specific genetic test that allows you to determine the sensitivity of colon cancer and to targeted therapy with Setuximab. The drug is a monoclonal antibody that selectively blocks EGFR receptors on tumor cells. The aggressiveness of colon and rectal cancer directly depends on the expression of specific epidermal growth factor receptors (EGFR).

K-RAS is a protein that is involved in a cascade of reactions that control cell division in the intestinal epithelium. Mutations in the gene encoding this protein make treatment with Setuximab ineffective. Approximately 60% of people do not have this mutation, so a drug can be given if the test is negative.

The K-RAS test is extremely important diagnostic criterion in modern oncology. This is due to the fact that treatment with Setuximab prolongs life by 2-5 years or even leads to complete recovery of patients with advanced forms of neoplasms of the colon and rectum. Even 10 years ago, metastatic cancer of these parts of the gastrointestinal tract was considered incurable and patients received palliative therapy; with the introduction of biological therapy, patients got a chance for recovery.

EGFR mutation test

This genetic test is used for non-small cell lung cancer. There are two enzymes that control cell reproduction - tyrosine kinase and epidermal growth factor EGFR. Therefore, in modern methods Targeted tumor therapy uses two drugs that inhibit these enzymes, Erlotinib and Gefetinib.

According to statistics, from 15 to 20% of patients have an EGFR gene mutation, so they need to be prescribed targeted treatment in the form of monoclonal antibodies instead of second-line chemotherapy drugs. This is especially true for stages 3 and 4 of non-small cell lung cancer with the presence of metastases. Erlotinib and Gefetinib can inhibit the growth of cancer cells for years and cause a long-term remission in the patient. In addition, monoclonal antibodies do not have negative side effects, like chemotherapy (cytotoxic effect), since it does not affect healthy cells.

Comprehensive survey Target Now

Each atypical cancer cell has its own unique set of receptors and gene expression, just like each person has a unique fingerprint. The effectiveness of chemotherapy and treatment with biological targeted drugs depends on their presence or absence.

The current stage of development of treatment with monoclonal antibodies has acquired such a scope that for the maximum effective selection drug, you need to conduct a lot of molecular tests. The Target Now methodology allows you to combine them all into one study that accurately reflects genetic code atypical cell.

For the first time, official test results were presented in 2009 at a conference of the American Association for Cancer Research. According to them, more than 98% of patients with an advanced form of cancer (the presence of metastases) managed to get complete picture molecular targets and select the appropriate targeted therapy. Moreover, in 30-35% of patients, as a result of modified therapy according to the results of Target Now, there was a significant improvement in the quality of life and increased life expectancy.

The test is indicated for use in patients in whom previous treatment has not been effective, or with metastases of any localization. For the study, material from the tumor tissue is needed (biopsy, or after surgery).

Mamma Print

This genetic test is designed to determine the risk of recurrence after breast cancer. According to the recommendations of the American Food and drug administration (FDA), the test is indicated for patients with any form of breast cancer younger than 60 years old, without metastatic lesions. lymph nodes and provided that the tumor is less than 5 centimeters in size.

The essence of the study lies in the molecular analysis of the expression of 70 genes of a cancer cell, followed by an assessment of the aggressiveness of the tumor and the derivation of the final risk of recurrence using mathematical formula. The result allows you to choose the tactics of treatment and determine the feasibility of prescribing chemotherapy to patients.

The difference between Mamma Print and similar genetic tests is that the study is carried out on a sample of “fresh” tissue, so the patient must stay in Israel for a puncture or operation. You need to wait about a week for the result, but after the procedure you can go home and get an answer in writing.

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