Targeted anticancer therapies

Content

Introduction

Targeted anticancer therapies involve the use of drugs that block the growth and spread of cancer cells by interfering with molecules involved in tumor progression, called "molecular targets." For this reason, targeted anticancer therapies are also called "molecular targeting therapies. ".

Targeted anticancer therapies differ from classic chemotherapy in several respects:

  • they act on specific molecular targets of cancer cells, while most chemotherapies target all rapidly reproducing cells, both normal and cancerous
  • block the proliferation of cancer cells (cytostatic), while chemotherapy drugs kill cancer cells (cytotoxic)
  • they interact specifically with their target, while many chemotherapies are identified on the basis of their cytotoxic capacity

Targeted anticancer therapies are currently at the heart of the development of many anticancer drugs. They are a cornerstone of precision medicine, a branch of medicine that uses information about an individual's genes and proteins to prevent, detect (diagnose) and treat disease.

In Italy, many targeted anticancer therapies have been approved for the treatment of specific types of cancer; others are being tested on humans; still others are being tested on animals (experimental phase preceding that on humans).

Identification of targets for targeted anticancer therapies

The development of molecularly targeted therapies requires the identification of targets that play a key role in the proliferation and survival of cancer cells. One approach to identifying potential targets is to compare proteins present on cancer cells with those present on normal cells.

Proteins present or modified or more abundant in cancer cells than normal cells represent potential targets, especially if they are known to be involved in cell proliferation or survival. One example is the human epidermal growth factor receptor 2 (HER-2) protein. HER-2 it is present in high quantities on the surface of some cancer cells. Several molecularly targeted therapies are directed against HER-2, including trastuzumab, which is approved for the treatment of breast and stomach cancers in which HER-2 is highly represented.

Another approach to identifying potential targets is to determine whether cancer cells produce mutant (altered) proteins that drive cancer progression. For example, the cell growth signaling protein B-RAF it is present in an altered form (known as BRAF V600E) in many melanomas. The drug vemurafenib targets this mutant form of the BRAF protein and is approved for the treatment of people with inoperable or metastatic melanoma that contains the altered B-RAF protein.

Another possibility is represented by the possible presence of abnormalities in the chromosomes of cancer cells compared to normal cells.Sometimes these chromosomal abnormalities lead to the creation of a fusion gene (a gene that incorporates parts of two different genes) whose product, called a fusion protein, can drive cancer development. Such fusion proteins are potential targets for targeted anticancer therapies. For example, imatinib mesylate targets the fusion protein BCR-ABL, consisting of pieces of two genes that join together in some leukemia cells and promote their growth.

Development of targeted anticancer therapies

Once a molecular target has been identified, the next step is to develop a therapy that affects the target in a way that interferes with its ability to promote the proliferation or survival of cancer cells. Some therapies use small molecules or antibodies. The small molecules are developed for targets that are inside the cancer cell as they are able to enter the cells easily. The antibodies, being relatively large, cannot, however, enter the cells and are used only for targets that are found on the outer surface of the cell itself.

Small molecules are identified by examining the effects of thousands of compounds on a specific target protein and in this way it is possible to select the compounds that affect the functionality of the target. These compounds are then chemically modified to produce numerous variants closely related to the compound from which they derive. Each variant is tested to determine which are the most effective and have the least effect on healthy molecules.

Antibodies are developed by injecting purified target proteins into animals (usually mice) to obtain different types. Next, they are tested to find the ones that bind best to the target without attaching to normal cells.

Targeted anticancer therapies available

Many targeted therapies have been approved in the treatment of cancer. They include hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies and toxin-releasing compounds.

Hormonal therapies slow or stop the growth of hormone-sensitive tumors, i.e. those that need hormones to grow. They work by preventing the body from producing hormones or by interfering with the action of the hormones themselves. Hormone therapies have been approved for both breast and prostate cancer.

Signal transduction inhibitors they block the activity of molecules that participate in the process by which a cell responds to signals from the external environment. In some cancers where malignant cells multiply continuously, signal transduction inhibitors that interfere with cell replication processes can be used.

Gene expression modulators they modify the function of proteins that play a role in controlling the functioning of genes.

The inducers of apoptosis cause cancer cells to undergo a process of controlled cell death, called apoptosis, which the body normally uses to eliminate unnecessary or abnormal cells. Cancer cells have strategies to avoid apoptosis. Inducers of apoptosis can circumvent these strategies to cause cancer cell death.

The inhibitors of angiogenesis block the growth of new blood vessels in tumors (tumor angiogenesis). Tumor angiogenesis aims to increase the blood supply to make the tumor grow beyond a certain size, as blood supplies the oxygen and nutrients that tumors need to grow continuously. Treatments that interfere with cancer. angiogenesis can block tumor growth.Some targeted therapies that inhibit angiogenesis interfere with the action of vascular endothelial growth factor (VEGF), a substance that stimulates the formation of new blood vessels.

Immunotherapies they activate the immune system to destroy cancer cells. Some immunotherapies use antibodies that recognize specific molecules on the surface of cancer cells. The binding of the antibody to the target molecule determines the destruction of the cells that carry it by the immune system, releasing toxic molecules that can cause the death of cancer cells. When the antibody binds to the tumor cell, the toxic molecule that is attached to the antibody, such as a radioactive substance or poisonous chemical, is absorbed by the cell, killing it. The toxin does not affect cells that are not targeted for the antibody, which is the vast majority of healthy cells in the body .

Use of targeted anticancer therapies

In most cases of cancer it is possible to search for the suitable target to be attacked by targeted therapy. Chronic myeloid leukemia is one example: most people with chronic myeloid leukemia have the BCR-ABL fusion gene. For other types of cancer, however, the person's tumor tissue must be tested to determine whether or not an appropriate target is present. In these cases, the use of targeted therapy is limited to people with tumors characterized by gene alterations that constitute a suitable molecular target.

Limitations of targeted anticancer therapies

Targeted anticancer therapies have some limitations. One is the tumor's resistance to the effects of the treatment.Resistance can occur in two ways: the target changes so that the targeted therapy no longer interacts with it and / or the tumor finds a new way to continue to grow, bypassing the action of the therapy.

For this reason, targeted anticancer therapies work best in combination. For example, a recent study found that using two drugs in melanoma with the BRAF V600E mutation slows the development of resistance and disease progression to a greater extent than using just one drug.

Another approach is to use molecularly targeted therapy in combination with one or more traditional chemotherapy drugs. For example, therapy using trastuzumab has been used in combination with docetaxel, a traditional chemotherapy drug, to treat women with metastatic breast cancer with HER-2 protein.

Another limitation of targeted therapy is that drugs for some identified targets are difficult to develop due to the structure of the target and / or the way its function is regulated in the cell. An example is Ras, a family of proteins involved in the transmission of signals within the cell, which have mutated in a quarter of all cancers. To date, it has not been possible to develop Ras signaling inhibitors. However, new pharmacological approaches show promising preliminary results for the future.

Side effects of targeted therapies

Although targeted anticancer therapies have been developed with the aim of reducing toxicity compared to chemotherapy, they can still have undesirable effects (side effects).

The most common side effects are diarrhea and liver problems, such as hepatitis and elevated liver enzymes. Other side effects observed include:

  • skin problems (acne-like rash, dry skin, nail changes, hair depigmentation)
  • problems related to blood clotting and wound healing
  • high blood pressure
  • gastrointestinal perforation (rare side effect of some targeted therapies)

Some side effects of some therapies have been linked to better outcomes. For example, in people who develop acneiform rash (skin rashes that resemble acne) while being treated with the signal transduction inhibitors, erlotinib or gefitinib, both targeting the epidermal growth factor receptor (EGFR), the effectiveness of therapies is greater than in people who do not develop the rash. Similarly, people who experience high blood pressure while being treated with the angiogenesis inhibitor bevacizumab generally have better results from treatment.

The few targeted therapies approved for use in children can cause different side effects than in adults. These include immunosuppression and impaired sperm production.

In which tumors are used

As for the most common cancers, targeted therapies have already been in use for several years, but research has greatly expanded the range of molecules available. Therefore, the following list is not exhaustive and is to be considered only indicative of a constantly evolving picture.

Non-small cell lung cancer

Targeted therapies for non-small cell lung cancer belong to several categories and are numerous. They include those that block blood vessel proliferation (bevacizumab and ramucirumab), signal transduction inhibitors (gefitinib, erlotinib, afatinib, osimertinib, crizotinib, ceritinib, alectinib), and immunotherapy drugs (nivolumab, pembrolizumab).

Colon cancer

Some types of colon cancer respond to therapies with epidermal growth factor receptor (EGFR) inhibitors, cetuximab and panitumumab; others are treated with inhibitors of blood vessel proliferation such as bevacizumab or regorafenib which also includes an action to inhibit signal transduction.

Renal cell carcinoma

Various treatments are used for kidney cancer including immunotherapy (nivolumab), blood vessel proliferation inhibitors (bevacizumab) and various types of molecular target drugs (sunitinib, sorafenib, pazopanib, temsirolimus, everolimus).

Breast cancer

For breast cancer, hormone therapies are available in the case of cancer cells with receptors for female hormones. There are two mechanisms of action of hormone therapy: to prevent the cancer cell from using estrogen for growth (anti-estrogen drugs such as tamoxifen) or to inhibit the endogenous production of estrogens (aromatase inhibitors such as anastrazole, letrozole, exemestane or analogues of 'LH-RH).

Some cancer cells that have HER-2 growth factor receptors respond to therapy with antibodies directed against this molecule, trastuzumab and pertuzumab.

Melanoma

In advanced forms of melanoma, with specific mutations in some molecules involved in signal transduction, some inhibitory drugs such as vemurafenib, dabrafenib, trametinib, cobimetinib or others can be used. In other cases, people respond well to immunotherapy (ipilimumab, nivolumb, pembrolizumab).

Leukemias and other blood cancers

In some forms of leukemia characterized by a specific chromosomal abnormality (Philadelphia chromosome), molecularly targeted drugs such as imatinib and others of the same class (signal transduction inhibitors) are used.Some types of multiple myeloma use bortezomib, a drug that induces programmed cell death, and other drugs of the same class (called proteasome inhibitors).

Bibliography

Italian Medicines Agency (AIFA). Medicines database

In-depth link

National Institutes of Health (NIH). National Cancer Institute. Targeted Cancer Therapies (English)

American Cancer Society. Targeted Therapy (English)

Italian Association for Cancer Research (AIRC). Targeted therapies

Italian Association of Medical Oncology (AIOM). Targeted therapies. One Hundred Questions, One Hundred Answers

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