Revolutionary Treatment

Revolutionary Treatment

Targetted therapy seeks block the growth and spread to cancer by interfering with specific molecules involved in the growth, progression and spread of cancer
By Dr. Anish Maru

Targeted therapy is a special type of chemotherapy which takes advantage of small differences between normal cells and cancer cells. It is sometimes used alone, but most often other cancer treatments are used with the targeted drug.
Targeted therapies are currently the focus of most anti-cancer drug development. They are a cornerstone of precision medicine, a form of medicine that uses information about a person’s genes and proteins to prevent, diagnose and treat diseases.
Many targeted cancer therapies have been approved by the Food and Drug Administration (FDA) to treat specific types of cancer. Others are being studied in clinical trials (research studies with people) and many more are in preclinical testing (research studies with animals).
The development of targeted therapies requires the identification of good targets – that is, targets that play a key role in the growth of cancer cells and their survival. Targeted drugs can be used as the main treatment for some cancers, but in most cases they are used along with other treatments such as chemo, surgery, and/or radiation therapy.
With disease investigations serving as a base, the doctors will be able to know more about the differences in cancer cells (or other cells near them) that help them grow and thrive; they have been able to develop drugs that target these differences. Treatment with these drugs is often called targeted therapy.
Targeted therapy drugs, like other drugs used to treat cancer, are technically considered chemotherapy. But targeted therapy drugs do not work the same way as standard chemotherapy (chemo) drugs. For instance, many targeted drugs go after the cancer cells’ inner workings – the programming that sets them apart from normal, healthy cells. These drugs tend to have different (and often less severe) side effects than standard chemo drugs.
Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules called molecular targets that are involved in the growth, progression and spread of cancer. Targeted cancer therapies arecommonly known as molecularly targeted drugs, molecularly targeted therapies, precision medicines or with such similar names.
The targeted therapies differ from standard chemotherapyin several ways. Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells. Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells. Targeted therapies are often cytostatic (that is, they block tumour cell proliferation); whereas standard chemotherapy agents are cytotoxic that is, they kill tumour cells.
The primary approach to identify potential targets is to compare the amounts of individualproteins in cancer cells with those in normal cells. Proteins that are present in cancer cells, but not normal cells or that are more abundant in cancer cells would be potential targets, especially if they are known to be involved in the growth of cells or their survival.
The research is still going on abnormalities in chromosomes that are present in cancer cells, but not in normal cells. Sometimes, these chromosome abnormalities result in the creation of a fusion gene (a gene that incorporates parts of two different genes) whose product, called a fusion protein, may drive cancer development. Such fusion proteins are potential targets for targeted cancer therapies. For instance, imatinibmesylate targets the BCR-ABL fusion protein, which is made from the pieces of two genes that get joined together in some leukaemia cells and promote the growth of leukemic cells.
Development
Once a patient target has been identified, the next step would be to develop a therapy that affects the target in a way to interfere with its ability to promote cancer cell growth or survival. For instance, a targeted therapy could reduce the activity of the target or prevent it from binding to a receptor that it normally activates, among other possible mechanisms.
Most targeted therapies are either small molecules or monoclonal antibodies. Small-molecule compounds are typically developed for targets which are located inside the cell because such agents are able to enter cells relatively more easily. Monoclonal antibodies are relatively large and generally cannot enter cells, so they are used only for targets that are outside the cells or around their surface.
Types of targeted therapies
Many different targeted therapies have been approved for use in cancer treatment. These therapies include hormone therapies, signal transduction inhibitors, gene expressionmodulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies and toxindelivery molecules.
• Hormone therapies slow or stop the growth of hormone-sensitive tumours, which require certain hormones to grow. Hormone therapies act by preventing the body from producing the hormones or by interfering with the action of the hormones. Hormone therapies have been approved for both breast cancer and prostate cancer.
• Signal transduction inhibitors block the activities of molecules that participate insignal transduction, the process by which a cell responds to signals from its environment. During this process, once a cell has received a specific signal, the signal is relayed within the cell through a series of biochemical reactions whicheventually produce the appropriate response(s).
In some cancers, the malignant cells are stimulated to divide continuously without being prompted to do so by external growth factors. Signal transduction inhibitors interfere with this inappropriate signalling.
• Gene expression modulators modify the function of proteins that play a role in controlling gene expression.
• Apoptosis inducers cause cancer cells to undergo a process of controlled cell death called apoptosis. Apoptosis is one method which the body uses to get rid of unwanted or abnormal cells, but cancer cells have strategies to avoid apoptosis. Apoptosis inducers can get around these strategies to cause the death of cancer cells.
• Angiogenesis inhibitors block the growth of new blood vessels to tumours (a process called tumour angiogenesis). A blood supply is necessary for tumours to grow beyond a certain size because blood provides the oxygen and nutrients that tumours need for continued growth.
Treatments that interfere with angiogenesis may block tumour growth. Some targeted therapies that inhibit angiogenesis interfere with the action ofvascular endothelial growth factor (VEGF), a substance that stimulates new blood vessel formation. Other angiogenesis inhibitors target other molecules that stimulate new blood vessel growth.
• Immunotherapies trigger the immune system to destroy cancer cells. Some immunotherapies are monoclonal antibodies that recognize specific molecules on the surface of cancer cells. Binding of the monoclonal antibody to the target molecule results in the immune destruction of cells that express that target molecule. Other monoclonal antibodies are bound to certain immune cells to help these cells kill the growth of cancer cells.
• Monoclonal antibodies that deliver toxic molecules can cause the death of cancer cells. Once the antibody is bound to its target cell, the toxic molecule that is linked to the antibody, such as a radioactive substance or a poisonous chemical, is taken up by the cell, ultimately killing that cell. The toxin will not affect cells that lack the target for the antibody – i.e., the vast majority of cells in the body.
• Cancer vaccines and gene therapy are sometimes considered targeted therapies because they interfere with the growth of specific cancer cells. Information about such treatments can be found in the NCI fact sheets called Cancer Vaccines and Biological Therapies for Cancer.
For some types of cancer, most patients will have an appropriate target for a particular targeted therapy and thus will be able to get treated with that therapy. CML is an example: Most patients have the BCR-ABL fusion gene. For other cancer types, however, a patient’s tumour tissue must be tested to determine whether or not an appropriate target is present. The use of a targeted therapy may be restricted to patients whose tumour has a specific gene mutation that codes for the target; patients who do not have the mutation would not be the fit candidates as the therapy would have nothing to target.
Sometimes, a patient is an appropriate candidate for a targeted therapy only when he or she meets specific criteria (for example, their cancer did not respond to other therapies or isinoperable). These criteria are set by the FDA when it approves a specific targeted therapy.

Limitations
Targeted therapies do have some limitations. One is that cancer cells can become resistant to them. Resistance can occur in two ways: the target itself changes through mutation so that the targeted therapy no longer interacts well with it, and/or the tumour finds a new pathway to achieve tumour growth that does not depend on the target.
Targeted cancer therapies would be less toxic than traditional chemotherapy drugs because cancer cells are more dependent on the targets than the normal cells. However, targeted cancer therapies can have substantial side effects.
The most common side effects seen with targeted therapies are diarrhoea and liver problems, such as hepatitis and elevated liver enzymes. Other side effects seen with targeted therapies, include skin problems (acneiform rash, dry skin, nail changes, hair depigmentation), problems with blood clotting and wound healing, high blood pressure and gastrointestinal perforation.
Certain side effects of some targeted therapies have been linked to the better outcomesof patients. For example, patients who develop acneiform rash (skin eruptions that resemble acne) while being treated with the signal transduction inhibitors, both of which target the epidermal growth factor receptor, have tended to respond better to these drugs than patients who do not develop the rash. Similarly, patients who develop high blood pressure while being treated with the angiogenesis inhibitor bevacizumab generally have had better outcomes.
The few targeted therapies that are approved for use in children can have different side effects from adults, including immunosuppression and impaired sperm production.

(The author is, MD, DM- Senior Consultant, Action Cancer Hospital, New Delhi)