Targeted Therapy: What Are The 10 Hallmarks of Cancer?

Targeted cancer therapy aims to strangle cancer cells by targeting processes and proteins the tumor needs to survive and grow. This is different that chemotherapy and radiation, which tends to destroy cancer cells and healthy cells indiscriminately.

Targeted cancer therapy is a specialized treatment for certain cancers with medications that target the proteins and cell-signaling pathways in the cancer cells which drive their growth and proliferation. Targeted therapies also aim to stop some of the other mechanisms in the tumor microenvironment which the cancer cells enslave to foster their growth and metastasis.

Advancement in gene technology has enabled better identification of specific changes in the DNA and cell-signaling pathways which cause cancer. A new generation of medications have made it possible to penetrate into the cell and attack these defective cell mechanisms and change the way proteins carry out an impaired gene’s instructions (gene expression), in order to control the growth of cancer.

Many novel targeted therapies are still evolving while researchers discover more about cell changes that lead to cancer. The primary goal of targeted therapy is to find the right combination of medication to directly attack the defect in the cell mechanism that causes a specific cancer, while avoiding damage to other healthy tissue.

Targeted therapies can be used as an adjunct to traditional cancer therapies such as surgery, chemotherapy or radiation.

Both targeted therapy and chemotherapy can be effective treatments for cancer, but both therapies also have several side effects. A limitation of targeted therapy drugs is that cancer cells can develop resistance to them. The two main differences between chemotherapy and targeted therapy are:

• Chemotherapy medications can have a toxic effect on normal cells also, while targeted medications mostly do not affect the normal cells.
• Chemotherapy kills the cancer cells directly, while targeted therapy identifies and attacks the specific defective mechanism in cancer cells to prevent them from multiplying.

Targeted therapies are most effective for tumors which have targets that are clearly identifiable. Cancers vary hugely in the way they form and grow, and some may not have an identifiable target to attack. Different types of cancers are caused by different gene changes in the cells.

Some types of cancers, such as chronic myeloid leukemia (CML), almost always have a target cell mechanism that targeted therapy can focus on. Conversely, some types of breast cancer may not respond to targeted therapy unless caused by a specific genetic change in the cancer cells.

Some cancer patients may require a tumor biopsy to determine a suitable targeted therapy. Some patients may require traditional cancer therapies along with targeted therapy.

Cancer is an uncontrolled proliferation of abnormal cells that defy and evade the normal cell mechanisms of growth, division and programmed death (apoptosis). Old cells or cells with damaged DNA continue to live and multiply, in some cases, forming a mass of tissue growth known as tumor. The unchecked growth of cancer cells depletes nutrient supply to normal tissue and starves them.

Cancer is a large group of diseases, some caused by genetic changes in normal cells, some by environment factors, and some, for no known reason. Cancer can develop in any part of the body as a local tumor, and ultimately spread (metastasize) to other parts of the body.

Cancers arise from multiple genetic mutations and epigenetic changes that occur during cell division, which drive the transformation of a normal cell into a malignant one. Genetic mutations permanently change the DNA sequence of the cell, while epigenetic changes do not change the DNA sequence but alter the way a gene is expressed in the cell.

All gene mutations need not necessarily cause cancer. Proto-oncogene is a type of gene that has a potential to cause cancer if it mutates to become an oncogene, because proto-oncogenes control cell growth and division.

Normal cells have several regulatory mechanisms which control how they grow, divide, stop growing and die. Tumors grow abnormally by breaching these natural defense mechanisms, which are the hallmarks of most types of cancers. Cancer is said to be malignant when cancer cells start invading nearby normal cells, and metastasize.

Targeted therapy’s goal is to control cancer by inhibiting these aberrant hallmark changes in the cancer cells.

Genetic and epigenetic changes

There are six types of genetic and epigenetic changes (hallmarks) in cell physiology that drive the growth of cancer.

• Self-sufficiency in growth signals: Normal cells have certain proteins known as receptors on the cell surface which require external signals from hormones and growth factors to activate cell growth. Some types of mutated cells have excessive receptors on the surface, which get stimulated by growth factors, causing uncontrolled growth. Some cancer cells grow and divide without external stimulation by developing their own signals, or do away with signaling altogether.
• Insensitivity to growth-inhibitory signals: Normal cells respond to growth regulatory mechanisms and stop growing and dividing when certain proteins such as those coded by tumor suppressor genes signal to them to stop growing. Cancer cells lose this inhibitory mechanism and do not respond to these signals.
• Evading programmed cell death: When normal cells reach the end of their life cycle or when there is damage to the DNA, they undergo an orderly process of programmed cell death known as apoptosis. The apoptosis signaling mechanism fails to function in cancer cells enabling them to evade apoptosis and continue to multiply their diseased genes.
• Limitless replication potential: Normal cells are programmed for a certain number of divisions, after which they stop dividing and undergo apoptosis. The DNA change in the cancer cell gives them the ability to multiply infinitely.
• Sustained angiogenesis: Angiogenesis is a process by which new blood vessels develop, a necessary process in wound healing and embryo development. Cancer cells need sustained blood supply to support their growth, and they produce chemical signals to activate the cells that make new blood vessels, and enable angiogenesis.
• Invasion and metastasis: Invasion and metastasis are important hallmarks of malignancy. Cancer is said to be invasive when individual cells or groups of cells from a malignant tumor break off and invade nearby tissue to start new tumor growths.

Metastasis occurs when the cancer cells develop the ability to change shape and become mobile. These cells travel to other parts of the body through the bloodstream or lymphatic fluid and start growing in healthy tissues in new areas.

Microenvironment factors

Tumor cells learn to subvert other normal cells and processes in the tumor microenvironment to aid their growth and metastasis. Four mechanisms (hallmarks) have been discovered and studied for applying targeted therapy.

• Immune evasion: The immune system reacts to the tumor both positively and negatively. Antibodies develop when the immune system initially detects tumor antigens, but tumor cells rapidly mutate to grow without these antigens and avoid detection.
  • Tumors outstrip the nutrient and oxygen supply because of uncontrolled growth, leading to an alteration in metabolism and an acidic microenvironment. This results in attracting immune cells that help in healing, and also suppress the antitumor immune response.
• Stress response: Reduced oxygen (hypoxia) and nutrient supply causes stress to the tumor cells, leading to further DNA damage. The stress elicits a protective response from the body which stabilizes the tumor cell, furthering the tumor growth.
• Stromal subversion: Stroma is the structure that plays a supportive and connective role to all the tissue in the body. Stromal cells form a structure known as extracellular matrix, on which all other cells are embedded. Cell signals from the tumor cells cause mutations in the stromal cells which assist in angiogenesis and mobility of the tumor cells, enabling invasion and metastasis.
• Cytokine factors: The tumor microenvironment is full of immune cells which release inflammatory signals in the form of proteins known as cytokines. The resulting inflammation induces the immune cells to release proteins which promote angiogenesis and directly assist tumor growth.

There are two main types of targeted therapy:

• Small molecule drugs: Small molecule drugs are tiny particles that can work on the surface of the cells and also get into the cell and work on the proteins and signaling pathways inside the cancer cell.
• Monoclonal antibodies: Monoclonal antibodies are lab-made protein molecules that are too large to get inside a cell. Monoclonal antibodies instead attach to proteins on the cancer cell surface to work in one of the following ways:
  • Block the cancer’s spread. 
  • Signal to killer immune cells, which kill the cancer cell.
  • Carry and deliver drugs that are toxic to the cancer cell.

The types of targeted therapies available include:

• Hormonal therapy: Hormonal therapy prevents the production of certain hormones, or interferes with their action, to control the growth of cancer in hormone-dependent cancers such as breast cancer and prostate cancer.
• Signal transduction inhibitors: Signal transduction is the process by which appropriate downstream biochemical changes take place inside a cell after it receives a signal. Signal transduction inhibitors interfere with the defective signal transduction in cancer cells, which makes them keep growing.
• Gene expression modulators: Gene expression modulators modify the proteins that control the way the abnormal gene is expressed.
• Apoptosis inducers: Apoptosis inducers block the cancer cell’s apoptosis evasion tactics and induce them to undergo apoptosis.
• Angiogenesis inhibitors: Angiogenesis inhibitors block the activation of growth factors that enable new blood vessel formation in the tumor.
• Immunotherapies: Some immunotherapies bind to immune cells and improve their ability to kill the cancer cells. Other immunotherapies use monoclonal antibodies that bind to the tumor cells and enable the killer immune cells to identify and kill them. 

The side effects of targeted therapy are dependent on the type of therapy. They may include:

• Nausea
• Vomiting
• Diarrhea
• Constipation
• Fatigue
• Liver damage
• High blood pressure
• Mouth sores
• Problems with blood clotting and wound healing
• Gastrointestinal perforation (rare effect of some therapies)

Targeted therapy can have some severe side effects, especially on skin, hair and nails, because many of the growth factors they inhibit are also required for a healthy skin. The side effects include:

• Itchy, stinging or painful rashes
• Dry cracking skin
• Feeling like a bad sunburn
• Extreme sensitivity to sunlight
• Swollen, painful sores on the nails
• Hair loss and sores on scalp
• Swollen and red eyelids than can curl inward and irritate or damage the eyes