What is cancer target therapy?
Targeted therapy is a specialized cancer treatment that targets specific cancer-causing proteins and mechanisms in the cellular level. Targeted cancer therapy uses medications that alter the way cancer cells function to inhibit their abnormal growth.
When a tumor relies heavily on one mutated gene to keep growing and spreading, this is called oncogenic addiction. Certain therapies target these mutated genes (oncogenes) necessary for tumor growth and aim to stopping the genetic activity of that gene. Ideally, this strangles the tumor and keeps it from growing further.
Targeted cancer therapy is administered with two primary types of medications:
- Small molecule drugs: Small molecule drugs are tiny particles that can work on the surface of the cells and can 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 attach to proteins on the cancer cell surface and work by activating the immune system
What is cancer?
Cancer is a unique group of diseases caused by abnormal growth of cells due to certain defects. The life cycle of a normal cell in the human body is strictly regulated by several mechanisms which instruct the cells when to grow, divide, differentiate or die. Cancer cells have flawed genetic material which helps them evade these mechanisms to grow uncontrollably.
Cancers arise due to several reasons such as genetic mutations, environmental factors, certain viral infections, and sometimes for no apparent reason. Cancers can develop in any part of the body and ultimately spread all over the body (metastasis).
What is genetic mutation?
Genetic mutation is the alteration in genetic material that occurs during cell division. The human genetic material consists of 23 pairs of chromosomes which contain the DNA, proteins, and genes that encode the growth and function of each human cell.
When activated by growth factor proteins, cells grow and divide by making exact copies of the chromosomes for every new cell. Errors often occur in copying the DNA, and mostly, the inhibitory mechanism in the cells identifies faults in the DNA, stops the dividing process, and destroys the defective cell.
But some cells defy this process, carry on the mutation and continue growing and dividing. Many of the mutations are harmless and sometimes even beneficial. But some genetic mutations can lead to serious illnesses. Cancer is primarily caused by mutations in two classes of genes:
- Proto-oncogenes: Genes that enhance growth and development.
- Tumor suppressor genes: Genes that inactivate mutated genes.
What is an oncogene in cancer?
Oncogenes are genes that have high potential to cause cancer, and a leading reason for cancer. Oncogenes are the mutated form of proto-oncogenes which play an essential role during embryonic development and tissue growth.
Proto-oncogenes instruct (encode) proteins that stimulate growth and division of cells, inhibit differentiation (maturation of a cell with a specialized function) and stop cell death (apoptosis).
Proto-oncogene activity is normally turned off once the development process is complete. Mutations in proto-oncogenes turn them into oncogenes which continue to remain active and cause unrestrained cell growth leading to cancer.
What is oncogenic addiction in cancer cells?
Usually there are several overlapping reasons for cancer. Continued division of defective cells leads to multiple genetic mutations, and all of them further contribute to cancer cell growth and proliferation.
Research indicates that cancer cells may rely more heavily on oncogenic mutations that originally gave rise to the particular cancer, rather than other reasons for their growth. Such cancers are termed to have an oncogenic addiction to the particular oncogene, because they mainly depend on that oncogene’s continued activity for survival.
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What is targeted therapy for oncogenic addiction in cancer?
Targeted therapy for oncogenic addiction involves identification of the oncogene specific to a cancer and inhibiting the activity of the proteins it encodes. Most of the targeted therapies for oncogenic addiction are small-molecule inhibitors, which bind to cell proteins and block their activity.
Targeted therapy may be administered as a monotherapy or in combination with chemotherapy.
Following are some of the oncogenic addictions found in cancers and therapies that target them:
BCR-ABL is an oncogene resulting from the fusion of two genes (BCR and ABL), because of a switch in their positions in the chromosomes. The chromosome with BCR-ABL oncogene is called the Philadelphia chromosome.
The BCR-ABL mutation leads to unregulated activity of a protein known as tyrosine kinase. Tyrone kinase activates uncontrolled growth and division of cells with this mutation. There are several mutant forms of BCR-ABL. BCR-ABL oncogene causes:
Following are some of the small molecule inhibitors that target BCR-ABL oncogenic addiction:
Many BCR-ABL mutations develop resistance to drugs. Novel formulations to combat these resistant mutations are in clinical development.
Mutations in the proto-oncogene c-KIT, and a growth factor known as ‘platelet-derived growth factor receptor’ (PDGFR) lead to several types of malignancies including:
- Gastrointestinal stromal tumor
- Hypereosinophilic syndrome
- Systemic mastocytosis
- Dermatofibrosarcoma protuberance
- Chronic myelomonocytic leukemia (CMML)
Targeted therapies for c-KIT/PDGFR driven cancers are:
- Imatinib mesylate
- Sunitinib malate.
HER family of genes
HER (human epidermal growth factor receptor) family with four types of proto-oncogenes (HER1 to HER4) were the first to be selected for targeted therapy. HER family of genes encode HER proteins which activate cell-signaling pathways inside the cell enabling cell growth and division.
HER1 and HER2 growth factors switch on an important protein known as RAS in the cell membrane which activates a cascade of downstream cell-signaling pathways which stimulate cell growth, division and differentiation. HER growth factors also activate other cell-signaling pathways that assist in cell growth.
Mutations and amplification of the HER2 gene can lead to excessive presence (overexpression) of HER2 proteins on the cell surface, a major cause for breast cancer. Cancers caused by HER oncogenes include:
- HER2 positive breast cancer
- Non-small-cell lung carcinoma
- Glioblastoma multiforme
- Head and neck cancers
- Prostate cancer
- Metastatic stomach cancer
- Colon cancer
- Pancreatic cancer
- Ovarian cancer
Non-HER2 breast cancers cannot be treated with targeted therapy.
Following are the FDA-approved monoclonal antibodies for HER oncogenic addiction:
- Trastuzumab (Herceptin) for HER2 positive breast cancer
- Trastuzumab-dkst (Ogivri) for HER2 positive metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma)
- Trastuzumab-pkrb (Herzuma) for HER2 overexpressing breast cancer
- Pertuzumab for HER3 overexpressing tumors of ovary, prostate, breast, colon and lung
- Cetuximab for HER1 mutation cancers of colon, head and neck
- Panitumumab for HER1 specific cancers of colon, head and neck
- The FDA-approved small molecule drugs include the following:
- Erlotinib (Tarceva) for HER1 specific non-small-cell lung carcinoma and metastatic pancreatic cancer
- Gefitinib (Iressa) for HER1 specific non-small-cell lung carcinoma
- Lapatinib ditosylate (Tykerb) for HER1/HER2 breast cancer resistant to trastuzumab
More HER-targeted therapies are under clinical trials.
MET is the gene that encodes a protein, c-MET, which activates many signaling pathways enabling new blood vessel formation (angiogenesis), cell mobility, migration and invasion. A mutation in the MET gene can help the tumor build up its own blood supply and enables cells to break off from the tumor, migrate, invade and metastasize.
Researchers have observed MET oncogene’s involvement in lab studies of many cancers including:
Therapies to target c-MET are in the clinical trial stage.
PI3K/AKT are a family of enzymes encoded by PIK3CA gene. PI3K/AKT enzymes play an important role in cell-signaling for cell division, differentiation and migration. Mutations in PIK3CA gene help tumor growth by promoting these activities in the tumor cells.
Many therapies targeting PI3K/AKT signaling pathways are in various stages of development.
The RET proto-oncogene is involved in cellular mechanisms that include cell proliferation, nerve cell navigation to their appropriate position in the nerves, cell migration and cell differentiation.
Mutations in RET proto-oncogene cause hereditary and sporadic (other than hereditary factors) medullary thyroid carcinoma (MTC). Beside familial medullary thyroid carcinoma, RET mutations also cause other tumors and disorders such as:
Several targeted therapies directed at c-RET are in clinical trials. Some of the c-RET targeted therapies have also shown effect against other proteins involved in cell proliferation and angiogenesis in tumors.
B-RAF is a protein kinase found inside the cell and plays a key role in cell proliferation and transformation (that is, the cell’s transition from healthy to cancerous). B-RAF is encoded by BRAF proto-oncogene. BRAF mutations have been found in cancers such as:
- Papillary thyroid carcinoma
- Colorectal cancer
- Non-small-cell lung carcinoma
- Renal cell cancer
- Hepatocellular cancer
BRAF mutations are found to frequently occur in many cancers, and many kinase inhibitors are in clinical trials specifically targeting B-RAF kinase. Currently there is only one FDA-approved small molecule drug which targets many other oncogenes besides BRAF:
- Sorafenib, approved for renal cell and hepatocellular cancers
Anaplastic lymphoma kinase (ALK) encoded by ALK gene is a receptor tyrosine kinase protein which plays a role in nerve cell differentiation and regeneration, formation of synapses (micro spaces linking nerve cells to one another) and muscle cell migration.
Translocation of ALK gene in the chromosome causes fusion with other genes, giving rise to an ALK fusion gene. Different mutations of ALK fusion oncogene have been found to cause cancers that include:
- Anaplastic large cell lymphoma
- Inflammatory myofibroblastic tumor
- Non-small-cell lung cancer
Therapies targeting ALK protein are in the early phase of clinical trials as of 2020.
Tropomyosin receptor kinase (TRK) proteins include TRKA, TRKB and TRKC encoded by neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2 and NTRK3, respectively. TRP proteins are involved in cell survival and proliferation.
Mutations due to chromosomal fusion in the NTRK genes have been identified in many solid tumors. FDA has approved one targeted therapy for TRK-fusion-positive solid tumors in adults and children:
Targeted therapy for cancers with oncogenic addiction aims to stop the mutated "oncogene" that fuels the tumor. Research indicates that cancer cells may rely more heavily on oncogenic mutations that originally gave rise to the particular cancer, rather than other reasons for their growth. Such cancers have an oncogenic addiction because they mainly depend on that oncogene’s continued activity for survival.
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Related Disease Conditions
Second Source article from Government
Second Source article from Government
Breast cancer is an invasive tumor that develops in the mammary gland. Breast cancer is detected via mammograms, breast self-examination (BSE), biopsy, and specialized testing on breast cancer tissue. Treatment of breast cancer may involve surgery, radiation, hormone therapy, chemotherapy, and targeted therapy. Breast cancer risk may be lowered by managing controllable risk factors.
Cancer Risk Factors
Though it's difficult to say why some people develop cancer while others don't, research shows that certain risk factors increase a person's odds of developing cancer. These risk factors include growing older, family history of cancer, diet, alcohol and tobacco use, and exposure to sunlight, ionizing radiation, certain chemicals, and some viruses and bacteria.
Cancer is a disease caused by an abnormal growth of cells, also called malignancy. It is a group of 100 different diseases, and is not contagious. Cancer can be treated through chemotherapy, a treatment of drugs that destroy cancer cells.
Certain behavioral, lifestyle, and environmental factors contribute to cancer. Cancer prevention involves modifying these factors to decrease cancer risk. Tobacco use, alcohol consumption, physical inactivity, inadequate fruit and vegetable intake, and obesity increase the risk of certain cancers. Vaccines, genetic testing, and cancer screening also play a role in cancer prevention.
Cancer pain results from the tumor pressing on nerves or invading bones or organs. Cancer treatments like chemotherapy, radiation, or surgery can also cause pain. Over-the-counter pain relievers, prescription medications, radiation, biofeedback, and relaxation techniques are just some treatments for cancer pain.
Cancer fatigue is a lack of energy that is caused by cancer or cancer treatment, including chemotherapy, radiation, biological therapy, or bone marrow transplantation. Strategies to combat cancer fatigue include scheduling rest, pacing oneself, planning ahead and prioritizing work and activities, eating the right foods, exercising, and practicing proper body mechanics.
What Is the BRCA Gene?
BRCA genes (BRCA 1 and 2, when normal, repair damaged DNA) are among the genetic mutations linked to breast cancer, ovarian cancer, and other cancers when mutated. Every woman with a BRCA mutation is at high risk for breast cancer, irrespective of whether she has a family history of breast cancer or not. By age 80, a woman with a BRCA mutation has about an 80% chance of developing breast cancer. BRCA1 and BRCA2 gene mutations also increase the risk of ovarian cancer, by 54% and 23%, respectively.
What Is Usually the First Sign of Breast Cancer?
A lump in the breast or in the armpits is often the first sign of breast cancer. This may be felt while in the shower. There may or may not be changes in the structure of the breast. Other early signs include changes in breast skin, breast pain and others.
Which Is the Deadliest Cancer?
Lung cancer is considered to be the most deadly cancer. More people die from lung cancer each year than from breast, colorectal and prostate cancer combined.
What Are the Top Ten Cancers?
Lung cancer is the number one killer cancer in the world. It is the most common cause of cancer-related deaths in both men and women.
At What Stage of Cancer is Chemotherapy Used?
The decision to use chemotherapy may vary depending on the aggressiveness, stage and type of cancer. Usually, chemotherapy may be used for all stages in most cancer types. Chemotherapy is a type of medicine or combination of medications that is used to treat or kill cancer cells.
What Type of Cancer Makes You Very Tired?
Extreme and recurrent tiredness is one of the common symptoms of most types of cancers. Tiredness is usually considered a warning sign of cancer progressing. Tiredness related to cancers usually does not get better with adequate rest or sleep.
What Foods Increase the Risk of Cancer?
Cancer is one of the leading causes of death globally. Certain foods are deemed co-carcinogenic or have the potential to cause cancer. There is strong evidence linking diet with an increased incidence of specific cancers.
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Medications & Supplements
- gefitinib - oral, Iressa
- trastuzumab - injection, Herceptin
- Herceptin (trastuzumab)
- gefitinib (Iressa discontinued in the US)
- erlotinib (Tarceva)
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