Targeted Cancer Therapy - An Evolving Approach for Cancer Treatment
- What is targeted cancer therapy?
- How does targeted cancer therapy work?
- Where do the molecular targets come from?
- Types of targeted cancer therapies
- Research on targeted cancer therapy won 2018 Nobel prize in Medicine
- Who will be a suitable candidate for targeted cancer therapy?
- Examples of targeted cancer therapies
- Differences between chemotherapy and targeted cancer therapy:
- Advantages and limitations of targeted cancer therapies
- Future directions
What is targeted cancer therapy?
Targeted cancer therapy finds its foundations in precision medicine. It is a type of cancer treatment that targets the genetic changes in cancer cells that help them grow, divide, and spread. Each drug acts on a specific molecular target within or on the surface of cancer cells (for example, a gene or protein). Blocking them can slow cancer cell growth or kill cancer cells, while minimizing damage to healthy cells which lack the specific mutation. This novel therapeutic approach fights cancer cells with more precision and fewer side effects that the current conventional treatments.
Targeted therapy drugs circulate throughout the body, therefore can act on the primary tumor as well as its distant metastasis. Targeted drugs can be used as the main treatment for some cancers, but in most cases, they’re used alongside other treatments such as chemotherapy, surgery, and/or radiation therapy .
How does targeted cancer therapy work?
Cancer cells have changes in certain critical genes that make them different from normal cells. These phenotypic changes confer the cancer cell with a selective advantage over the surrounding cells; they may grow faster than normal cells or acquire the ability to spread and survive at distant sites (metastases). Targeted cancer drugs work by ‘targeting’ those differences that a cancer cell has. By targeting these molecules, the drugs block their signals and stop the growth of cancer cells while harming normal cells as little as possible. There are many different targets on cancer cells, leading to development of different drugs that target them.
Targeted drugs might :
- stop cancer cells from dividing and growing
- selectively seek out cancer cells and kill them
- stop cancers from growing blood vessels
- encourage the immune system to attack cancer cells
- help carry other treatments such as chemotherapy, directly to the cancer cells
The Food and Drug Administration (FDA) of the United States and many other countries have approved multiple targeted drugs, and many more are being studied in clinical trials either alone or in combination with other treatments .
Where do the molecular targets come from?
One approach to identifying potential targets is to compare the amounts of individual proteins in cancer cells with those in normal cells. Certain proteins are more abundant in cancer cells and are therefore potential targets, especially if they are known to be involved in cell growth or survival. An example of such a differentially expressed target is the human epidermal growth factor receptor 2 protein (HER-2). HER-2 is a receptor that is expressed at abnormally high levels on the surface of some cancer cells. Her2 is over-expressed in 25-30% of human breast cancers and is associated with a poorer prognosis. Several targeted therapies are directed against HER-2, including trastuzumab (Herceptin®) , a humanized monoclonal antibody which is approved to treat certain breast cancer and gastric cancer that overexpress HER-2.
Another approach to identify potential targets is to determine whether cancer cells produce mutant (altered) proteins that drive cancer progression. For example, the cell growth signaling protein BRAF is present in an altered form (known as BRAF V600E) in many melanomas . Vemurafenib is an anti-cancer drug targeting this mutant form of the BRAF protein and has been used to treat patients with inoperable melanoma that contains this altered BRAF protein.
Many targeted therapies are examples of immunotherapy, i.e. using our immune system to fight cancer. It works by helping the immune system recognize and attack cancer cells.
Types of targeted cancer therapy
There are two main types of targeted therapy. The first type is small molecule drugs, which are small enough to enter cells. They attach to proteins that are inside cells and block their actions. Tyrosine kinase inhibitors and proteasome inhibitors are examples of small-molecule drugs. Small-molecule drugs are given as pills or capsules that can be taken orally .
The second type is monoclonal antibodies, also known as therapeutic antibodies, which are too large to enter cells. Instead, monoclonal antibodies affect targets on the surface of cells or nearby . Some of these antibodies mark cancer cells so that they will be better recognised and destroyed by the immune system. Other monoclonal antibodies directly stop cancer cells from growing or cause them to self-destruct. Monoclonal antibodies are usually given intravenously, either alone or in combination with other classical anticancer agents.
Some monoclonal antibodies trigger the immune system to attack and kill cancer cells. So these monoclonal antibodies are also a type of immunotherapy.
Some targeted drugs stop cancers from growing blood vessels. A cancer needs a good blood supply to provide itself with nutrients and oxygen, and to remove waste products. The process of growing new blood vessels is called angiogenesis . Anti-angiogenic drugs can slow the growth of the cancer and sometimes shrink it.
Research on targeted cancer therapy won 2018 Nobel Prize in Medicine
Many targeted cancer therapies are examples of immunotherapy. Our immune system has the ability to find and destroy cancer cells. But cancer cells can sometimes hide from the immune system and avoid being destroyed, for example by upregulating the expression of certain inhibitory signals to immune cells. Immunotherapy can either boost or create immune responses to cancer that may be therapeutic; there is significant clinical evidence for the effectiveness of this approach.
Currently there is excitement surrounding ‘checkpoint inhibitors’, monoclonal antibodies that block signals that hold back cytotoxic T cells. For example, PD-1 is a checkpoint protein found on immune cells called T cells. It normally acts as a type of “off switch” that prevents the T cells from attacking normal body cells, therefore preventing an autoimmune response. It does this when it attaches to PD-L1 (sometimes known as CTLA4), a protein on some normal (and cancer) cells. When PD-1 binds to PD-L1, it provides an inhibitory signal to the T cell, to reduce its cytotoxic activity. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack by T cells. Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells.
Immunotherapy has shown a great deal of promise in treating certain cancers. Two cancer researchers, Dr James P Allison from USA and Dr Tasuku Honjo from Japan, have been awarded the 2018 Nobel Prize in Medicine for their fundamental work on immunotherapy . For example, drugs that target PD-1 or PD-L1 have been shown to be helpful in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma . They are also being studied for use against many other types of cancer.
Checkpoint inhibitors are exciting for many reasons; firstly, some patients, with advanced metastases, who have failed conventional therapy, show a dramatic regression of tumor and improvement in health. Secondly, some go on being healthy for at least many months. Indicating that drug resistance seems to develop more slowly than with conventional chemotherapy.
Who will be a suitable candidate for targeted cancer therapy?
Different people with the same cancer type may receive different treatments based on their test results. Targeted therapy only works if a cancer cell has the gene or protein target that the drug is trying to block, so it isn’t suitable for everyone. According to the National Cancer Institute, a patient is a candidate for a targeted therapy only if he or she meets specific criteria . These criteria are set by the FDA of the United States when it approves a specific targeted therapy.
People who are given targeted therapy first need to have specialised tests to look for these targets. To test your cancer cells, your doctor needs a sample of either blood or tumor tissue. They might be able to use some tissue from a biopsy or operation that the patient had undergone previously.
Through the precision medicine approach, the treatment of each patient can be focused on drugs most likely to benefit him or her, sparing the patient the cost and potential harmful side effects from drugs that are unlikely to be beneficial. For instance, people with breast, lung, colon, and rectal cancers as well as skin melanoma usually have their cancers tested for certain genetic changes when they are diagnosed. For example, drugs targeted to the HER-2 protein are offered only to a subset of breast cancer patients who have disease that tests positive for high levels of HER-2.
Examples of targeted cancer therapies
Targeted therapy drugs have been approved for use in many countries for bowel, breast, cervical, kidney, lung, ovarian, stomach and thyroid cancers, as well as melanoma and some forms of leukemia, lymphoma and myeloma. Below are a few examples of targeted cancer therapies.
- Breast cancer. 25-30% of breast cancers express a high level of HER-2 protein in their cancer cells. HER-2 is a receptor whose ligand is epidermal growth factor (EGF), which promotes growth and proliferation of cells. If the cancer is HER-2 positive, several drugs, such as trastuzumab (Herceptin®), can be used in targeted treatment .
- Colorectal cancer. Colorectal cancers often make too much of a protein called epidermal growth factor receptor (EGFR). Drugs that block EGFR may help stop or slow cancer growth. Another option is a drug that blocks vascular endothelial growth factor (VEGF), a vital protein required in angiogenesis.
- Lung cancer. Drugs that block the protein called EGFR may stop or slow lung cancer growth. This may be more likely if the EGFR has certain mutations . Drugs are also available for lung cancer with mutations in the ALK and ROS genes. Doctors can also use angiogenesis inhibitors for certain lung cancers.
- Melanoma. About half of melanomas have a mutation in the BRAF gene. Researchers know specific BRAF mutations make good drug targets . So the FDA has approved several BRAF inhibitors. Vemurafenib is a targeted therapy that may be used to treat patients with these melanomas.
Differences between chemotherapy and targeted cancer therapy
Both chemotherapy and targeted cancer therapy are two effective methods for cancer treatment. But these drugs work in different ways. Chemotherapy drugs also circulate throughout the body, but they particularly affect any cells that divide rapidly. They kill cancer cells but can also damage other rapidly dividing non-cancerous cells, such as the healthy cells in a person’s mouth, stomach, skin, hair and bone marrow. This can lead to side effects associated with the destruction of cells, including mouth sore, diarrhea, poor appetite, anemia, weigh and hair loss, etc.
Unlike traditional chemotherapy, targeted therapy directs drugs to specific genetic features on cancer cells. Because targeted therapy specifically seeks out only cancer cells, it is designed to reduce the harm to healthy cells, which may lead to fewer side effects. To help identify an appropriate targeted therapy for the cancer, doctors may order a series of laboratory tests, including advanced genomic profiling, to learn more about the genetic disposition, protein composition and other traits the tumor possesses.
Advantages and limitations of targeted cancer therapies
Targeted cancer therapies such as targeted molecular therapy give medical oncologists a better way to customize cancer treatment. Advantages of molecularly targeted therapy include:
- Less harm to normal cells
- Fewer side effects
- Improved effectiveness
- Improved quality of life
There are some limitations to targeted therapies and their role in cancer treatment. For example, cancer cells can develop resistance to the therapy. This can occur by a change in the genetic makeup of the target so that the target is no longer present, or by the tumor developing a new method to grow without dependency on the target of the therapy. To minimize the effect of this limitation, it is usually recommended to use targeted therapies in combination with other targeted therapies or with traditional cancer treatments, such as chemotherapy and radiotherapy.
As with any other medication that has an effect on the body, targeted therapies may also cause undesirable side effects, such as alterations to the skin and the blood or hypertension.
Drugs for targeted cancer therapy are hard to develop, and as these drugs are monoclonal antibodies, many of the anti-cancer drugs are expensive.
The development of targeted therapy drugs has led to improved survival rates for several types of cancer and some people have had very encouraging outcomes. These drugs are becoming an increasingly important part of cancer treatment.
As our medical knowledge advance, targeted cancer therapies will play a central role in precision medicine, which is a form of medicine that utilizes specific characteristics of a patient’s proteins and genetic makeup to treat disease.
The hope of targeted cancer therapies is that treatments will one day be tailored to the genetic changes in each person’s cancer. Scientists see a future when genetic tests will help decide which treatments a patient's tumor is most likely to respond to, sparing the patient from receiving treatments that are not likely to help. As our ability to analyze and integrate patient characteristics increases, we can expect faster and broader implementation of precision medicine across the spectrum of cancer care, from cancer prevention and early detection to treatment of late-stage disease.
- American Cancer Society: What Is Targeted Cancer Therapy? https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/targeted-therapy/what-is.html. Retrieved 17 August 2019.
- National Cancer Institute: Targeted Cancer Therapies. https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet. Retrieved 17 August 2019.
- Breastcancer.org: How Herceptin works. https://www.breastcancer.org/treatment/targeted_therapies/herceptin#how. Retrieved 17 August 2019.
- Flaherty KT, Infante JR, Daud A, et al: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. New England Journal of Medicine 2012; 367(18):1694-1703. [PubMed Abstract]
- NobelPrize.org: The Nobel Prize in Physiology or Medicine 2018. Retrieved 17 August 2019.
- American Cancer Society: Immune checkpoint inhibitors to treat cancer. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html. Retrieved 17 August 2019.
- Michels S, Wolf J: Targeted therapy of lung cancer. Oncology Research and Treatment 2016;39:760-766. DOI: 10.1159/000453406. [PubMed Abstract]
© 2019 Kai Chang