Targeted Therapy in Treatment of Cancer
Personalized treatment is expected to be the wave of the future in oncology, and one part of that trend is the development of targeted therapy drugs. This exciting area in cancer research involves finding drugs that interrupt the ability of the cancer to grow in the body – drugs that don’t simultaneously harming healthy tissue the way conventional chemotherapy agents can
Conventional chemotherapy drugs are “cytotoxic”. Cyto- means cell. These chemicals kill cells – both cancerous and healthy. They work by inhibiting cellular division. Because cancer cells tend to multiply faster than healthy cells, the chemotherapy agents kill malignant cells at a greater rate than they kill healthy cells. This differential in killing rates is what makes chemotherapy effective against cancer. However, there are major costs with this type of approach to attacking cancer. First, plenty of healthy cells are affected the killed. Tissues that have rapid cell division tend to do worst. This is why you see the side effects of chemotherapy showing up in areas of the body where rapid cell division happens. The insides of the digestive system are such as place – which is why chemotherapy patients often feel nauseous. The interior of the nasal passages and the follicles on the scalp are affected – which is why common side effects include loss of taste and going bald. And the cells in the bone marrow that make red blood cells are affected – which is why anemia is so common.
The side effects are not just discomforts for the patient. They present real challenges for doctors attempting to manage the cancer. The limiting dose – the highest amount of the chemotherapy drug that can be administered – is often set by the toxicity of the drug to the body. Indeed, when designing combination regimens of more than one chemotherapy drug, a major factor in the choice is to pick drugs with different organ-limiting toxicities.
Further, cytotoxic drugs are a blunt tool for attacking cancer. They go after all cells, not just the malignant ones.
Scientists long dreamed of a “magic bullet” that would attack cancer and leave the rest of the body unscathed. In the 1990s the research community got excited by research into angiogenesis inhibitors. These chemicals – some of which occurred naturally in tbe body and some of which were new synthetic compounds – slowed the growth of blood vessels. The idea was that by stopping the growth of capillaries (small blood vessels), these new drugs would stop the growth of tumors. Without a supply of blood, the tumor could not grow to be big enough to cause problems.
While the initial excitement around angiogenesis inhibitors faded to some extent, there are some drugs in this category on the market, and others in development. Indeed, Avastin (generic name bevacizumab) is the biggest selling (total revenue) cancer drug in the country. This is partly because of its high cost. Avastin is FDA-approved for several types of cancer, including lung cancer when used in combination with in combination with carboplatin and paclitaxel. Other drugs on the market include Erbitux (cetuximab) and Sutent (sunitinib). Recent developments in genetic sequencing have led to new treatments for melanoma, the deadliest form of skin cancer. A new drug (vemurafenib) targets the gene that signals the growth of new blood cells in melanoma tumors; choking off the blood supply they need to grow.
Another major area of investigation is the class of drugs called tyrosine kinase inhibitors or just kinase inhibitors. These interrupt the ability of the tumors to stay together. The malignant cells cannot clump together as a tumor, and the ability of the cancer to harm the body declines. Gefitinib and erlotinib are among the kinase inhibitors on the market used for treatment of lung cancer, and others are in development.
The oncogene in most cases of chronic myelogeneous leukemia is BRD-AML. Imitatinib blocks the BRD-AML and blocks the signals for cell proliferation, controlling tumor growth. Imitinib could be used in other cancers with BRD-AML oncogenes.
Drugs that induce apoptosis (cause the cells to kill themselves) are also being developed as a form of targeted therapy, and some researchers are looking for ways to use monoclonal antibodies as delivery mechanisms for toxic payloads. The specitivity of the antibody allows the toxin to be placed exactly where it should be to kill the malignant cells, without harming healthy cells.
Targeted therapy drugs have the downside that the body frequently develops resistance. The mutation may develop a second mutatation that somehow bypasses the target protein. A mutation in a downstream protein may be the culprit, too. Oncologists often combine targeted therapies with conventional chemotherapy drugs for this reason.
Challenges to developing new targeted therapies include identification of targets, and indeed the right targets. Sometimes drugs are found effective against targets in laboratory glassware. When the drugs are tried in animals or humans, it turns out the target turns out to be less important than originally thought. The underlying knowledge of biology of cancer promises to raise the success rate for new cancer drugs, but it is still likely that most drugs will wash out in clinical trials.