Gene Therapy: Targeting the C... Health Article

The American Cancer Society estimates that about 160,00 people die of lung cancer  each year. This is more than the deaths caused by the next three leading cancers—colon, breast, and prostate—combined. The current treatment of lung cancer often includes combinations of chemotherapy drugs. While chemotherapy often helps people live longer, with better quality-of-life, and may even cure lung cancer in a few patients, the outlook for someone with advanced lung cancer is generally not good. In most patients with advanced lung cancer, the tumor comes back or becomes resistant to chemotherapy. As a result, scientists are searching for new types of treatment that will more accurately target lung cancer cells with the goal of reducing the damage to normal cells. Gene therapy is one example of these targeted therapies. It’s being studied in the lab and in a few clinical trials.

How Gene Therapy Works

Scientists have been studying the cellular defects linked to the growth of lung cancer. Some changes in the DNA of lung cells cause mutated cells that become cancerous. These are called genetic mutations. These abnormal cells reproduce rapidly and fail to die. Over time, the cells grow into a cancerous tumor. Gene therapy is designed to kill cancer cells by targeting the very genes that cause the cancer in the first place.

Scientists know that two major types of genes are involved in the growth of lung cancer. They are oncogenes and tumor suppressor genes.

Understanding oncogenes. Normal variants of oncogenes, called proto-oncogenes, exist in cells. Proto-oncogenes play a role in normal cell growth, reproduction, and death. These are “good guys” that can go down the wrong path, become confused, and turn into dangerous oncogenes that facilitate cancer development. A mutated proto-oncogene may become an oncogene. And oncogenes cause abnormally rapid cell growth and the reproduction of cancer cells.

One approach to gene therapy is to block, or turn off, oncogenes in cancer cells. This stops the growth of cancer cells, allowing them to die naturally. Researchers have been able to block oncogenes by inserting a special DNA fragment into the cancer cell. The DNA fragment binds to and blocks the oncogene. Once blocked, the oncogene can no longer contribute to the cancer process.

Joan H. Schiller, MD, a professor at the University of Wisconsin Medical School, believes that an oncogene known as K-ras is a promising target for this type of gene therapy in lung cancer. K-ras is involved in the reproduction and spread of lung cancer cells.

Understanding tumor suppressor genes. Normally, these genes kill cancer cells or keep them from growing. If these genes become mutated, cancer may occur. In a cancer cell, the tumor suppressor gene is mutated and no longer able to kill the cancer cell or prevent its continued growth.

One approach to gene therapy is to replace mutated tumor suppressor genes in cancer cells with normal tumor suppressor genes. When the new, functional gene is incorporated into the cancer cell, the gene becomes activated and the cancer cell dies. In lung cancer, mutations in a tumor suppressor gene called p53 play a role in the growth of cancer cells. “Replacement of the mutated p53 gene with a normal p53 gene is a promising technique,” says Schiller, who is involved in a p53 gene therapy study.

Other Ways of Using Gene Therapy

Scientists are also searching for other ways of using gene therapy to treat lung cancer.

• Drug-sensitizing proteins. Scientists are looking at how to insert a gene for a drug-sensitizing protein into cancer cells. When a relatively nontoxic drug is given to the patient, the sensitized cancer cells are killed. Here’s how it works: Once the drug is inside a cancer cell, it binds to the sensitizing protein. The drug-protein combination is toxic to the cancer cell. Normal cells don’t have the sensitizing protein that binds to the drug, so the drug has little effect in normal cells.

• Genetic modification. In this type of gene therapy, researchers modify the genes of cancer cells in the lab. The modified genes are injected back into the patient. In recent years, scientists have added the gene for interleukin-2 (IL-2) to lung cancer cells. IL-2 is a natural protein that stimulates an immune response. When IL-2-modified cells are injected into a tumor, they produce and secrete IL-2. The IL-2 stimulates the immune system to destroy cancer cells. This approach has seen limited success against lung cancer cells in the lab, but more studies are needed to see if it will work in people with cancer. Similar approaches have also inserted the gene for another immune stimulant known as GM-CSF into cancer cells.

The Limitations of Gene Therapy for Lung Cancer

Scientists must conquer major challenges before gene therapy becomes a useful treatment. According to David P. Carbone, MD, PhD, the director of experimental therapeutics at Vanderbilt-Ingram Cancer Center, the two biggest challenges are “finding the right genes to use and inserting them into cancer cells.” Carbone says that many options need to be sorted out, and none are “clear winners” as of yet.

Finding the right genes to use in gene therapy can be tricky. The gene that causes lung cancer in one patient (p53 or K-ras for example) may not be the cause of lung cancer in another patient. Gene therapy that targets the wrong cancer-causing gene will have little effect. Plus, cancer cells undergo many genetic mutations as the tumor grows. Some of the cells in a tumor may contain one set of mutations, while other cells in the tumor will contain different mutations. This means that any single gene therapy will only affect some of the cancer cells. As a result, finding the right gene or combination of genes that will benefit any particular patient is a daunting challenge.

Once scientists do find promising genes to use, they still have to insert them into cancer cells. One current technique uses weakened viruses, such as those used in vaccinations. Scientists splice the therapeutic gene, such as normal p53, into the genetic code of the weakened virus. The virus is then injected directly into the tumor. Inside the tumor, the virus infects cancer cells and inserts the therapeutic gene into the cell’s genetic code. The therapeutic gene then becomes activated, or turned on, and destroys the cancer cells.

“Getting the gene into the tumor is a challenge,” says Schiller. “Currently, the viral vectors must be injected directly into tumors, which is a problem if the tumor is inaccessible. Researchers are studying the use of new viruses that may target cancer cells better than the current viruses.” The use of more specific viruses may allow gene therapy to be injected intravenously. The genes would then circulate in the blood to wherever cancer cells are located in the body.

It’s important to understand that gene therapy is experimental and not yet ready for use in most lung cancer patients. “There are a lot of unfounded expectations that gene therapy has failed to live up to,” says Carbone. “Patients should view gene therapy as one experimental treatment among a lot of other promising therapies.”

Gene Therapy in Clinical Trials

Patients who meet specific criteria may be able to receive gene therapy by enrolling in a clinical trial. Gene therapy trials generally enroll patients with advanced cancers.

As a first step in learning more about gene therapy or enrolling in a clinical trial, patients should speak with their doctor. Carbone cautions that patients should only consider enrolling in a trial sponsored by the National Cancer Institute (NCI) or a major cancer center. This ensures that the trial is well designed and conducted in a controlled manner to further the understanding about the effectiveness of gene therapy. Much recent media attention has brought concern to the field of gene therapy from deaths associated with clinical trials aimed at trying to fix noncancerous conditions. In advanced cancer, it’s generally thought that the potential risks of well-designed gene therapy investigations may be worth the opportunity to learn more about this interesting new strategy to control and fight cancers that might otherwise be uncontrollable.