Tumor-Based p53 Therapy

Gene Therapy

While treatment options like surgery, chemotherapy and radiation therapy are the current standards for lung cancer treatment, medical researchers constantly strive to develop new approaches that offer improved responses and fewer unwanted side effects.

Recent advances in our understanding of the relationship between cancer and human genetics have uncovered some promising implications; the science of genetic manipulation has opened the possibility for doctors to treat and prevent cancer by altering a patient’s genes. This experimental treatment is known as gene therapy, and researchers have already tested a variety of different techniques in clinical trials.

One notable example of gene therapy is tumor-based p53 therapy, an approach that is showing great potential for the management of lung cancer. Approved for widespread use in China after five years of clinical trials, p53 therapies are currently being evaluated in a number of U.S. studies. If approved by the U.S. Food and Drug Administration (FDA), lung cancer doctors could one day add this innovative treatment option to their repertoire.

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p53: Guardian of the Genome

Gene Therapy

At the heart of tumor-based p53 therapy is the p53 gene. Often described as “the guardian of the genome,” p53 plays a central role in blocking the formation of tumors. Carcinogens like asbestos and tobacco smoke often damage cell DNA, and these genetic changes can trigger the development of lung cancer. Improperly functioning p53 genes are known to affect aspects of cancer like aggressiveness, response to treatment and ability to spread to distant sites.

To prevent cancerous cells from dividing uncontrollably, the p53 gene activates proteins that arrest cell division and repair corrupted DNA. In cases where the damage done is irreparable, p53 initiates a process called apoptosis that destroys the tainted cells. The p53 gene can also limit blood flow to tumors which prevents growth and alerts nearby immune cells to attack cancerous cells.

A mutation of the p53 gene is the most common abnormality observed in tumors. And that's not just for cancers of the lung, but all human cancers. After extensive study, researchers determined that the p53 gene is mutated in 50 percent of all cancers and 45 percent of non-small cell lung cancers. Researchers also believe that an abnormal p53 gene may be associated with lung cancer susceptibility, though this hypothesis is controversial and still under investigation.

How does p53 Therapy Work?

Preclinical Studies

The results of preclinical studies show that restoration of  p53 gene function can activate apoptosis, thus destroying cancerous cells. But  replacing cancerous genes with healthy p53 genes is no simple task. To achieve  this, doctors have used genetically engineered viruses known as viral vectors.  Vehicles for DNA transport are typically infectious, doctors  have prevented the viruses from replicating by modifying their genetic code.

Stopping Tumor Growth

Filled with high concentrations of p53, viral vectors are injected directly into malignant tumors. As the virus releases the contained genetic material, the effects of the cancerous genes are reversed. Damaged cells are either destroyed or replaced with p53, which stops the tumor from growing or spreading. To improve treatment effectiveness doctors will sometimes follow up with radiation therapy or a chemotherapy drug such as Cisplatin.

Clinical Trial Results

Chemotherapy

While the FDA has yet to approve gene therapy for widespread use in the United States, lung cancer clinical trials on p53 therapies have demonstrated notable success. Phase I and II studies proved that this treatment is not only safe, but also far less harmful to healthy cells than chemotherapy.

In one phase II clinical trial conducted on 19 non-small cell lung cancer patients, a p53 therapy called Advexin was given in combination with radiation therapy. After three months, 63 percent of patients had no detectable signs of cancer. This is four times the response expected from radiation treatment alone.

Another phase II trial evaluated INGN-225, a cancer vaccine treated with Advexin immune cells. Among small cell lung cancer patients who were previously given chemotherapy, 66.7 percent treated with INGN-225 experienced a reduction in tumor size greater than 50 percent. Some of these patients were cured of all visible signs of cancer.

Researchers continue to recruit lung cancer patients for tumor-based p53 therapy clinical trials, and a diagnostic test was  developed to detect specific changes to the p53 gene. By determining exactly  how the p53 gene is expressed in an individual, doctors may soon be able to  identify patients that will respond best to gene therapy. Only through ongoing  trials will researchers be able to unlock the true potential of tumor-based p53  gene therapies.

Additional Resources

  1. Roth, J., Swisher, S., & Meyn, R. p53 Tumor Suppressor Gene Therapy for cancer. (1999). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10550840
  2. Gene Therapy (Gendicine). (2011). Retrieved from cancertherapychina.com/index.php?option=com_content&view=article&id=84&Itemid=23 http://cancertherapychina.com/index.php?option=com_content&view=article&id=84&Itemid=23
  3. Introgen’s Advexin(R) and INGN 225 Featured in Special Session at the American Society of Gene Therapy Annual Meeting. (2005). Retrieved from http://www.prnewswire.com/news-releases/introgens-advexinr-and-ingn-225-featured-in-special-session-at-the-american-society-of-gene-therapy-annual-meeting-54493967.html
  4. Takahashi, T., Suzuki, H., Hida, T., Sekido, Y., Ariyoshi, Y., & Ueda, R. The p53 Gene is Very Frequently Mutated in Small-Cell Lung Cancer with a Distinct Nucleotide Substitution Pattern. (1991). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/1656362

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