Tumor-based p53 therapies attempt to fix the mutated p53 gene and protein that causes cells to grow out of control, resulting in cancer in some people. Targeting p53 could be a successful treatment for mesothelioma or lung cancer. Research and clinical trials are ongoing.
About Gene Therapy
Targeting p53 is one focus of gene therapy research. Gene therapy is an emerging, ongoing area of study for treating mesothelioma and other types of cancer.
Gene therapy involves manipulating genes in the DNA of living cells to treat or cure disease.
Genes and their proteins are necessary for living cells and, therefore, all living organisms to grow, reproduce, and function. They can be faulty, though. A mutation or a change in genes can have disastrous consequences, including cancer.
Asbestos, for instance, may cause mesothelioma by altering the genes in a person’s cells, resulting in out-of-control spread and growth.
Gene therapy manipulates genes to change protein production and cell actions. In cancer treatment, this may involve inserting new genes.
New genes can be placed in immune cells to make them attack cancer cells or may be placed in cancer cells to cause them to self-destruct. The standard way to deliver new genes into healthy cells or cancer cells is with deactivated viruses.
What Is p53 in Cancer?
One of the most important strategies in gene therapy involves manipulating a gene called p53. This gene is also often referred to as the guardian of the genome. p53 is a tumor suppressor gene, which means that it codes for a protein that stops the formation of tumors and the growth of cancer cells.
How Does p53 Prevent Tumor Formation?
The protein created by the p53 gene works through several steps to prevent tumor formation:
- It attaches and binds to DNA at a specific location.
- This stimulates the production of a second protein called p21.
- This protein then interacts with a protein that is related to cell division. The interaction prevents a cell from dividing and growing. This is important in preventing the uncontrollable division and growth seen in cancer cells that lead to the development of tumors.
- When the p53 gene is missing or inactivated, the p21 protein never gets made, and cells don’t have their “stop sign.”
How Is p53 Activated in Cancer?
Researchers have found that some people are predisposed to cancer because they inherit just one working copy of this gene from their parents. This is referred to as a germline mutation. This is a rare condition called Li-Fraumeni syndrome.[1]
More commonly, genetic mutations arise from the cancerous tumor itself, called somatic mutations. A somatic p53 mutation is common in most cancers. Many mesothelioma patients have a mutation in p53 in their cancer cells.
A mutated copy of p53 can be activated by many different stressors. These include oxidative or environmental stress, DNA damage, nutrient starvation, and the expression of other specific genes.[2]
Do All Cancers Have a p53 Mutation?
A p53 mutation can arise in most types of cancer, but not all cancer patients have a p53 mutation. Some types of cancer are more likely to have it, while it is rare in others. Studies show that approximately half of all cases of cancer involve mutations in p53.[3]
Does p53 Cause Metastasis?
Metastasis is the spread of cancer from the original tumor to more distant parts of the body. Metastatic, or stage 4, cancer is generally terminal and difficult to treat.
Metastasis is particularly important in mesothelioma. Because mesothelioma is aggressive and spreads rapidly, researchers need to understand how metastasis works to slow its progression.
The role of p53 in metastasis is not fully understood, but it does seem to play a role. Knowing how this works will add to the effectiveness of p53 gene therapies for mesothelioma and other patients.[4]
Can p53 Mutation Be Reversed to Treat Cancer?
Researchers have long targeted the p53 gene because it is so often involved in cancer. The basic idea is to restore the gene’s function after something has gone wrong with it, causing cancer to develop.
First, the mutated gene must be identified in the cancer cells, as not all cancers result from this p53 mutation. Ideally, the treatment restores the gene and allows it to return to its primary function: to stop cancer cells from dividing.
The strategy for delivering a working copy of the gene is similar to that used for other gene therapies, including suicide gene therapy:[5]
- A vector, or a carrier, delivers a gene.
- The virus is first inactivated so that it will not make a patient sick.
- The desired gene, in this case, p53, is then inserted into the virus’s DNA.
- The virus is injected into the patient’s cells, and it transfers the p53 gene to the cells’ DNA.
- Viruses work so well in this role because they are already programmed to insert and attack cell segments of DNA, usually to cause infection, but in this case, to help kill cancer cells.
The vector used in p53 treatment is often a virus that has been modified to safely deliver genetic material without infecting the patient. These are called non-replicating viruses because they do not invade cells to replicate and infect the body.
Other types of vectors include nanoparticles, non-viral particles that can carry genetic materials to cancer cells. Nanoparticles address one particular risk of viral vectors. Although the viruses do not infect healthy cells, they can trigger an immune response and symptoms.
Most recently, researchers have developed a dry gene powder as a non-viral delivery system. It is an inhalable powder that has already been tested in patients with mesothelioma. Researchers showed that it enhances the effects of chemotherapy.[6]
p53 Clinical Trials and Use Outside the U.S.
The U.S. Food and Drug Administration has not yet approved any p53 gene therapy to treat cancer. The therapy has been tested in clinical trials and has particularly shown great promise for treating lung cancer.[7]
Researchers continue to look at mutations found in several cancers to determine if there may be treatments that can be used on tumors with this mutation, regardless of where the cancer initially started.
Some clinical trials have used p53 gene therapy in combination with other types of treatment, including radiation. In one of these trials, gene therapy with radiation resulted in survival times four times longer than is normally achieved with just radiation therapy.
In another clinical trial, some patients with lung cancer were effectively cured when the gene therapy was combined with chemotherapy and immunotherapy.
China has advanced the use of p53 gene therapy further than the U.S. It has already been approved for widespread use in treating certain types of cancer. This approval dates back to 2004.
China was the first to approve gene therapy cancer treatments. Though much of the research into advancing p53 gene therapy occurs in China, American researchers and patients hope to benefit from it as well.
Can p53 Gene Therapy Treat Mesothelioma?
So far, not many researchers have focused on the use of p53 gene therapy for the treatment of mesothelioma. Still, asbestos lung cancer patients may soon benefit from it.
The limited research into altering p53 to treat mesothelioma does show promise.[8] The p53 pathway that leads to tumor growth is abnormal in most cases of mesothelioma. Also, the injection of viral vectors for gene therapy into the chest cavity has been shown to be relatively safe for patients. More research will hopefully find effective ways to target p53 to treat pleural mesothelioma.
The advances in gene therapy to treat all types of cancer are truly astounding. New techniques and strategies are constantly being developed because the technology that allows for manipulation is advancing at such a fast pace.
The targeting of p53 is expected to remain at the center of gene therapy because of the major role it plays in preventing, stopping, and, when mutated, spreading tumors throughout the body. Thanks to this research, patients with mesothelioma and their loved ones have hope for the future.
