A mutation in the p53 gene therapy, which maintains normal cellular function, can be found in many cases of cancer. Gene therapy restores p53 and prevents cancer growth.
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Main attractions
- The p53 gene therapy encodes a protein required for normal cell function.
- Many cancers, including mesothelioma, have mutations in the p53 gene.
- Gene therapy restores p53 to its normal function and helps stop cancer cell growth.
- Like other emerging treatments, p53 gene therapy is only available in clinical trials.
p53 Gene therapy is an experimental therapy currently being studied for the treatment of lung cancers including mesothelioma. The goal of this therapy is to improve effectiveness and reduce side effects compared with standard therapies such as surgery, radiation, and chemotherapy. This experimental therapy involves introducing normally functioning genes into tumor cells to fight cancer-causing mutations. To date, several clinical trials have shown success.
What Is P53 Gene Therapy?
One of the genes that researchers have focused on in the gene therapy of tumors is the p53 gene. The p53 gene encodes an important protein responsible for regulating normal cell function. It is often the “guardian of the genome” because of its important role in stopping tumor growth.
Almost every cancer has a mutation in the p53 gene. This genetic mutation occurs in 10% of hematopoietic malignancies (tumors affecting the blood, bone marrow, lymphatic system, and lymphatic system) and in 96% of high-grade ovarian cancers, with Its occurrence falls within this range in other cancers. Among human cancers, the p53 gene is the most commonly mutated tumor suppressor gene, which is known to be associated with poor prognosis in many cancers, making it a good therapeutic target.
The p53 protein also plays an important role in the cellular response to stress. In the presence of cellular stress, p53 activates cellular responses that initiate cell cycle arrest, growth arrest, or apoptosis (programmed cell death), all of which are important in the control of cell death. control tumor cell growth. It is also an important regulator in preventing tumor metastasis.
How Does P53 Gene Therapy Work?
Techniques have been developed in the field of biotechnology that scientists can use to restore the healthy, functioning p53 gene to cells with cancer mutations in the p53 gene. This complex task involves a viral vector used to transport the healthy p53 gene to cells. Through genetic engineering, scientists alter the DNA of the virus vector, regulating its natural infectious nature by preventing it from replicating.
This “safe version” of the virus is then used as a vehicle for transporting the p53 gene at high concentrations. The scientists injected these viral vectors directly into the tumor. If gene therapy is successful, the p53 gene will produce a functional p53 protein inside tumor cells, killing tumor cells or restoring normal p53 function to the cells, preventing the growth of tumor cell cancer.
p53 Gene Therapy For Mesothelioma
Preclinical studies have targeted a common genetic abnormality in mesothelioma that causes p53 pathways to be inactivated. Preclinical studies performed on mesothelioma cells using gene therapy with viral vectors have been successful in restoring p53 pathways against tumors.
In clinical studies, researchers have yet to achieve success in using gene therapy with the p53 gene to significantly reduce tumor size. Studies have been performed using a viral vector to deliver the p53 gene, in an attempt to achieve direct cytotoxic (toxic to living cells) effects on tumors, but regression of the tumor is very few. Instead, clinical studies have turned to “immune gene therapy,” which involves the introduction of immunostimulating agents into the pleural space to activate the body’s defense mechanisms.
The great success is due to the introduction of these immunostimulants through viral vectors. This process has produced positive clinical outcomes for mesothelioma patients, suggesting the feasibility of delivering viral vectors into the pleura. Specifically, a phase 1 clinical trial was conducted on mesothelioma patients in the first human trial using gene therapy to introduce the interferon gene, which reduces tumor volume and prolongs the duration of time. patient life.
What Are The Benefits Of P53 Therapy?
While the development of p53 therapy is still in its infancy, gene therapy with viral vectors may have benefits over conventional therapies such as radiation and chemotherapy, in that it does not suppress the immune response. Clinical studies have also shown that there are fewer toxic side effects associated with gene therapy.
Although gene therapy is currently an experimental approach for mesothelioma, the extensive research and clinical trials conducted to date may pave the way for future treatment, which Can be combined with other treatments. Biomarkers will need to be developed to determine clinical eligibility.
Vectors For The P53 Gene Therapy
The big challenge of gene therapy is finding a reliable way to deliver the tumor suppressor gene to the cells that need it. Researchers have tested a number of different DNA or vector delivery vehicles on several types of cancer, but to date, no FDA-approved gene therapy technique has been used to treat mesothelioma.
Nonreplicating Viruses
Many researchers have tried using genetically modified viruses to deliver the p53 gene to cancer cells. First, the researchers removed the dangerous viral DNA from the viruses to make sure they couldn’t infect patients. The researchers then injected the modified viruses directly into the tumors.
This method has been shown to be safe, with very mild side effects, but currently it is not effective in delivering genes to cancer cells. Harmless viruses may not reach all of the cancer cells in a tumor, or the body’s immune system may hunt them down before they can deliver the p53 genes.
In 2003, China’s State Food and Drug Administration approved a p53 gene therapy treatment for head and neck cancer called Medicine. The US version of the treatment, Advexin, was submitted to the FDA in 2008, but it was not approved.
Oncolytic Viruses
Some researchers are trying to combine gene therapy with virotherapy. Virotherapy involves modifying viruses to infect and destroy cancer cells while keeping healthy cells intact. Experts have had limited success using a modified form of the measles virus to target mesothelioma cells.
The researchers hope that adding the p53 gene to the cancer-causing virus will make the treatment more effective than gene therapy or virotherapy alone, but the technology still needs to be tested.
Nanoparticles
Instead of modifying viruses, another group of researchers is designing artificial vectors to deliver genes to cancer cells. Synthetic nanoparticles can carry tumor suppressor genes such as p53 or they can carry targeted chemotherapy drugs.
Like viruses, nanoparticles can be engineered to deliver their contents specifically to cancer cells, leaving healthy cells unaffected. However, in theory, the nanoparticles would also be safer than viruses, pose no risk of infection, and they could travel throughout the body without triggering a response from the immune system.
Reactivating p53 with Drugs
Another experimental cancer therapy under development involves “patching” mutated p53 genes in cells so they can function normally again. Doctors can use this drug to treat and prevent cancer by repairing faulty p53 genes before cells have a chance to become cancerous.
Clinical Trials for p53 Gene Therapy
China is going the furthest in clinical trials and approval of p53 gene therapy. In 2003, p53 gene therapy was approved by the State Food and Drug Administration of China for the treatment of head and neck cancer. P53 gene therapy has not yet been approved by the FDA in the US
There has been much research and early-stage development for p53-directed therapies. However, only a small and sporadic effect has been demonstrated in trials, with a small percentage of tumor cells being reversed.
However, there have been notable successes in the treatment of some types of cancer, including lung cancer. A successful gene therapy compound currently in clinical trials is APR-246. APR-246 was able to restore the normal function of mutant p53 in small-cell lung cancer (SCLC) cell lines. It has also been successfully used in combination with the chemotherapy drug cisplatin to treat p53 gene-mutated non-small cell lung cancer (NSCLC) cell lines.
A phase I/II clinical trial has also been successfully completed for APR-246 in the treatment of prostate cancer and hematologic malignancies, including those with mutations in p53 gene. This trial included 22 patients with hormone-resistant prostate cancer or hematological malignancies. It was found that APR-246 is safe, has good pharmacokinetic properties, and that it induces biological effects in tumor cells that are consistent with the mechanism of action of p53 (induction of cell cycle arrest). cells, apoptosis, and changes in genes that regulate cell growth and cell death). Two patients showed a positive clinical effect.
Successful early-stage clinical outcomes have also been achieved using p53 gene therapy through a different mechanism of action, one that induces an immune response in the patient rather than directly activating p53. This gene therapy compound, INGN-225, was shown to be well tolerated and it provided an immune response in patients with small cell lung cancer in Phase I/II clinical trial.
Researchers are still recruiting lung cancer patients for clinical trials of p53 gene therapy. These studies are needed to understand the true potential of p53 gene therapy and which patients will respond best to treatment.