Cancer gene therapy - P53 and PTEN
Gene therapy P53 and PTEN at Saisei
Cancer gene therapy using normal P53 and PTEN tumor suppressor genes
Acquired gene mutations are the most common cause of cancer
- They occur from damage to genes during a person’s life.
- They are not passed from parent to child.
- Cancer gene therapy is a type of treatment which uses normal genes to destroy cancer cells.
- The gene is usually taken into the cancer cell by a carrier called a vector.
- The most common vectors used in gene therapy are viruses.
- However, Saisei has started using liposomes instead of whole viruses as a vector in order to decrease side effects.
So cancer gene therapy attempts to introduce genetic material (DNA and RNA) into living cancer cells to cause apoptosis.
Gene therapy – P53
- Tumor suppressor gene P53 is the most frequently mutated gene in human tumors.
- Widely regarded as the “guardian of the genome”.
- P53 is a powerful tumor suppressor that inhibits tumor growth in multiple ways.
- Since P53 is mutated and inactivated in most malignant tumors, it has been a very attractive target for developing new anti-cancer drugs.
- P53 has been reported to affect almost all cellular compartments and organelles, including mitochondria, lysosomes, endoplasmic reticulum and more.
Both wild-type P53 (wtp53) and mutant P53 (mutp53) can also modulate the tumor microenvironment (TME), rendering it more cancer inhibitory or cancer supportive, respectively.
Tumor-suppressive effects of wild-type P53 and oncogenic effects of mutant P53
Mutp53 can support tumor progression by modulating exosome content in a manner that leads to reprogramming of macrophages to an M2 state, thereby generating a more favorable tumor microenvironment.
The activation of P53 can occur in response to DNA damage, oncogene activation, and hypoxia, in which P53 subsequently orchestrates the biological outputs such as cell-cycle arrest, senescence, apoptosis and autophagy modulation.
Gene therapy – PTEN
- Phosphatase and Tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene.
- After P53, PTEN is the second most commonly mutated tumor suppressor in human cancer.
- Up to 70% of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis.
- Frequent genetic inactivation of PTEN occurs in glioblastoma, endometrial cancer and prostate cancer.
- Reduced expression is found in many other tumor types such as lung cancer and breast cancer.
- This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly.
- Functions as a tumor suppressor by negatively regulating the Akt/PKB signaling pathway.
p53-based genetic theories
Wild-type p53 (wtp53)-encoding DNA and RNA can be introduced into cancer cells by several approaches, including recombinant viruses and nanoparticles.
This drives p53 expression and transcription of wtp53 target genes, resulting in anticancer effects
- Liposomes can complex with negatively and positively charged molecules.
- Liposomes provide greater protection for DNA from degradation and improved permeation through cell membranes.
- Liposomes can carry large pieces of DNA, potentially as large as a chromosome.
- Liposomes, due to being phospholipids, are safe even for the transport of vitamins and food supplements into the human body.
- Liposomes avoid the issues of immunogenicity and replication competent virus contamination.
- Cationic liposomes can complex with DNA and form lipoplexes through a combination of electrostatic interactions.
A novel drug delivery system
Liposomes could serve as tumor specific vehicles (even without special targeting)
Liposomes better penetrate into cancer tissues with disrupted endothelial lining
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