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''' MOLECULAR ONCOLOGY STUB..... '''

- SOURCES:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1275628/

The role of MDM2 amplification and over-expression in therapeutic resistance of malignant tumors

Gene Therapy Leaves a Vicious Cycle

PTEN Tumor-Suppressor: The Dam of Stemness in Cancer

Targeting epigenetics for cancer therapy

The Role of Checkpoint Inhibitors and Cytokines in Adoptive Cell Based Cancer Immunotherapy with Genetically Modified T Cells

Advances in the Techniques and Methodologies of Cancer Gene Therapy

https://www.ncbi.nlm.nih.gov/pubmed/24116914 (Helmy)

- OUTLINE:

- Summary w/ examples

Immunotherapy

- Summary

- Example: CAR-T Cells

- Problems with CAR-T Therapy

- Gene Therapy

- DRAFTING

 Tumor Suppressor Genes 

The human genome has mechanisms in place to guard against uncontrolled cellular reproduction. Tumor suppressor genes oversee and manage cellular growth, division, and maturation of body cells (Sun et al, 2019, p. 47; TAZAWA 1569). Maintenance of regulatory pathways suppressed cells that, if allowed to pass through the cell cycle with an unstable genome, could turn into cancer. Cell cycle regulation is important to a functioning organism; remove that process and cells can multiple uncontrollably with severe error, as seen in cancerous tumor cells. Each time damaged DNA is allowed to replicate allows for further mutations to be created and passed on, one way that cancer cells to continue to evade other cellular mechanisms (Xue 1). Genomic instability is a hallmark of cancer cells (Liu 93).

P53 Gene

One of the most studied tumor suppressor genes is the p53 gene, which has been shown to be mutated in about 50 percent of human cancers (Tazawa et al, 2013, 1569). p53’s primary purpose, via manipulation of various cellular mechanisms, is to ensure the cellular genome remains intact and, if needed, signal for cell death if the DNA is damaged beyond repair (Räty et al, 2008, p. 17). This process is crucial to normal functionality of cells and the body as a whole. Without p53 and its genomic pathways, cells with damaged DNA would continue to pass down its damaged genome to daughter cells and mutations would accrue. The mechanisms and pathways controlled by p53 are a main reason chemical and radiation therapies work -- the purpose of chemical or radioactive stress is to damage the cancer cells so badly the cells recognize the damage and signal for cell death (Tazawa 1569). However, if cellular pathways where p53 plays an integral role are mutated enough, they will not signal for cell death and the chemo or radiation will not kill cancer cells, rendering chemotherapy and radiation therapy ineffective.

PTEN Gene

Like the p53 gene, the PTEN gene is classified as a tumor suppressor because of the pathways it controls. Its regulatory reach stretches to transcription, advancement through the cell cycle and towards cell death, stimulation of angiogenesis, and stem cell renewal (LUONGO 2019, p. 2). Usually, PTEN expression is localized to the cytoplasm, but movement into the nucleus allows for control over genomic stability and apoptosis (LUONGO 2). In this regard, PTEN acts as a checkpoint regulator and is responsible for arresting the cell cycle if errors during DNA replication pre-mitosis are detected (BRANDMAIER 2). Surpassing these checkpoints with damaged genomic material could allow for accumulated adaptations that lead that cell to become cancerous (BRANDMAIER 2). PTEN is such an important genomic regulator it controls both the primary and various alternative pathways to protect against genomic instability (BRANDMAIER 2).

GENE THERAPY

Cancer is unregulated and out-of-control cell growth -- it is a breakdown of normal checks and balances of cellular life. Cancer cells do not behave like normal cells, so the methods for ridding the body of these cells are more complicated. With the advance of gene analysis technology in the last few decades, gene therapy has emerged as a targeted way to treat cancer. Gene therapy introduces foreign genetic sequences to diseased cells in order to change the expression of these cancerouxs cells that are functioning with severely damaged genomes (Sun et al, 2019, p.45). Manipulation of the pathways controlled by the p53 and PTEN genes and regulation of p53 expression with the MDM2 protein have been shown to be a fruitful focus of cancer research but there are still many avenues to explore. This review provides an update on the current knowledge of mechanisms of these two gene pathways, their regulatory systems, therapies already in use and those that are still being developed, and a look into viral vector delivery methods.

PUT INTO ARTICLE.....Immunization Gene Therapy

Immune therapy is a targeted approach to cancer therapy where actual immune cells of the patient and their genes are manipulated to produce an anti-tumor response. The body's own immune system is used to attack the tumor cells and therefore the immune system hold a memory of the specific cancer cells to attack in the future if necessary. Many types of immunotherapies exist including bone marrow transplants, antibody therapies, and various manipulations of host immune cells to target and kill cancer cells. Cellular receptors, antigens, and cofactor molecules are some such cellular manipulations to target cancer cells.

Chimeric Antigen Receptor T

Chimeric antigen receptor T cell immunotherapy, possibly combined with cytokines and checkpoint inhibitors, are regularly used form of immune gene therapy. Chimeric antigen receptor T Cell immunotherapy (CAR-T) involves manipulation of a patient’s natural T cells to express a chimeric antigen receptor. This receptor, now on millions of the patient’s T cells, recognizes cancerous cells that express specific antigens. Usually, the T cell antigen receptor  is inactive but when the receptor recognizes a certain cancerous antigen, the physical structure of the T cell changes to destroy the cancer cell. Combining CAR-T with Checkpoint Inhibitors, Cytokines

Some regulatory proteins -- immune checkpoint inhibitors -- have been found to reduce the ability of T cells to multiply within the body. In order to optimize the efficacy of CAR-T gene therapy, these checkpoint inhibitors can be blocked to stimulate a robust antitumor immune response, spearheaded by the CAR-T cells. There are various known inhibitory receptors on the CAR-T cell; through manipulation of these receptors and the molecules that bind them, expression of the CAR-T cell can be amplified.

CAR-T cells can also be combined with cytokines to improve the efficacy of the immunotherapy method. Cytokines are messenger molecules that can act on themselves, nearby cells, or distant cells. The signal pathways of these cytokines can be used to enhance CAR-T antitumor characteristics. For example, Interleukin 2 is a cytokine that acts as a growth factor for various immune system cells, including T cells. In regards to gene therapy, IL2 can be used to increase replication and dispersing of CAR-T cells throughout the body. Problems with CAR-T Therapy

There is room for improvement with this gene therapy approach. Firstly, the antigens of interest expressed on the cancer cells may sometimes be expressed on regular body cells, too. This means the body’s T cells will attack its own healthy cells instead of the cancer cells when the antigen is lacking specificity with just the cancer cell. A possible solution to this problem is to include two different antigen receptors on the CAR-T cells to make them more specific. The second issue with the CAR-T immunotherapy approach is that it can cause cytokine release syndrome when an excess of proinflammatory factors are released by the immune system due to the artificial manipulation of pathways, which can cause unpleasant side effects for the patient like nausea and a high fever.