Gene Therapy in Cancer

Cancer can be considered a genetic disease at the cellular level. Mutations accumulating in genes controlling multiplication and relationships with other cells lead to cancer.

There are 3 critical gene types. These are oncogenes, tumor suppressor genes and metastasis suppressor genesas the categories involved.

• Oncogenes arise when genes normally controlling cell multiplication (protooncogenes) undergo mutation as the causal change.
• Tumor suppressor genes prevent uncontrolled cell growth. 
• Metastasis suppressor genes control mechanisms preventing abnormal migration to other tissues and organs.

Increased oncogene activity and failed tumor suppressor function cause cancer. Gene therapy aims to eliminate cancer cells by modifying or removing cancer-causing genes and adding healthy genes.

Are Gene Therapy and Treatments Targeting Genetic Changes Different?

Gene therapies and treatments targeting genetic changes are not the same!

Gene therapy replaces disease-causing genes with healthy ones and is calledgene editingas its technical term.

Treatments targeting genetic changes, called targeted smart drugs , do not replace the damaged gene; they prevent it from producing a defective cellular product such as areceptor, growth factor or similar substance.

Gene therapy can potentially eliminate a genetic disorder entirely, whereas targeted drugs can only control disease, for example shrinking tumors or preventing growth.

Two key gene-editing examples, detailed below, are CRISPR/CAS9 and the oncolytic virus vaccine Talimogene, developed for malignant melanoma skin cancer.

A good targeted-drug example is Larotrectinib against TRK fusion, a major oncology development of 2017. Such drugs date back to the 1990s, however (for breast cancer, Herceptin targeting the Her2 receptor in 1996 FDA approval was granted).

Cancer Gene Therapies Can Be Grouped Under 6 Main Headings

1. Making cancer cells more “sensitive” to drugs. Genes delivered to cancer cells aim to improve treatment effectiveness. Current studies seek to overcome radiation resistance. One study transferred genes via viruses and found that cancer cells could no longer resist radiotherapy. Safety and effectiveness are still being tested.
2. Applying gene therapy to immune cells so they attack cancer more strongly. One of cancer's 10 hallmarks is learning to become invisible to immunity. Immune cells are removed, “trained” through laboratory gene transfers and made to attack cancer. T cells, among the most important active immune cells, offer promising results. Gene-armed T cells were given with chemotherapy combinations; trials continue, with slower tumor growth observed in most patients.
3. Eliminating mechanisms protecting cancer cells. In normal cells, DNA damage activates the tumor suppressor P53, stopping division and attempting repair. If irreparable, apoptosis eliminates the cell through programmed death. In 50 percent of human cancers, p53 is mutated. Mutant P53 cancer cells therefore fail to undergo normal programmed death. Researchers aim to replace defective p53 with healthy p53 to induce cellular “suicide”. Viruses entering only cancer cells carry the healthy gene. Drugs developed include China's Gendicine and Advexin, neither FDA-approved. Main problems are immune attacks on viruses and uncontrolled viral infection. Recent studies seek delivery through nonviral carriers, such as fat droplets. Trials continue.
4. Genetically modifying viruses to target cancer cells. As discussed previously, oncolytic viruses target and destroy cancer cells. Researchers reprogram viral genetic information to attack cancer. The first therapeutic oncolytic virus vaccine designed this way, approved by the FDA last month, is Talimogene laharparepvec, used for melanoma when surgery is impossible.
5. Specifically targeting cancer with new-generation “prodrug” treatments: Cancer cells are first manipulated with particular genes, acquiring the ability to convert an administered prodrug into another molecule, aiming for self-destruction. The prodrug does not harm normal cells. Promising brain tumor studies exist. In mice, gene transfer was followed by ganciclovir; cancer cells converted it into another molecule and lost viability.
6. CRISPR/CAS9 Gene-Editing Technology: Becoming world-renowned in 2013, crispr/cas9 gene-editing technologywas discovered while studying bacterial-viral interactions. Viruses attach to bacteria and inject DNA, which enters bacterial genetic material and produces viruses. Bacteria developed a defense: recognizing viral DNA, they cut it with the cas9 enzyme. The cut viral DNA fragment is called crispr . Bacteria incorporate it into their genetic material, retaining viral DNA in memory and defending faster against the same virus. Thus, the crispr/cas9 systemcan be viewed as bacterial immunity. Briefly, crispr is a naturally occurring bacterial gene region forming the antiviral defense with cas9. Researchers adapted crispr/cas9 for gene editing.

As we know, cancer's fundamental cause is damage in genes . Crispr can remove mutated sequences and/or replace genes encoding faulty proteins with ones encoding correct proteins, eliminating cancer-causing mutations. Immune warrior T cells can also be programmed to attack cancer more effectively.

Gene therapies are still undergoing clinical trials. By targeting cancer's causes, they offer great hope.

-Related Topic: A Drug Targeting the TRK Genetic Change Is Effective Across Different Cancers and in Children and Adults for the First Time: Larotrectinib

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