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Better understanding of cancer nets better treatments

For cancer treatment, researchers can use CRISPR-Cas gene editing to cleave out mutant segments of DNA that are causing the cancer cells to continuously replicate.

In December of 1971, Richard Nixon signed the National Cancer Act, which dedicated $1.5 billion over the ensuing several years to cancer research. It was a pivotal moment of the “War on Cancer,” a movement that emerged in the 1960s that brought a new sense of urgency to cancer research.

Many thought that the discovery of chemotherapy’s potential to cure cancer was the final frontier in fighting the disease, but they lacked a thorough understanding of cancer as a disease, which meant they had no way of predicting what chemicals might be effective in different cancers. This led to an era defined by trial and error when treating cancer patients could seem like just another experiment.

Fifty years on, as the urgency of that era has somewhat faded, understanding of normal cells and cancer cells has advanced significantly, enabling clinicians to prescribe individualized treatment based on different cancers or even different stages of the same cancer. Cancer researchers have not found the “magic bullet” they have been hunting for as long as the disease has been killing people. But they have found that the lives of most cancer patients can be extended at least a little bit and often they can have a comfortable and peaceful death.

This is all possible because of the thorough understanding of cancer that has been developed, allowing researchers to continue to build on this knowledge to advance existing treatments and come up with new ones.

BREAKING DNA DOUBLE STRANDS

Radiation therapy has been a fundamental tool of cancer treatment beginning more than a hundred years ago, but even it has advanced with understanding of the disease. It kills cancer by breaking the double strands in the cell’s DNA, and though all cells have mechanisms to repair this type of damage, they rely on specific components that stop the cell’s progress in the cell cycle, which can only work for so long. If the damage is not fixed in time, “apoptosis” occurs, which is when a cell is killed intentionally by the body.

The most common type of radiation involves continuous irradiation of the cancer for a few minutes at a time. However, research has shown that exposure to extremely short bursts of radiation in a very large dose can create double strand breaks that are more complex, with more damage condensed in a small area. This increased complexity of the breaks can lead to a significantly longer repair process. When testing the two types of radiation treatment, researchers found that 24 hours after exposure the cells exposed to ultrashort radiation had up to 2.9 times more double strand breaks than the cells exposed to continuous radiation (Babayan et al. 2020).

Along with this, drugs have emerged that can inhibit double strand break repair, whether that is through the prevention of cell cycle arrest or by targeting other necessary components of the repair process, which in tandem with the advances in radiation, could lead to radiation therapy that can kill cancer much more efficiently than it can now.

Though these concepts are in varying stages in the process to become an established treatment, they show that improving our fundamental understanding of cancer and how treatments affect cells can lead to improvements to even our most basic treatment methods.

However, the most innovative discoveries lie in revolutionary treatments that attempt to cure cancer in a whole new way, and they have the potential to change the way cancer is treated forever.

Cancer treatments mostly consist of killing off the entire cancer cell, but a developing new treatment, CRISPR-Cas gene editing, focuses only on one segment of DNA rather than the whole cell. CRISPR-Cas gene editing works in the patient at the cellular level to cleave out unwanted DNA sequences and replace them with a non-functioning segment.

Essentially, researchers use two molecules to accomplish this: a guide RNA and a Cas protein.

The guide RNA consists of complementary base pairs that match up with the unwanted DNA. The guide RNA locates and binds to the segment of DNA that needs to be cut out and indicates its location to the Cas protein. Next, the Cas protein cleaves the DNA. The native biological machinery then takes over, eliminating the unwanted segment of DNA, and replacing it with a non-functioning segment of DNA.

For cancer treatment, researchers can use this system to cleave out mutant segments of DNA that are causing the cancer cells to continuously replicate.

Researchers have had some success with mice when they used a CRISPR-Cas system to edit out a mutated gene in pancreatic cancer (Zhao et al.). This mutated gene’s name is KRAS-G12D. Researchers have learned that KRAS-G12D is specifically important for cancer’s ability to progress and grow rapidly inside of the patient. So, by editing out KRAS-G12D and replacing it with non-functioning DNA, the hope is that the patient’s cancer growth will slow and eventually stop. So far, editing KRAS-G12D showed some slower tumor progression, but not an elimination of the cancer in the mice. Even though there was not complete destruction of the cancer, the slower progression shows signs of hope for the future of CRISPR-Cas systems in cancer treatment.

How can these new cancer treatments be used in the future? Although both improvements in radiation treatments and use of new CRISPR-Cas gene editing systems are in the early stages of development, this research could be the new face of cancer treatment through more clinical trials and testing.

Now that there’s a better understanding of cancer cells, there’s a better idea of the weaknesses of those cells. Researchers can be more specific in targeting components of cancer cells, even editing the DNA itself. These targeting treatments could minimize or even eliminate the need for more invasive treatments, such as chemotherapy or surgery.

Overall, if these systems show success in human trials, they will change the way we think about cancer treatments in the future.

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Babayan, N., N. Vorobyeva, B. Grigoryan, A. Grekhova, M. Pustovalova, S. Rodneva, Y. Fedotov, G. Tsakanova, R. Aroutiounian, and A. Osipov. 2020. “Low Repair Capacity of Dna Double-Strand Breaks Induced by Laser-Driven Ultrashort Electron Beams in Cancer Cells.” International Journal of Molecular Sciences 21 (24): 1–10. https://doi.org/10.3390/ijms21249488.

Zhao, Xiao, et al. “A CRISPR-Cas13a System for Efficient and Specific Therapeutic Targeting of Mutant KRAS for Pancreatic Cancer Treatment.” Cancer Letters, vol. 431, Elsevier Limited, Sept. 2018, pp. 171–81. ProQuest, doi:http://dx.doi.org/10.1016/j.canlet.2018.05.042.

 

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