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zohaab Ishrat Aug 31, 2020
Problems Surrounding Targeting DNA Mutations To Cure Cancer
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The Ask:
What if instead of undergoing generalized, painful, and long procedures to treat cancer, we could have simple medication derived from our DNA to fight cancer indigenous to our own body? What if our body could detect and correct every mutation, translocation, DNA break, etc.? The question then becomes, what are the problems involved in targeting DNA mutations instead of treating cancer as a whole?
The Insight:
The idea is to equip oncologists with the biotechnological equipment that will enable them to utilize the information present within the genetic code of the patient and personalize the treatment specifically as per their need.
By targeting specific DNA mutations that are found in tumors and other cancerous growths, the oncologists can empower the DNA of the patients with the ability to identify cancerous growths and remove them naturally. But of course, it is not as simple as it sounds and involves several technical complications. Moreover, are we ready to take such an advanced leap in the first place?
Call to Action:
Researchers and enthusiasts are welcome to suggest their opinion on the matter. Ranging from manually programming the DNA to target specific mutations in the genetic code to the introduction of genetically enhanced bacteria and viruses to deliver cancer-fighting agents in the body, the age-old virgin domain is awaiting any major development that can be portrayed as a significant development to help develop a common cure for cancer.
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Creative contributions
Cancer is a combination of various alterations
Cancer disease have for most of the case (>80%) sporadic origin, while a small part is inherited. This is the case for example of mutation in BRCA1 and BRCA2 genes which are linked to breast cancer and ovarian cancer and in same instances to prostate cancer (https://www.cancerresearchuk.org/about-cancer/causes-of-cancer/inherited-cancer-genes-and-increased-cancer-risk/family-history-and-inherited-cancer-genes). Cancer Genome Project and Cancer Genome Atlas have analyzed more than nine thousand samples encompassing 33 different cancer types, providing a general signature of cancer associated aberrations. These mutations are typically divided into “driver”, that directly promotes cancer initiation and progression, and “passenger”, contributing to cancer development as a consequence of their accumulation(1). In most of the cases, cancer does not arise from a single genetic mutation, but rather is a combination of multiple genetic alterations that support cancer on-set and progression (https://www.bionews.org.uk/page_96227). For this reason a therapy based on tackling cancer by correcting single mutation will face two challenges:
1- Correcting one mutation is not enough, you may need different mutations to be corrected at the same time
2- You need to correct more than 99.9% of the cancer cells to make sure that you correct almost all the malignant cells and you reduce the risk of rebound
These two points, although the great progress in field of molecular biology, are far from being fulfilled. Thus, an approach aiming to correct the mutations in cancer – as therapy – is doomed to fail.
Current therapies will rather try to find some week spot in cancer cells and exploit it. An example is taking advantage of the fact that some cancer cells have defects in the DNA repair choice. Using an approach that overloads the capacity of the cancer cells to respond to the damage burden, it is possible to induce apoptosis. Such approach is also defined as synthetic lethality. For example, tumor cells have a dysfunctional HDR repair pathway. Also in these cases, the use of agents that lead to the formation of DNA damage is typically explored to create overt DNA damage in cancer cells, leading to their death. For instance, PARP-1 inhibitors have been widely used to inhibit Single strand break (SSB) repair and to promote double-stranded break (DSB) formation in ovarian or prostate cancer. Another mechanism to induce DNA damage makes use of cisplatin causing intra- and interstrand crosslink. This in turn leads to critical distortions of the DNA double helix and, if not resolved, to apoptosis . Interestingly, combination of the PARP-1 inhibitor Niraparib with cisplatin has been used to overcome the acquired platinum-resistances of cancer cells that typically arises in some cases of metastatic ovarian cancer. Although the potential of “synthetic lethality” strategies to combat some forms of tumors is unquestioned, in some cases. it fails due to the presence of a few tumor cells capable of counteracting the mode of action of the used compound (https://www.mdpi.com/2073-4409/9/7/1665/htm#B83-cells-09-01665).
So far, synthetic lethality has been the key strategy when it comes to cancer. In future, as the genetic engineering will improve we may have the possibility to change multiple genes at the same time with very high frequency and within the whole targeted cells of interest. But so far, there are no approaches in this direction.