In this innovative proposal, we examined the therapeutic and preventive (work in progress) value of the DNA-editing system when destroying/avoiding predominant oncogenic mutations in lung cancer such KRAS mutations. Therapeutically, we see the regression of KRAS-dependent tumors and so, overcome the current limitations of conventional cancer therapies with their side effects caused by unselective cell killing methods. Our approach is compatible with delivering into both normal and cancer cells because cells that lack target sequences should not be edited and, therefore won’t have any adverse effect. Despite editing efficiency is not 100%, in a continuous presence context and using an efficacious delivery system, it would be expected to target the entire oncogenic DNA eventually.
Despite diagnostic and therapeutic advances, lung cancer remains highly lethal: only about 15 % of patients survive five years after diagnosis in developed countries. Currently, despite intensive effort, no effective anti-KRAS strategies have made it to the clinic. In the past 2-3 years there has been a huge effort in the pharmaceutical industry directed to develop KRAS-mutant inhibitors (G12Ci) and change the paradigm of the “undruggable” state of KRAS oncogenes. Some inhibitors are being tested in clinical trials and, even though they are showing encouraging results, they also raised some concerns such the developing of resistance. Importantly, G21Ci resistance mechanisms rely on the relentless presence of newly synthesized mutant KRAS. Conversely, our strategy induces the deletion of mutant KRAS at DNA level and the tumor cells wouldn’t be able to re-express the oncogenic protein.
The other main objective of this proposal is focused on developing a completely new angle not studied so far: its role at preventing the establishment of especially relevant mutations driving carcinogenesis in key oncogenes, thereby acting as a "genetic vaccine". Although this part of the project is being developed, the applications derived from this angle can be innumerable. For example, we can combine this technology with the advances in tissue engineering that have recently led to the development of lung tissue for in vivo implantation in order to create lung tissue resistant to mutations in KRAS or other oncogenes. In the future, we can use these “genetic vaccines” to both avoid the occurrence of especially carcinogenic mutations and to correct mutations in already developed tumors.
