Key barriers that we have that might be limiting us from exploiting the full potential of chromosomal instabilities, there are a couple of important ones. One is the lack of adequate models that allow us to dissect the role of chromosomal instability from other genomic and genetic and epigenetic alterations that might happen in the tumor. Chromosomal instability is not a single pathway...
Key barriers that we have that might be limiting us from exploiting the full potential of chromosomal instabilities, there are a couple of important ones. One is the lack of adequate models that allow us to dissect the role of chromosomal instability from other genomic and genetic and epigenetic alterations that might happen in the tumor. Chromosomal instability is not a single pathway. It’s not a mutation in a single gene that you can kind of turn on or off. It involves chaotic missegregation of many chromosomes and each chromosome harbors thousands of genes. So a single missegregation event can alter the levels of, you know, gene expression levels of hundreds if not thousands of genes and can have other consequences, genetic, epigenetic, can lead to DNA damage, complex rearrangements, so it’s a bit of a chaotic process and designing careful experimental models that can separate and dissect one process from another is going to be really important. And so the field has really advanced over the past five years, or five to 10 years, to develop these isogenic models where we can dial up and dial down instability in otherwise cells that look very similar. They have the same mutational background, they’re the same cancer type, they’re the exact same cells. And using these models, we’re able to see significant differences in tumor behavior, in metastatic potential, in immune infiltration in the tumor microenvironment, et cetera. And also it allows us to understand vulnerabilities that might spare cells with low levels of instability, but be very lethal in cells with high levels of instability. Otherwise, they’re the same cell line or the same cell model. So that’s one barrier. The other barrier in targeting chromosome instability is identifying genetic targets. You know, we live in the era of precision medicine, and I think it’s really important to identify targets that might be selectively lethal to a subtype of instability, perhaps, because instability is a very broad term, and it captures many subtypes of heterogeneity and genomic instability mechanisms. For example, homologous recombination deficiency, bridge formation and mitosis, mitotic missegregation defects, et cetera. So I think it’s really important to start becoming a little bit more specific as to which type of instability we’re going after. What is that specific genetic target that we’re going after? And that also will facilitate patient selection down the line. So I do think getting a little bit more sophisticated and understanding the mechanisms of instability rather than thinking about it as a chaotic process in a very general term will help the therapeutic approaches that will develop out of it.
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