There are two broad approaches for exploiting chromosomal instability. We can go after this problem in a cancer cell intrinsic manner. So how do cells cope with chromosomal instability and can we then, you know, regardless of the immune system, go after it in a cell intrinsic manner. And this can range from targeting replication stress, driving it over the edge, targeting mitotic vulnerabilities, targeting metabolic vulnerabilities, because instability creates a lot of metabolic demand that the cancer cell has to adapt to...
There are two broad approaches for exploiting chromosomal instability. We can go after this problem in a cancer cell intrinsic manner. So how do cells cope with chromosomal instability and can we then, you know, regardless of the immune system, go after it in a cell intrinsic manner. And this can range from targeting replication stress, driving it over the edge, targeting mitotic vulnerabilities, targeting metabolic vulnerabilities, because instability creates a lot of metabolic demand that the cancer cell has to adapt to. So there’s a lot of opportunities to interfere at these adaptive nodes or steps that the cancer cell employs. In addition, chromosomal instability enables immune evasion. And so there’s also additional areas where we can intervene to enable the reawakening of the immune system to look at instability as a foreign property or as an you know, usually the immune system is typically blinded to chromosomally unstable cells. It is important to notice that, or to note that at the, during the early steps of tumorigenesis, the onset of instability can actually activate the immune system to clear these tumors or to edit these tumors. And so what we’ve noticed by looking at human tumors early on and later is that at some point, cancer cells are able to adapt to evade and tolerate this immune pressure. And then they can tolerate instability with no T cell or lymphocytes be found anywhere in the vicinity when you look at this tumor, you know, under the microscope. So there are mechanisms by understanding how these adaptive steps take place. There are ways to intervene, and we’ve published on this in the past. One example is ENPP1, which is an extracellular ectonucleotidase that breaks down a molecule that is an immunostimulatory molecule called cGAMP that is generated in response to chromosomal instability that typically would activate the immune system. And it’s actually a molecular immunotransmitter that is used typically by the body in host defenses against viruses. By overexpressing this enzyme, which is usually reserved for a normal negative feedback loop employed by, you know, fibroblasts during wound healing. So it’s just, it’s kind of like, it’s not reinventing the wheel. By overexpressing this enzyme, cancers with chromosomal instability are able to break this immunostimulatory molecule into adenosine, which is an immunosuppressive molecule, by kind of completely turning the switch upside down. So this enzyme, for example, has been an area of a lot of interest from a drug discovery and development perspective, and it can be an immune vulnerability in chromosomally unstable tumor cells. But that’s just one example of many opportunities where we can intervene.
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