The idea of using CRISPR/Cas to detect tumor-specific mutations that aren't necessarily oncogenic and then kill the cell is not a new one [0, 1, 2]. However, previous studies used Cas9, which just damages the DNA at the target site; this uses Cas12a2, which is far more destructive because it shreds the chromatin in the cell once activated by detecting the target sequence.
As with any cancer treatment, it's likely the tumor will evolve resistance. My guess is that cells will find ways to reject the lipid nanoparticles used to deliver the CRISPR/Cas mRNA and associated guide sequence(s), either via modifications to the cell surface (preventing LNP uptake) or via changes to endosomal/lysosomal pathways (causing the mRNA payload to get degraded before it has a chance to be translated into protein).
[0] https://pubmed.ncbi.nlm.nih.gov/28575452/
turn the stick around and grasp the other end.
evolution isnt about generating a response to a challenge, its about differential success.
those cells [oncocytes] that have properties conferring resistance carry it as un-utilized baggage, those without said properties make a living without that fetter.
the selective factor comes into play when payloaded LNP [in this case] facillitates destruction of "nonresistant" oncocytes and spare the "resistant"
the resistance is not generated in response to the challenge, it is already present, and confers survivorship in the face of the administration of the drug.
But cancer isn't an organism. Cancer cells in any specific individual may evolve that way, but "human cancers" as a group will not. (The only way they could is by evolving human DNA, but "survival of the fittest" pushes the opposite direction for that.)
Indeed, there's no "be a better/stronger cancer and spread more effectively to more hosts" the way there is with bacteria or a virus. It's not like the flu where we need a new shot every winter because every winter is a new flu.
Once we solve the cancers we know about, they're solved forever, with the one caveat that more people will live longer, so that will increase the window for eventually still ending up dying to one of the cancers that happens to have a non-evolved built in resistance to this or that treatment. Which is a great deal of course, especially if it's a treatment that sounds way less destructive of QoL than chemo, radiation, etc.
>there's no "be a better/stronger cancer and spread more effectively to more hosts"
No, but there is "be a better/stronger cancer cell and don't succumb to whatever therapy is killing its neighboring cells." It's exactly akin to how dosing isolated populations of bacteria with antibiotics selects for individual cells that are resistant, which then multiply and dominate [0], just like a tumor.
[0] https://www.youtube.com/watch?v=plVk4NVIUh8
Right, but that's within a single host isn't it? Like patient A gets that mutation and succumbs, that sucks, but the stronger cancer cells don't them jump to patient B the way antibiotic-resistant bacteria do.
(barring the transmissible cancers article that your sibling comment linked to, but that's not the common case)
> Indeed, there's no "be a better/stronger cancer and spread more effectively to more hosts" the way there is with bacteria or a virus.
The rare exception: https://en.wikipedia.org/wiki/Clonally_transmissible_cancer
Well that's terrifying, TIL.
It's not very relevant here, but curiously some cancers are, in fact, contagious organisms. The most famous example is the devil facial tumour disease. Luckily cases of transmissible cancer in humans are extremely rare (if you count only transmission of cancer itself and not the cancerogenic agents).
Another curious case of "cancer being an organism" is the HeLa line derived from cervical cancer cells taken from a woman called Henrietta Lacks.
Nonetheless, we see the exact same resistance mechanisms to the same therapies recur across individuals, e.g. [0]. Convergent evolution is a harsh mistress.
[0] https://pmc.ncbi.nlm.nih.gov/articles/PMC2538882/
Surely a far simpler way to evolve resistance would be a trivial mutation in the p53 transcript that the guide RNA is looking for.
In practice, you’d use multiple guides targeting multiple mutations, so that the probability of having/acquiring multiple resistance mutations abrogating every guide from binding would be infinitesimal.
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There are some ideas about making it triggerable. So first you load the cells with a protein that is ready to start shredding but is inactive. Then you trigger it with a second compound.
This would shorten the timeframe for cells to mutate and acquire resistance mechanisms, but would not address the issue of cells with preexisting (epi)genetic resistance mechanisms that would then be promptly selected for.
Yes, and if you shorten the timeframe enough, there's a chance that it can clear all the cancerous cells. You also ideally would use multiple variations of the therapy to further reduce the chance of a pre-existing escape mutation.
That's how we deal with HIV. No single HIV therapy (so far) is effective enough to suppress the virus all by itself, but a combination of them provides a barrier that is too high for mutations to jump.
Agreed. Assuming it's ultimately proven to work in vivo, I think the endgame of this therapy is multiple guides targeting multiple mutations along with multiple delivery mechanisms (a formulation-diverse cocktail of LNPs + eVLPs [0]?). Sure, tech like [0] is futuristic and fanciful, but so is the tech of the OP, and both will probably reach in vivo maturity around the same time.
[0] https://pmc.ncbi.nlm.nih.gov/articles/PMC8809250/
This will also cause problems because too many cells die at once. See the comments in other threads; killing the entire cancer at once is very hard on the body.
Tumor lysis syndrome is a thing, but it can be managed. It's far better than the alternative.
The new therapies will also likely be applied after surgical resection and/or classic therapies to reduce the bulk of the cancer.
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Depending on how the LNPs are designed, would resistance also potentially cripple the cancer cells? Like, it stops surfacing some cholesterol receptor because the drug is being delivered by LNPs that target that receptor, and now the cell is starved for cholesterol?
I've heard about drug resistance in bacteria leading to slower growth / reduced virulence. Maybe the same would occur with cancers. A drug that could effectively switch an aggressive cancer into a slow-growing one wouldn't be the worst thing.
I'm no expert, but p53 is known as "the guardian of the genome."
If p53 is reactivated, the cancer cell dies.
https://en.wikipedia.org/wiki/P53
Perhaps a different mutation that disables p53 could evade the pattern match.
This article is all about p53.
Edit: This section of the wiki best explains this critical cellular component...
p53 regulates cell cycle progression, apoptosis, and genomic stability through multiple mechanisms:
-Activates DNA repair proteins in response to DNA damage, suggesting a potential role in aging.
-Arrests the cell cycle at the G1/S checkpoint upon DNA damage, allowing time for repair before progression.
-Initiates apoptosis if the damage is beyond repair.
-Essential for the senescence response triggered by short telomeres.
>Depending on how the LNPs are designed, would resistance also potentially cripple the cancer cells?
Yes, if the LNP could be engineered to target an essential surface receptor, which is still a very tough problem. It would also not solve the issue of the payload successfully entering the cell but being subsequently degraded.
>I've heard about drug resistance in bacteria leading to slower growth / reduced virulence. Maybe the same would occur with cancers. A drug that could effectively switch an aggressive cancer into a slow-growing one wouldn't be the worst thing.
This is essentially how treatment for chronic lymphocytic leukemia happens (hence why it's called "chronic"). People with CLL can stay on BTK inhibitors for decades, often until they die of other natural causes.
Interesting, thanks for the info!
Another question: how does this approach compare to trying to repair the pathogenic variants in the cancer? I asked here about that approach recently and the response was mainly about delivery difficulties: https://news.ycombinator.com/item?id=48285386
Even with 100% delivery efficacy, editing efficacy is nowhere near 100%. CRISPR/Cas editors will reliably detect the target sequence but will not reliably edit it in order to repair the mutant allele, whereas CRISPR/Cas12a2 will activate and destroy chromatin ~100% of the time when it detects the target.
As is often the case, it's a lot easier to indiscriminately destroy than precisely (re)build.
>would resistance also potentially cripple the cancer cells?<
this is the concept of genetic baggage, and metabolic budget.
there is only so much energy to a cell, and scant amounts to "waste" on preservation of something that is not used. in the long term, carrying unused properties are disadvantageous, and reduce reproductive output [replication]
the result is "unfettered" oncocytes outgrow those with baggage, and occlude access to resource. if there is no challange that reduces population of nonresistant cells, the resistance will be minimized and extinct in the face of large disparity of success.