[strbean]

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.

[MontyCarloHall]

>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.

[strbean]

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

[MontyCarloHall]

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.

[chasil]

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.

[rolph]

>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.