CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

It's not as great as you might think, despite all the stories you see like this one. That's because most of the stories are in cells (this one) or mice.

The big success story, about 20 years old now, is testicular cancer. You can have metastatic testicular cancer with tumors all over your body (like Lance Armstrong had) and they can cure it. They use platinum based chemotherapy and it's not really well understood why it works for testicular cancer, but not others.

The story with childhood leukemias is similar. They figured out how to combine a bunch of chemotherapy to get the cure rate up pretty high. Leukemia in a child used to be (1990s) 90% fatal, it's like 10% now.

Besides those, most of the advances in the past few decades come from early detection/ surgery or just prevention (stop smoking).

There is some hope though. When people first started studying cancers at the molecular level, one of the first things they noticed was how often a gene called Ras was mutated in different cancers. It turns out that designing a drug for Ras was really hard, but it finally got done, it's called daraxonrasib. They just released phase III human trials with this drug in pancreatic cancer a week or two ago and it destroyed the standard of care (Chemotherapy), but that is saying people who were dying in 1-2 months were still alive after 5-6 months.

The former senator Ben Sasse was diagnosed with metastatic pancreatic cancer last December. Historically, that's like 5% survival rate for 5 years. He is on daraxonrasib. We will see how it works out.

It's difficult to do that because we don't even really know how many cancers there are.

Cancer is best understood as a family of tens of thousands of diseases. They're a whole range of different genetic changes that can happen which result in similar categories of symptoms and consequences. They can also be incredibly complex, such as being the result of hundreds of stacking genetic defects acquired over a lifetime. There can be a thousand varieties of one specific type of lung cancer, and they might all react differently. Some of our solutions might work on a lot of them, but others might only work on a handful. And we're at the beginning of figuring all this out.

CRISPR may eventually allow us to genetically profile a cancer and design highly targeted medications to cure them, but we don't know yet how well it will work. It may only work on a portion of them. It may have worse outcomes than chemotherapy or radiation. It's nice to think that we're going to find a magic solution to the entire problem, but things almost never work that way. I think we're going to be able to resolve a wide range of issues, but I don't think it will really cure cancer as a whole.

you should probably look at oncogenes in general.

https://en.wikipedia.org/wiki/Oncogene

at the simplest level, the particular gene, and particular perturberance, sets the "type" of cancer.

there will most often be additional genetic abnormalities giving nuance to the character of the oncotype.

the tumour is originated from a cell type of specific differentiation, and developmental potency, further widening the pool of possible cancer type.

immunotype of cancer also sets the relationship between cancer and the body.

the cells of the body are setup for a functional death and replacement so when you try to rescue a particular cell [or cohort] you are fighting against how the grand scheme of tissue maintenance operates.

unless you have concern for a particular long lived cell, it is best to destroy the tumour cell, and let the next cells in line replace them.

it is still a multifacet strategy being developed, inhibit the genetic properties of the tumour, and target the immunotype for destruction.

https://en.wikipedia.org/wiki/Cancer_immunology

Not exactly what you're looking for, but OWID has a bunch of great visualizations about cancer, including ones that really show the progress we've made (and how much we've yet to make!)

https://ourworldindata.org/cancer

All in all what a century to be alive in, 100 years ago many people were living in mud huts globally (even in rural Europe) and now we have CRISPR, self-driving and hopefully UBI in a few years/decades. So much to look forward to.

> We might have "AI" ...

Basically everything that was invented up to 3 years ago was invented without the help of "AI". And that includes "AI" itself, for we, humans, invented that too.

So yup, humans can be quite resourceful.

#TIL multiple myeloma went from being a death sentence in the 90's to quite manageable using a really old compound called thalidomide[1]. Though it sad that it was exploited for almost two decades to line the pockets of a dozen rich a*holes.

[1](https://www.propublica.org/podcast/revlimid-cancer-drugs-fda...)

I think it's difficult to objectively quantify "effectively solved". A good source with loads of information about many diseases and their clinical status is OpenTargets, e.g. https://platform.opentargets.org/disease/EFO_0003860

The foundational problem with cancer is that multicellular organisms rely on tight control of the cell division cycle and there are hundreds of ways that can go off kilter. The record of understanding and treatment is impressive, certainly, but the correct mental model is more ‘think of all the problems that can go wrong with a rocket launch - from contaminated fuel to software glitches’ than ‘here’s a list of cancers of different cell and organ types’.

Just as attacking such problems with rocket launches involves hundreds of different approaches, that’s the situation for cancer. I’d also point out that this is why it was really not trivial to identify microbial and viral causes of disease in the 19th century - especially since we now know that certain kinds of infectious disease can themselves result in cancer initiation. It’s definitely a hard set of problems.

I would also add, there was a concerted effort by industry to promote ‘inherent genetic malfunction’ as the cause of cancer in the late 1990s and early 2000s, but the reality is that exposure to industrial carcinogens tracks closely with a wide variety of cancers (skin, digestive tract, etc.). This was a very deceptive and dishonest approach to avoiding regulation.

Let the record reflect that I had this exact idea 2 years ago but never finished it, and remembered it this morning.

Exactly.Now these are the kind of matters the world should be more inclined to invest in.

Have you asked Claude to pull this and graph it over time? It could build a static site as well.

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.)

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.

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.

Surely a far simpler way to evolve resistance would be a trivial mutation in the p53 transcript that the guide RNA is looking for.

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.

You're correct about CRISPR Cas9. The off-target affects are difficult to manage.

The paper describes Cas12a2. This is a different mechanism with discovery origins in - of all things - agriculture. It does not attempt in any way to reprogram cells. It uses a guide protein to locate a specific mutation with exacting precision and, when it activates, unleashes total destruction of the cell.

The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound.

Source: I have personally funded novel research based on Cas12a2 for an undruggable condition I have. I have personally seen my condition "cured" in vitro using this technology and it left all of my WT cells unharmed. Some of the researchers I've funded are co-authors in the paper linked. I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.

Devils advocate, I also vehemently shat on RNAi therapeutics a decade back. We do have RNAi therapies in market now though. I do think Crispr will find its place similarly.