New cancer therapy holds potential to switch off major cancer types

No obvious side effects in mice with knockout gene and using the drug.

The drug doesn't disable the gene but make the protein unable to do its function by preventing the binding with another protein. If it can make cancer chronic disease, any side effects it may have will probably be less important then death.

Angiogenesis is going to be important in wound healing, I suppose, but compared to the current side effects of chemo this seems relatively minor.

I agree that "no obvious side effects" seems excessive if you interpret that as the expected result in humans. Still, on paper this looks much more specific that anything we have.

I know nothing about biology, medicine or evolution, but I don't think that's how it works. Lots of people inherit and pass on all kinds of bad genes that do terrible things to them, even kill them. And for such people, switching them off would be better pretty much irrespective of any side effects. (to the degree there even are any side effects at all)

> It's not like evolution would select for something that is useless outside of helping cancer.

Cancers often have genetic basis so in a sense evolution has already selected for it in some people or at least not selected against it.

IANAdoctor/biologist but i assume diseases that tend to strike after child bearing age have less negative selection pressure than other diseases.

Disclaimer: I’m not in these fields but I am curious enough about how the mechanisms work at a high level that I feel confident about the rest of this post.

Two things to keep in mind:

1. Biology has never selected genes to maximize longevity, only to maximize healthy breeding. There are very likely tons of genes that make sense as a growing child but are harmful at a later age, e.g. a post menopause/vasectomy adult does not need the genes to create gametes but those same genes may be causing cancerous issues for some.

2. Gene therapy (at least CRISPR-Cas9 like things) are in theory reversible[0]. Diagnose the cancer. Delete the notable gene or just make a point mutation to disable it. Treat/wait the cancer into remission. Re-add the notable gene or re-enable it with a point mutation. Hopefully such a strategy would minimize any long term effects and eliminate the cancer.

[0] There may be cases where a bio-engineer could design an effective yet irreversible edit. However, that seems like it would require serious effort and I doubt it would have enough value to be approved by the FDA for use.

A lot of proteins are involved in angiogenesis. Not to say it isn't important, but the body has many redundancies to make sure small errors don't break the whole system. That alone doesn't necessarily mean much, hence the MTDH knock out mice(model mice with the MTDH gene turned off) shows no obvious side effects. I suppose we'll see with time whether that holds up when applied in practice.

You're challenging someone with 15 years experience studying this particular gene... by quoting Wikipedia?

Might be important for sustained metabolism, but it might be eliminated for long enough to starve the disease.

I don’t know, but I do know the reality provides more combinations than I can imagine, especially when presented with binary and mutually exclusive scenarios.

I didn’t read the article fully but the parts of those two papers that are public and available to me (see Extended data Fig.4 comment at the bottom of the first paper), those do not talk about turning off a gene that encodes MTDH.

The paper is talking about a compound (two compound candidates) that inhibit binding of two proteins: AEG-1 (encoded by MTDH) and SND1, those compounds do that by binding to either AEG-1’s or SND1’s site where otherwise SND or AEG-1 would have bind, and they likely do this with stronger bond than SND1 and AEG1 would have had.

So in short, this compound does not leave you without some vital protein but disrupt formation of some bonds with SND1 protein.

The MTDH gene clearly has some utility in the human body. We know that because natural human knockouts are under-represented in the population. The Gnomad project has sequenced very many people's DNA, and they have been able to work out a formula for how many loss-of-function mutations they would expect to see in a gene (which mainly depends on the size of the gene). For the MTDH gene [0] they would expect to see on average 30.5 LoF mutations, but they only actually see 7. This is reasonably strong evidence that knockouts of this gene are selected against - that is, having two working copies of this gene conveys some advantage of some kind.

Knocking out the gene and gaining protection from cancer is likely a bigger advantage than whatever you lose, especially if you currently have cancer. Also, the proposed drug doesn't knock out the gene - it just prevents the protein from performing one of its interactions. Side effects are likely to take a while to work out, but if they're milder than the side effects of chemotherapy (which isn't hard) then that's a win.

The other thing I would like to point out is that humans and mice differ. It looks like most of the work they have done so far has been in mice. Knockout of this gene in mice doesn't seem to cause any ill effects. Working out whether the same is true in humans is a long and very careful process.

[0] https://gnomad.broadinstitute.org/gene/ENSG00000147649?datas...

There’s also a lot of redundancy in biology. A protein could be essential for cancers and non-essential for healthy cells. That’s the holy grail.

Entirely possible that while it’s involved in angiogenesis, it’s not a critical component of that process, and angiogenesis can continue just fine without it.

The statement “not important for normal cells” doesn’t mean it serves zero purpose outside of cancer, all it means is that it’s not critical for body functions.

Metastatic research really needs more funding. It's the true killing mechanism of cancer, and when this can be controlled, metastatic cancer can be classified as a chronic condition, not a terminal one.

Acquiring endless regulatory approvals.

From the article:

"yet it doesn’t seem to be important for normal development"

Gene space is huge. My cancer is cured, but now I'm dying of mange. So that's why that mouse kept licking itself. Big ask for someone else. They have trouble getting blood thinners, statins and beta blockers right. And there's no genetics there. It's stuff people ate out in the woods for hundreds of thousands of years.

> There are so many people close to dying in cancer finding volunteers for a Phase 1 test should be easy

I take the opposite approach. These people have few days left. It's a time to make things nice. It can get much worse quick. Cancer, which can be managed, is nowhere near as bad as it can get.

Disease tends to hit all at once. It's really just dying. Cancer, strokes, heart attacks and infections all tend to gang up at once. The trial will kill these people no doubt. If you have a ticket out of the hospital, take it! Don't squander it trying to wash mud.

Also the patient pays a lot for clinical trials. Hundreds of thousands of dollars.

I have a friend who about 15 years ago was told he was going to die from melanoma in about a year.

Within that first year he was put on a trial that added another 2 or so years to his life. Then during that time another experimental treatment was created and tested on him and that gave him another couple of years. A decade and a half later here we are, he still has cancer but his family (wife and two kids) has got to keep him around a while longer.

He’s been “patient one” on a number of studies, some have helped him extend his life expectancy, others have done nothing. Sometimes he has the mental and physical energy to start a trial and other times he does not.

The cancer has never gone away, and there have been so many moments of false hope that I’m never really sure where he sits mentally anymore (he really doesn’t want to talk about cancer when we’re together and I don’t think anyone can blame him) but I know he’s grateful for the chance to add more time onto his life when the experimental treatments are available.

The article seems to suggest that they only just found a compound which will interfere with the gene's action. So up until now, there was nothing to test.

The 2014 result only showed that gene editing before birth might prevent cancers.

Assuming you have found a drug that is safe and binds the target in the intended way (which itself can take years), you then have to manufacture it according to GMP standards. That takes at least a year and $1 million. Next, you have to run toxicity and pharmacokinetics (how the drug is absorbed and distributed in the body) in two different animal models. That takes 6-12 months and $1-2 million. Then you apply for permission to start phase I trials, and wait for the green light.

One reason RNA drugs are so exciting is that their manufacture is simple and can be standardized, cutting the GMP manufacturing step to a few weeks instead of a year or more. Small-molecule drugs are ”bespoke” in that each needs its own, different, manufacturing process. In contrast, all RNA molecules are essentially chemically identical, differing only in the ordering of the nucleotides.

Need to make a drug out of the small molecule inhibitor. There is a medicinal chemistry process that takes quite a while (several years at times) to get to something you can actually give to people.

Then there is safety testing in animals. Then regulatory approval. Then starting the phase I trial. The trial might take a year or more. Then you need to show the drug works compared to some standard treatment, which in a phase 3 trial in breast cancer takes 3 years and many hundreds of patients at least. Longer if you want to show it prolongs overall survival. Then the drug needs to be approved.

There is also the matter of funding but there is a lot of money for early stage biotechs at the moment.

In my (unpopular) opinion trials for people with incurable cancer are quite predatory. You are supposed to participate to help science, not yourself. But in reality many people desperately cling to anything that gives them hope.

Actually, we can: I think we already have working gene therapy for several diseases.

Just look at the current list on wikipedia: https://en.wikipedia.org/wiki/Gene_therapy#Treatment_of_gene...

Neo: “Are you trying to tell me that I can alter DNA?”

Morpheus: “no Neo, I’m trying to tell you that when you’re ready you won’t have to”

Altering the DNA is unnecessary if you can control the expression of genes or add additional genetic material later in the DNA->RNA->protein process. mRNA vaccines are already a great example of this. Another example might be the cystic fibrosis therapy Trikafta.

Curing 30 to 40% of a population is still a big win.

A small molecule is exactly what it says on the tin: small compounds. Small enough that they can pass through cell membranes.

Inhibitors block some biological pathway, which in general could be any number of things.

In this case the drug blocks a specific protein that we believe cancer cells specifically need, meaning the cancer cells might fail faster than the rest of your body if we inhibit it.

...and human tissue.