Scientists tame chaotic protein fueling 75% of cancers | Hacker News Reader

Scientists tame chaotic protein fueling 75% of cancers

phys.org

294 pointsbirriel56 comments

How is it that this MYC protein “has no structure”?

As far as I know, protein structure comes out naturally during transcription, as the various amino acids are attracted to each other or repel each other. The mechanisms of protein interaction depend on their three-dimensional shapes! If a protein has no structure, how can it serve a function?

Of course I’m not suggesting that they’re wrong in any way, this is clearly a hole in my understanding of proteins that I wasn’t able to plug with google.

There are proteins known as "Intrinsically Unstructured Proteins" or "disordered" proteins. That function with no fixed configuration. Typically a good way of thinking about them is an ensemble of transient more common states, where things like post translational modification alters how long and which conformations the protein visits. The other replies you've gotten are inaccurate and about 15+ years out of date in thinking about protein structure.

Think of a roiling noodle where sections or the whole thing linger in certain shapes and configurations longer than in other positions.

This paper can give you a better idea about MYC specifically https://europepmc.org/article/MED/22457068

If you want to know more about disordered proteins in human DisProt is a good place to start https://disprot.org

> The other replies you've gotten are inaccurate and about 15+ years out of date in thinking about protein structure.

I do not believe the case, speaking as one of the others replies, and having reviewed the others. But since you do, could I request the extra work of some pointers to the inaccuracies?

NMR-driven descriptions of protein structure flexibility are far more than 15 years old, and common in all graduate bio courses since the 90s, so if I'm perpetuating some sort of inaccuracy I'd really like to know so I can stop.

The other replies that are "about 15+ years out of date" do cite literature that is more than 10 years newer than your references, though...

The structure comes from having a consistent configuration of the bond angles. Most proteins are fairly ordered, and even if they wiggle around a bit and are jiggly, they fold back into the same shape.

However, it's not uncommon to have disordered or unstructured parts of a protein, that have no consistent shape, and are completely moveable.

MYC is kind of on the extreme end of this. There's just one domain of the protein with a consistent structure, and the rest kind of conforms to the other proteins it binds to, or wiggles about.

This may not be the best paper on it, but it does review a bit of the unstructured nature of MYC among lots of other stuff too:

https://www.cell.com/trends/cell-biology/pdf/S0962-8924(22)0...

I think what they mean is that the protein does not have a single conformation that it adopts and then remains in. It's fairly common when solving the x-ray crystal structure of a protein to find that some regions of the molecule are just disordered and don't have a clear shape. If you're asking what is going on at the atomic level, the answer would be that the protein is continuously changing shape as it flops around its solution environment. Of course, if you could freeze time at any one instant, you would find that every atom has defined coordinates and therefore the overall molecule has some shape. The point is just that it's dynamic.

That's how I interpreted the article, but I don't have any specific knowledge of this protein.

There are also chaperone proteins that help in the folding process: https://en.m.wikipedia.org/wiki/Chaperone_(protein)

Proteins have moving parts. Some function like turnstiles, others walk along microtubes. "Intrinsically disordered proteins" is a key word that might help. Biochemistry is like a stochastic soup sometimes.

So MYC is involved in DNA transcription but they don't say for sure that it's abnormally over active in cancers. They've found a way to slow it down though.

Sounds like something that will need to be targeted at the cancer specifically because MYC needs to be active in every cell. So to me this just looks like interesting cell biology more than cancer cure.

I have followed HN for about 10 years and a few times a year there is an announcement about a major finding in cancer research.

Fortunately, I had no contact with oncology, so I cannot assess if any of these findings have made it to actual treatments.

Is oncology moving by continuous small steps or via leaps after these major findings are put in production, so to speak?

I have no experience in the field, but I have a close family member with a fairly uncommon kind of cancer (multiple myeloma).

One thing that is clear through speaking with doctors and moving through the process of treatment is that a _lot_ of the treatments he is receiving are quite new. Everything from drug selection to the process of marrow transplantation enjoys the benefits of recent scientific advance.

We have been told regularly something to the extent of: "the best time to get cancer is always now/in the future". If he had this cancer 1 or 2 decades ago his projected outcome would have been very different.

It seems like the story is similar for many cancers. There's a lot of new immunotherapy based treatments.

My mother is a doctor (not an oncologist). Over the years I've heard multiple stories of people she knew or treated, saying "if they had gotten that cancer 5 years later, they'd still be alive today".

I'm not a biomedical scientist but I do software / analysis to support drug discovery groups.

>Is oncology moving by continuous small steps or via leaps after these major findings are put in production, so to speak?

Regarding this question, I think it is a different type of 'breakthrough' in that it can lead to direct target discovery for drug development, which is very close to the end of approval and clinical trials. My research institute has its strenghth in small molecule drugs but there is a much bigger world for therapeutics. In that sense I think it is closer to 'production'.

There seems to be small steps but steady progress on the treatment but questionable progress on not getting it in the first place. See eg this Guardian article:

>Cancer cases in under-50s worldwide up nearly 80% in three decades, study finds

>Experts are still in the early stages of understanding the reasons behind the rise in cases. The authors of the study, published in BMJ Oncology, say poor diets, alcohol and tobacco use, physical inactivity and obesity are likely to be among the factors. https://www.theguardian.com/society/2023/sep/05/cancer-cases...

That looks almost entirely population growth and increased testin

And those "causes" are just a list of everything suspected to be bad for health.

Smoking rate has been decreasing.

I think a lot of breakthroughs are significant in understanding but can end up being untenable are treatment or it takes a very long time. But to answer the last question: my brother works in cancer research and it goes both ways.

E.g. I would argue one of the most significant developments in cancer treatment is genome sequencing. It allows you to specifically treat the cancer a person has instead of the (mostly false) perception previously of discovering some panacea in the rainforest that cures all cancers. But the genome was sequenced 20 years ago. At the time there was a perception that that was going to be a step change in custom treatment and solving genetic disease. In reality we are just now reaching the $100 genome and if anything it only served to elucidate how much we didn't know about genetics back in 2000. But slow and steady work means we do indeed sequence people's specific cancer and customize treatment for that. So there was a leap: the Human Genome Project. But afterwards it took a lot of slow and steady progress to get to where we are at.

He thinks mRNA vaccines are going to be the same. A leap forward, and now we are looking at slow and steady progress to getting custom mRNA vaccines to effectively cure cancers on a person-to-person basis.

What makes you think that the things you hear about are breakthroughs and not small steps?

Wording like "fueling 75% of cancers" makes it look like a pretty huge step.

You can find the disclaimers around this comment page. This look like a minor step, but maybe one that helps with a much larger one.

So 75% of cancers are “tamed” now? Or is the headline slightly hyperbolic

It’s not terribly hyperbolic. The headline is that they tamed the protein (MYC). That’s more or less true, they found a molecule that binds to and blocks MYC’s activity. Then in the article they (correctly) note that MYC is dysregulated in 75% of cancer cases. They don’t claim that that they cured or tamed 75% of cancer.

Finding a MYC binder is legitimately a big deal. It’s been known as a primary target for cancer for decades but there are zero drugs that block it. Now this shows the way towards drugging it. It’s a big advance for the field.

If one can bind it, I wonder if that can be used as a generalized (75%) early test indicator for cancer.

If an assay can be made based off this compound i could imagine some sort of screening tool that could be made. You would just need some sort of linker that could fluoresce or produce a signal.

So would this become a prophylactic drug or a treatment once someone has cancer?

Definitely a treatment. MYC is only a problem once cancer finds a way to generate too much MYC protein. Only them is it necessary for a drug to knock it back down

Likely neither. Myc and p53 are these mythical whales that people have been trying to tame for many decades and nothing has happened. Nothing likely ever will. This would probably be the ten thousandth medium impact paper on myc in history to give some context and I’m not exaggerating.

Yeah I do cancer immunobiology and p53, myc, mTOR whatever have been the mythical pan-cancer targets forever. There's just no way they are going to be it. Could an anti-myc be another tool in the toolbox? Sure. But it'll just go in a new version of RCHOP that extends disease free morbidity for like 3 weeks

One exception seems to have been Ras. I would have bet money that Ras would have never been a viable target but here we are now.

Somewhat off topic: Have you read “Tripping over the Truth: The Metabolic Theory of Cancer”[0]? If so, I’d love to hear your thoughts.

[0] https://www.goodreads.com/book/show/23496164

I haven't read this, so I'm sorry, but I cannot really comment on it. I've heard of the Warburg hypothesis but I haven't seen data that support this as the root cause of cancer. I've had my colleagues talk about this book in a way that makes me think it has a pretty good history of cancer and then selects a body of work to convince people of this hypothesis despite a number of failed clinical trials for many cancers.

That being said, I haven't read this myself, so I have to emphasize that I ought to take a look at it before passing judgment. There have been a number of grand hypotheses for cancer that haven't panned out. That doesn't mean we can't benefit from other perspectives.

Hopefully, but it depends on how it acts in the body. Manx treatments are not used as the side effects are too bad*

Nope. Just awful science journalism as usual. That 75% number comes from the first sentence of the paper [1] introduction:

> MYC is a critical transcription factor whose aberrant activity is implicated in more than 75% of all human cancer cases.

The rest is just made up vaguely based on the abstract.

[1] https://pubs.acs.org/doi/10.1021/jacs.3c09615

The headline is an accurate reflection of the body of the article.

It's been a while since I worked in cancer, but being able to target MYC is a significant achievement, as it has generally been quite difficult to target transcription factors like MYC.

Nothing in the article seems vaguely or concretely "made up" to me, but I'm curious if you can point to some particular sentences that you think are made up.

Sounds like a pretty big deal to me, in the sense that defeating cancer requires a long chain of breakthroughs just like this. MYC-focused drugs might prove to be a promising way to interfere with the growth of tumors and have a real impact on people’s lives

It's a technical achievement, and the headline reads like a breakthrough. I completely understand why people's trust has eroded in media, and especially in science.

No, otherwise the title would be "75% of cancers are tamed."

Researched synthesized a chemical that deactivates a protein implicated in 75% of cancers.

It may be that deactivating the protein doesn't cure the cancer. Or it may be that it's infeasible to synthesize a delivery mechanism. Or it may be that the treatment causes significant side effects.

In a petri dish, sounds like it. Specifically it sounds like they can reduce the growth rate ("tame") it, but not necessarily cure it entirely.

It also sounds like they haven't turned this into a treatment yet. They're still working on how to effectively get it where it needs to go in the body. They haven't run things like human tests that might reveal side effects. They haven't turned the "technology" into a "product".

I don't think the headline suggests that they've done more than that. "taming a chaotic protein" isn't "curing cancer", it's "figuring out how to deal with one component of most cancers in isolation". It's a step forwards.

>They're still working on how to effectively get it where it needs to go in the body.

I skimmed the paper, and this is indeed the case. The full extent of their testing was in vitro testing against the lysate of a specific cancer cell line -- that is, against the "raw contents" of a bunch of cancer cells which have had their cell membranes removed.

In my lay understanding, getting their stuff where it needs to go -- and only there -- is likely to be very difficult.

No, otherwise the headline would be “Scientists tame 75% of cancers”. The title doesn’t even really claim to have solved anything. Good title imo

This is "mini breakthrough" in early stage of researches. Basically not interested to anybody outside the research community.

I'd say the headline is mostly accurate, but easy to misinterpreted by a general audience. It's "technically correct".

I wouldn't worry too much about the linked page though. This is the kind of website which underlines keywords for search terms on the same website... That's always a red flag for for me indicating an uninterested seo focused spammy publisher.

They do link to the original article, which is great. And they don't misrepresent it. There's this flexible molecule which enables and accelerates cancers and some scientists found a way to bind to it. Non-trivial first step on one possible path to someday cure most cancers.

They are able to deform a protein involved in DNA transcription so that they can design drugs that will bind to and deactivate it.

Their approach stops all DNA transcription when applied to a cell, so it’s fatal to the cell. It would also be fatal if applied to a mouse or human, except that they don’t have a way to actually deliver it outside cell cultures.

This is interesting basic research, but is far from leading to new cancer treatments.

Obligatory xkcd: https://xkcd.com/1217/

That's why I ignore phys.org they often have sensationalist headlines. They've cried wolf too many times for my liking. The only reason I am typing this is I clicked to see comments by mistake.

Bit of a garden path headline. First parsed it as scientists solved how to fuel chaotic proteins.

amazing new cancer cure = amazing new battery

In mice, right?

In MYC.

Slow clap

I'm already skeptical with all these cancer research results being practical. One would say cancer is already curable when looking on the HN search results for cancer from the past 10+ years

Cancer might not be generally curable, but it is curable in the sense that many people survive cancer with treatment. And the increase of people who do survive is improving all the time.

I think that the gap is for people (like me) who don't understand what creating a medical treatment based in research looks like. I see a study like this and I think "oh great, they can just do this on people and then cancer is solved".

There's obviously a lot more complexity in applying research in practice, so it isn't that simple. Still, this kind of research clearly is leading to improvements in cancer care, even if it isn't completely cured every time.

Good for these scientists, but…

First they have to make something that works in a whole cancer cell.

If they get that far, you then have to show it works in animals.

If it works in animals, you then have to do phase 1, phase 2, and phase 3 clinical studies in humans.

Things fail at all three steps along the line.

Even in the highly unlikely event that everything went right from here it’s likely at least a decade from any clinical application. The odds of this particular approach being the one that leads to the blockbuster drug are very small.

(Note: not an expert on medical science, but married to a medical scientist who works in the drug discovery pipeline).

Then she has probably also told you that it's normal for scientists to publish these initial findings so the rest of the world can build on them. "This is not a viable drug and may never become one" doesn't need to be restated every time something gets reported. We know.

She’s also told me (and I know from other fields) that promising results in individual proteins are a dime a dozen, and generally not worth paying attention to unless you’re one of the very few scientists working in that specific field.

All true. Still need an initial attack vector and those are valuable.

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