Drug trio found to block tumour resistance in pancreatic cancer in mouse models

Because research on real humans and real diseases is exceptionally difficult. Clinical research is notoriously expensive, results are likely to differ from non-human (preclinical) models, and trials take forever to get started, gather enough data, and get a drug actually reviewed and approved. So even when everyone is excited by the preclinical data, there are so many barriers (both scientific and non-scientific) that getting to an approved drug is pretty unlikely.

1. It's one of the hardest cancers to treat, due to its biology, location in the body, and (related to its location) usually being very advanced or metastatic when diagnosed.

2. Mice =/= humans, as noted.

However we're heading into a new era of treatments for some cancers including pancreatic. New agents targeting RAS/KRAS pathways will likely deliver the first meaningful treatment advances in decades.

Daraxonrasib (which was used in the linked study) is leading the charge, but there are multiple other drugs (including agents that are a little more targeted, and therefore likely slightly better tolerated, like pan-KRAS or KRAS G12D inhibitors) in development too.

In the past decade, the five-year survival rate for pancreatic cancer has nearly doubled, from 7% to 13%. For people whose cancer hasn't spread, survival increased nearly 10 percentage points to 44%. So it's wrong to say that nothing ever seems to make it to daylight.

Source: https://www.uchealth.org/today/slow-but-steady-progress-impr...

In addition to the reasons already mentioned (natural difficulties in translating results from animal models to humans), even attempting to achieve the same results in vitro and in animal models is complicated. They estimated that the reproducibility of these studies is approximately 50%. See Errington, T. M., Mathur, M., Soderberg, C. K., Denis, A., Perfito, N., Iorns, E., & Nosek, B. A. (2021). Investigating the replicability of preclinical cancer biology. elife, 10, e71601. https://doi.org/10.7554/eLife.71601

That is the problem with symptoms in general. Most people who go to the hospital with "chest pain" are not having a heart attack - but it is still the best symptom we have and so emergency rooms "waste" a lot of time one people who have nothing wrong. Or more likely they just have a mild constipation case (look up constipation, and then look up the individual symptoms - most of them are also symptoms of GET TO THE ER NOW type things)

And they shouldn’t raise red flags. 99.9% of the symptoms any individual experiences in their life are not life threatening. If you got scans and interventions at every symptom, you’d end up in debt and with iatrogenic harms. Until we can get more accurate data from our bodies more easily, this is the reality. The good news: there’s so much room for innovation and progress in medicine.

>Only thing that I'm doing differently is having blood tests done on an annual basis

Tumor markers? Did one once because it was a cheap add on to my annual medical. Which then led to a rather more expensive MRI (lucky for me it wasn't cancer). Genuinely curious if those tests have helped anyone here as a preventative measure.

What's MSK?

How expensive? Let's say you're Bill Gates or, say, Steve Jobs. What would it cost for someone with their wealth to get that shot?

Yeah putting myself in the shoes of someone with this disease or a loved one with this disease I would be so incredibly angry that we weren't allowed to try something when the alternative is certain death

Ethics is a topic I would never trust HN on.

There are already many "compassionate use" exceptions out there already. I've family friends be grated that. It helps the pharma company as well as the patient. I'm sure that will happen here.

Things are, at least, getting better with the passage of right to try laws: https://en.wikipedia.org/wiki/Right-to-try_law

These drugs seem to all be only allowed after Phase 1 trials, so still not quite at the level you're describing here.

I had a relative who died from this around 20 years ago. 50yo slim, sportive and healthy and after going to a diagnostic as she didn't feel good, she was gone within a few months .. So yeah, if there is even a slight chance it works, this should be tried and that'd save people :(

> what's the worst that can happen?

The patient dies from complications of the drug's use before the cancer.

We might take it too far, but the fear of quack medicine is extremely rational.

IMO, if you view your question from the ethical framework of "do no harm" i.e. the hippocratic oath instead of "move fast and break things", I can clearly see reason for the apprehension. The standards aren't positioned to catch "quack medicine" but to require full understanding before asking someone else to put something in their bodies. It's somewhat of an entitled stance that youd be okay with other people possibly needlessly dying in any circumstance for something experimental, and not one I'd ever want taken as an official stance by a regulated medical body.

good news, are current FDA has many ways of fast tracking a treatment and a willingness to do so

That’s because we have a system that financially punishes fraud and mismanagement which is what we want and should keep.

There should be a way for terminal cases to volunteer for early trials and I believe there is already legislation that provides that but it’s not used and funded enough.

> Our society's morbid, irrational fear of quack medicine

It is not an irrational fear.

Brandolini's Law applies: "The amount of energy needed to refute bullshit is an order of magnitude bigger than that needed to produce it."

The only way to prevent quackery is to cut it off hard before it gets started.

Wakefield demonstrated the disaster that happens when you don't.

(And if you have been reading this site for very long, you know the experimental treatments are already around--we're not currently lacking for possible cancer treatments. The problem is finding the trial. Then the problem is getting people through the process and then getting them to the trial. See: "Please be dying, but not too quickly": https://bessstillman.substack.com/p/please-be-dying-but-not-...)

The ethics of life and death are murky at best. When is it acceptable? 6 months to live? 1 year to live? 5 years? What is the cut point? The answer is, there isn't a clear answer. Yes, that is a cop out, but it is also true. I agree with allowing people of sound mind to make informed healthcare decisions towards the end of their lives that involve high risk. but I would be wary of weakening the process too much. We should have a push-back because people in these positions are exceptionally vulnerable and therefore easy to take advantage of and, even worse, likely to be unable to defend against abuse for very long. Weakening this process would likely lead to drug companies doing what they always do, abuse their position for money. Why even go to expensive traditional trials? Just give some promising, cherry picked, results in a press release and now people are coming to you signing every waiver and paying their last penny to live next to the trial that will kill them because the drug wasn't even close to ready. I would likely feel very different if I was near death, but that is the point isn't it? Again, I'm not saying this shouldn't be an option. I just think it needs a lot of scrutiny and a high level of skepticism.

Somebody has to pay for the trial. Drugs are expensive and the amount needed to dose a single person is orders of magnitude more than mice. So who funds the study?

If it's the government or philanthropic fund, you have to put in a grant and show that it's competitive in terms of preliminary results etc.

If it's the drug companies, you have to deal with lots of complicated things with combination therapies. Drug companies don't like their drug paired with other drugs that aren't in their portfolio. They also need to see a way to make a profit on it, which means they need to evaluate whether this is the most likely successful trial, assess bang for buck etc.

If you want to go compassionate use, then you need to get the pharma to donate the drugs or insurance to cover it. This is spain, so I guess insurance is just the government since they have universal healthcare. I have no idea how that works but I am guessing it doesn't move fast.

Knowing whether drugs work isn’t trivial. Patients are typically very heterogeneous in their responses to drugs. For example, pembrolizumab (the most successful cancer drug ever) typically only works in, say 30% of patients depending of the cancer type. Just throwing therapeutic ideas out there and letting physicians sort out how to use them and in which patients, isn’t a panacea. Looking at clinical data can be like star gazing even in planned studies. Structured, statistically powered studies, and costly rigorous assays on biomarkers and correlative studies are essential for understanding how and in what patients drugs are working. I’m all for expanding access to drugs, and there is abundant waste and greed in big Pharma and venture, but there are also people doing hard expensive science, medicine and manufacturing. Im not sure I have the answer. A “yelp for medicine” won’t improve immediate outcomes, nor longer term understanding and progress. A great and excruciating read about the tension there is a real-time blog (the story’s story) that was written by Jake Seliger unt he passed in 2023.

If nothing else, it's not the only hail mary you could potentially go out on. Would you give up the potential of being part of a trial for a drug that has actually done the work and demonstrated real promise in various pre-trial tests just to take a gamble on this alternative which hasn't even had the initial test replicated yet?

Further there is the potential for a false negative. If they don't understand enough about how the drug would work in humans, they may trial inappropriate doses or delivery methods. If those don't help or make things worse, it could be mistaken for the drug being ineffective and lead to the whole line of inquiry being abandoned. Then not only do you die, but countless others are potentially harmed by an effective version not being developed.

Finally, cancer treatments aren't just for the terminal. Drugs which primarily help during the early stages by necessity need to be trialed on people who still have a chance, maybe even a decent one, going with other, well established treatment options.

> Am I misunderstanding the headline?

Yes, what’s being blocked is “tumor resistance” to treatment.

“potentially overcoming treatment resistance in one of the deadliest cancers.”

It's an awkward headline that, when read a certain way, says the opposite of what it means.

Absolutely there is, which is why they haven’t genetically modify the mice for useful experiments.

People cancer outcomes have improved a lot in recent decades. Many forms of cancer are essentially cured if you detect them early enough.

I have absolutely no idea what the current frontline treatment drugs are for literally any form of cancer, and would bet the same is true for almost everyone else here. Most of the exceptions are people who know the frontline treatment drugs for one or two forms of cancer that impacted them personally. "And then you never hear about it again" is subtly implying that the drugs behind headlines never proceed beyond that point, but I didn't hear about it when the current frontline became the frontline treatment for any form of cancer. Most people just aren't in the loop about the evolution of the field of oncology, beyond pop-sci headlines.

And yes, most headlines like this don't result in changes to the care provided to anybody outside of clinical trials, but some do, and you and I probably won't hear about those either.

I think this is one of the expected outcomes of "Science by Press Release" (universities motivated to maximize their grants and IP), combined with media/press that wants clicks (articles that talk about cures for cancer get clicks).

It's not funny how people make judgments like this without any factchecking, just by their gut.

Talk to any actual healthcare worker from an oncology ward. (A nurse will do.) With most cancers, your chances of survival are non-trivially better now than even in 2010. Immunotherapy absolutely exploded in the meantime. For example, the vast majority of monoclonal antibodies (not just for treatment of cancer) were only approved in the last 15 years.

There are some notable holdouts like glioblastoma and pancreatic cancer, and these tend to draw attention. But there is real progress.

The stories are written for a general audience and often lack detail or nuance. "Promising" doesn't mean "likely". "Possible breakthrough" is not a breakthrough. And it may just mean we learn something that we don't know today.

I lost my wife to metastatic melanoma a few years ago. Words used in reference to cancer are often terms of art that have a distinct meaning from the general meaning. Her particular cancer was pretty awful and lacked mutations that allowed for the use of targeted therapy that buy time. Even still, her chances of survival were about 65% in 2023 as compared to 0% in 2013. Unfortunately, the odds didn't end in her favor, despite the incredible efforts of a team of doctors at a national cancer center.

Anything with cancer research and treatment is an testament to standing on the shoulders of those who came before. Many people suffered to give my Molly those odds - she had hope where many others had nothing. And today, we have trials of custom vaccines that will offer others more hope and perhaps safer treatment. Perhaps in some small way her journey and ideal helped those or other developments. That's all we have.

As a rule of thumb, if you’re not a researcher in the area ignore any media reports of a study that include the words “in mice”.

Also, there’s a tendency on HN for commenters (mostly software engineers) to think that they are smarter than the scientists who work on this stuff day in, day out. Let me tell you, you, random HN reader are not smarter than random biomedical scientists.

This isn't quite as bad as the garden variety "in mice" studies:

> The combination therapy also led to significant regression in genetically engineered mouse tumours and in human cancer tissues grown in lab mice, known as patient-derived tumour xenografts (PDX).

I opened the comments fully expecting the top reply to be “In mice.” Bingo.

There really has never been a better time to be a critically-ill mouse. They've got something for you.

Mice have the best drugs.

I wonder how long until we'll start seeing these breakthrough cancer treatment articles for clinical trials done in dogs. Oncologists think dog research is a better fit than mice because of greater genetic similarities to humans and the fact that pet dogs live in similar environments as their owners. I think in general people definitely wouldn't be as ok with inducing cancer in dogs as in mice, but finding volunteers owners of dogs with existing cancer is certainly easier.

This context is very important.

"Little by little, over-inflated results and breathless breakthroughs betray trust. They throwing dimes in a wishing well which people rapidly start to expect will never pay compound interest."

"Then, when one of those people is elected to parliament, or Congress, and start to cut the budget for the National Science Foundation, or declares that All Research Should Be In The National Interest (whatever that is), I wonder how much we reap what we have sown."

Same, I'll never look at them the same again.

me too

there must be some sort of word for "games-bleeding-into-real-life" for stuff like this.

I remember years ago playing some games, and hearing similar sounds in real life would startle (or amuse) me. And you can't really explain it to anyone around you, lol.

thank you, I did a double take. Drugtrio is my new favorite Pokémon

It's okay, I thought it was a drug cartel

Apparently 50 mice days is equivalent to about 5 human years, so even if these other causes of death here directly caused by the treatment (not alleged), surviving this much longer (5-20 years) would be pretty incredible for humans.

So: half (1+5) of them made it at least 50 days without cancer, and the other half made it at least 50 days with a smaller tumor? This sounds excellent to me. I agree that the sentence you quoted is overselling, though.

Mice are very short-lived compared to us. In humans, the usual standard of judgment when it comes to cancer is "5 year survival". No mouse has ever lived for 5 years yet, that would be like 180 years for us.

Prolonging a mouse's life by a few months is non-trivial and hints (only hints) at potential efficiency of such treatment in other species as well.