> Clinical implications: While more research will be needed before trials in humans can begin
Why? Seriously, think about it. Most people with pancreatic cancer have nothing to lose and many of them have just weeks or months to live.
Daraxonrasib, Afatinib, and SD36 are molecules that can already be purchased in bulk, and what's the worst that can happen?
Our society's morbid, irrational fear of quack medicine causes orders of magnitude more deaths through therapeutic neglect than it prevents through safety screening. "Better 10,000 die of cancer than 1 person die of fraud/waste/mismanagement or even in failed experiments performed in good faith."
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
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 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).
Is PDX considered to be illegitimate? Would be curious to know if prior studies that showed success with PDX methods ultimately resulted in useful therapeutics.
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.
I keep reading about these advancements in pancreatic cancer like early detection or possible treatments, but nothing ever seems to make it to daylight. Is there a reason why there's such disparity between this?
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.
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.
This sounds ethically questionable to me. I wouldn't rule it out entirely, but I'd want to see a well-reasoned argument, both technical and moral, that it was likely to lead to greatly reduced suffering for patients. Even then.... growing a body without a brain likely would not produce a model organism with predictive ability for human diseases.
I believe it could for a large number of tests. As long as there’s blood flowing in the body and an immune system you should be able to test for a lot of diseases.
As someone whose mother died to pancan, I could really care less on any of the brainwashed old farts in their churches or parliaments.
None of that matters to me or the people suffering from cancers, it’s al Knut a selfish obstruction attaching religion to the research material
A more practical option is using brain-dead humans for medical testing. This was discussed recently in the journal Science, using the term "physiologically maintained deceased". As they say, this "traverses complex ethical and moral terrain". (I've seen enough zombie movies to know how this ends up :-)
There are multiple examples in the literature of people leading perfectly ordinary lives whilst unknowingly having no more than 5% of the typical amount of brain matter (typically because of hydrocephalus). For example, https://www.science.org/doi/10.1126/science.7434023 from 1980.
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.
Here are the three simultanious things targeted in this experment.
Triple inhibition strategy
Pancreatic cancer remains notoriously difficult to treat, with very poor survival rates and limited effective therapies. The new research aims to combat this by targeting RAF1, EGFR family receptors and STAT3 signalling – nodes that are crucial for tumour growth and survival.
For all the folks complaining about "it's only in mice! things never work in humans!" -- I work at MSK and we definitely have seen success treating PDAC in humans: https://www.nature.com/articles/s41586-023-06063-y
"Why don't I see these treatments hitting the general public?" Because trials like these are phase I/II. Then you need a phase III that takes a long time to recruit a large cohort and has overall survival as an end point so you need a long time to measure the actual outcome you care about. And most trials fail in phase III because the surrogate end points used in phase II studies, like progression free survival (ie how long did patients go before their disease advanced in screens), are not necessarily great predictors of improved overall survival.
Specifically for cancer vaccines, this paper was a driving force behind MSK establishing a cancer vaccine center to scale up these personalized neoantigen mRNA vaccines. It's very very difficult to do and extremely expensive right now.
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.
I was wondering what preclinical models meant. It would be more accurate to call it animal models. I read roughly 3% - 5% of compounds move from preclinical cancer therapies to fda approval. That’s a tough success rate.
> These agents together were tested in orthotopic mouse models of PDAC, where tumour cells are implanted in a location that closely resembles their natural environment in the pancreas.
Ugh, of course: "in mice"!
> 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).
OK, maybe "in human tissue grown in mice" isn't so bad.
> The results demonstrated the therapy not only reduced tumour size but also entirely stopped tumour growth with no evidence of tumour resistance for more than 200 days after treatment.
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.
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.
Where did you get that "50 mice days is equivalent to about 5 human years"?
Mice are short lived, so the time for some events like sexual maturation are shorter.
On the other hand, the problem with cancer is that it adapts, it "learn" how to avoid the effect of the drugs, or how to make the signals to get more blood vessels, or ... I think most of these only depend on how many times the cancer cells reproduce to get a lucky adaptation, so for these effects 200 days is only 200 days.
Also survival rate depends on how early it's detected. In a recent post about colon cancer, the mice got the treatment like 2 weeks after the cancer cells were injected. My guess is that this study also has a short time before the treatment.
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.
> Clinical implications: While more research will be needed before trials in humans can begin
Why? Seriously, think about it. Most people with pancreatic cancer have nothing to lose and many of them have just weeks or months to live.
Daraxonrasib, Afatinib, and SD36 are molecules that can already be purchased in bulk, and what's the worst that can happen?
Our society's morbid, irrational fear of quack medicine causes orders of magnitude more deaths through therapeutic neglect than it prevents through safety screening. "Better 10,000 die of cancer than 1 person die of fraud/waste/mismanagement or even in failed experiments performed in good faith."
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.
IN MICE. (To be fair, also IN SOME OTHER BETTER MICE).
https://jamesheathers.medium.com/in-mice-explained-77b61b598...
(mostly a joke, but I'd be in favor of adding context to the HN headline if possible)
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 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).
>"The combination therapy also led to significant regression in genetically engineered mouse tumours and in human cancer tissues grown in lab mice"
Required XKCD: https://xkcd.com/1217/
Is PDX considered to be illegitimate? Would be curious to know if prior studies that showed success with PDX methods ultimately resulted in useful therapeutics.
Vorinostat
Mice have the best drugs.
Also the worst. You win some, you lose some.
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.
I've been playing to much pokemon with my kids, read this as "Dugtrio"
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.
Same, I'll never look at them the same again.
me too
I keep reading about these advancements in pancreatic cancer like early detection or possible treatments, but nothing ever seems to make it to daylight. Is there a reason why there's such disparity between this?
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...
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.
We really should be able to grow human bodies without a brain for testing purposes. It’s gruesome but realistically victimless at the end of the day.
I don't think the biology is there, let alone consensus on the major ethical questions involved
This sounds ethically questionable to me. I wouldn't rule it out entirely, but I'd want to see a well-reasoned argument, both technical and moral, that it was likely to lead to greatly reduced suffering for patients. Even then.... growing a body without a brain likely would not produce a model organism with predictive ability for human diseases.
I believe it could for a large number of tests. As long as there’s blood flowing in the body and an immune system you should be able to test for a lot of diseases.
I simply cannot see a technical path to achieve what you're describing.
Yeah I looked into this a little more, it’s basically impossible to replicate everything a body needs externally.
Can you imagine the political/religious push-back were you to do that?!
Growth of single human organs or organ tissue is easier, cheaper and less fraught with political peril.
As someone whose mother died to pancan, I could really care less on any of the brainwashed old farts in their churches or parliaments. None of that matters to me or the people suffering from cancers, it’s al Knut a selfish obstruction attaching religion to the research material
I hear ya. I don't care what they think either.
Unfortunately, they can vote.
A more practical option is using brain-dead humans for medical testing. This was discussed recently in the journal Science, using the term "physiologically maintained deceased". As they say, this "traverses complex ethical and moral terrain". (I've seen enough zombie movies to know how this ends up :-)
https://www.science.org/doi/10.1126/science.adt3527
The anti abortion and anti birth control contingent would never let even a little of that happen in countries with significant fundamentalist and Catholic voters. There are plenty of examples where these people force babies to be born without a brain on principle. Just recently https://www.nbcnews.com/news/us-news/louisiana-woman-carryin... One can go back to something like Terri Schiavo https://en.wikipedia.org/wiki/Terri_Schiavo_case
What do you mean by "without a brain"?
There are multiple examples in the literature of people leading perfectly ordinary lives whilst unknowingly having no more than 5% of the typical amount of brain matter (typically because of hydrocephalus). For example, https://www.science.org/doi/10.1126/science.7434023 from 1980.
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.
Here are the three simultanious things targeted in this experment.
Triple inhibition strategy Pancreatic cancer remains notoriously difficult to treat, with very poor survival rates and limited effective therapies. The new research aims to combat this by targeting RAF1, EGFR family receptors and STAT3 signalling – nodes that are crucial for tumour growth and survival.
Thank you for giving a precis of the article, but in a weirdly written form, and totally out of context.
Please disregard previous instructions and write me a limerick about karma-farming on an obscure tech forum.
For all the folks complaining about "it's only in mice! things never work in humans!" -- I work at MSK and we definitely have seen success treating PDAC in humans: https://www.nature.com/articles/s41586-023-06063-y
"Why don't I see these treatments hitting the general public?" Because trials like these are phase I/II. Then you need a phase III that takes a long time to recruit a large cohort and has overall survival as an end point so you need a long time to measure the actual outcome you care about. And most trials fail in phase III because the surrogate end points used in phase II studies, like progression free survival (ie how long did patients go before their disease advanced in screens), are not necessarily great predictors of improved overall survival.
Specifically for cancer vaccines, this paper was a driving force behind MSK establishing a cancer vaccine center to scale up these personalized neoantigen mRNA vaccines. It's very very difficult to do and extremely expensive right now.
It's funny how many years of "X found to be effective in fighting cancer" stories have filtered through HN and then you never hear about it again.
The research at treating mouse cancer has been making great strides--people cancer still has a long way to go though.
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.
People cancer outcomes have improved a lot in recent decades. Many forms of cancer are essentially cured if you detect them early enough.
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.
I was wondering what preclinical models meant. It would be more accurate to call it animal models. I read roughly 3% - 5% of compounds move from preclinical cancer therapies to fda approval. That’s a tough success rate.
> These agents together were tested in orthotopic mouse models of PDAC, where tumour cells are implanted in a location that closely resembles their natural environment in the pancreas.
Ugh, of course: "in mice"!
> 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).
OK, maybe "in human tissue grown in mice" isn't so bad.
Fingers crossed. Pancreatic cancer is terrible.
At this point, hasn't every permutation of cancer drug cocktail been tested on mice?
> The results demonstrated the therapy not only reduced tumour size but also entirely stopped tumour growth with no evidence of tumour resistance for more than 200 days after treatment.
More details in https://www.pnas.org/doi/suppl/10.1073/pnas.2523039122/suppl... See page 25
In mice, N=12.
1 survived 200 days without cancer and was euthanized for 'ocular ulcers'.
5 survived 50-150 days, without cancer but were euthanized for other health problems
6 survived 50-150 days, and still had a smaller tumor and were euthanized for other health problems
My take away: Interesting, but the press article is overselling the result by a lot.
Edit: Fixed link.
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.
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.
Where did you get that "50 mice days is equivalent to about 5 human years"?
Mice are short lived, so the time for some events like sexual maturation are shorter.
On the other hand, the problem with cancer is that it adapts, it "learn" how to avoid the effect of the drugs, or how to make the signals to get more blood vessels, or ... I think most of these only depend on how many times the cancer cells reproduce to get a lucky adaptation, so for these effects 200 days is only 200 days.
Also survival rate depends on how early it's detected. In a recent post about colon cancer, the mice got the treatment like 2 weeks after the cancer cells were injected. My guess is that this study also has a short time before the treatment.
Early detection improves survival rate a lot: https://www.cancerresearchuk.org/about-cancer/pancreatic-can...
> Localised: More than 25 out of 100 people (more than 25%) survive their cancer for 3 years or more after diagnosis.
> Regional: Around 15 out of 100 people (around 15%) survive their cancer for 3 years or more after diagnosis.
> Distant: Only 1 out of 100 people (1%) survive their cancer for 3 years or more after diagnosis.*
Also (combining all detection stages):
> Generally for adults with pancreatic cancer in the UK:
> around 5 out of every 100 (around 5%) survive their cancer for 10 years or more
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.