Researchers uncover on/off switch for breast cancer metastasis in mice(news.stanford.edu)
news.stanford.edu
Researchers uncover on/off switch for breast cancer metastasis in mice
https://news.stanford.edu/2023/12/20/breast-cancer-metastasis-off-switch-revealed/
88 comments
For those who are not familiar, the I-SPY 2 trial is quite remarkable. It is an adaptive trial design - in essence reinforcement learning with human experiments.[1]
For all the criticism FDA gets, they should also get credit for leaning into new approaches to testing drugs like adaptive trials. Part of why the US remains one of the most innovative countries.
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731787/
For all the criticism FDA gets, they should also get credit for leaning into new approaches to testing drugs like adaptive trials. Part of why the US remains one of the most innovative countries.
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731787/
It should be clarified that adaptive trial design was studied for several decades before being applied to games and called reinforcement learning by computer scientists. The multi-armed bandit papers all reference "Asymptotically efficient adaptive allocation rules" because they derived the optimal lower bound for regret [1].
[1] - https://doi.org/10.1016/0196-8858(85)90002-8
[1] - https://doi.org/10.1016/0196-8858(85)90002-8
I genuinely appreciate the link, but not so much the campaigning for the FDA or USA more broadly, which, my stance aside, feels like a trap leading to a fruitless discussion.
It seems to be a typo. The credits at the bottom state:
> Additional co-authors are from the University of California, San Francisco, and Arc.
> Additional co-authors are from the University of California, San Francisco, and Arc.
university of california, san francisco
university of san francsico
to someone not from the area this is a very easy mistake to make
university of san francsico
to someone not from the area this is a very easy mistake to make
As someone who watches NCAAF, this is just the tip of the iceberg of confusing US college names.
Miami University comes to mind
Yeah, but I think that Indiana University of Pennsylvania which is located in Indiana, Pennsylvania probably takes the cake for confusing.
You can literally send physical mail to Indiana University of Pennsylvania, Indiana, Pennsylvania.
You can literally send physical mail to Indiana University of Pennsylvania, Indiana, Pennsylvania.
I always get super confused with the Indiana school acronyms IU, IUP, etc
IIRC they recruited and actually signed a kid (Football maybe?) who later decommitted once he realized it wasn't in Florida. I'm not sure that's entirely accurate because I don't think you get to signing without an on-campus visit but maybe that isn't always true.
Wasn’t that a plot point in an episode of the office?
Maybe -- I don't watch that show, too close to real life.
I tried to find any reporting on this, and while apparently it's happened to a few students (they applied, got accepted, then discovered the school is in rural Ohio and not Florida) but not the specific case of it happening with an athlete (seems really unlikely).
I tried to find any reporting on this, and while apparently it's happened to a few students (they applied, got accepted, then discovered the school is in rural Ohio and not Florida) but not the specific case of it happening with an athlete (seems really unlikely).
[deleted]
My wife was telling me about a foreign student who got a full ride scholarship to Miami university and was so excited to move to Florida… only to realize it was in Ohio
Miami of Ohio is a pretty good school, and I think Ohio still has academic freedom and other standard civil rights.
As much as I dislike many aspects of living in most of both Ohios (NE (which, to me, should be Cleveland/Akron/Canton/Kent/Youngstown/PGH/Buffalo),vs the rest of the state), I am super impressed with the leniency (latitude?) tolerated in that place re: "academic freedoms," while not going [dipshit] (ok, I cannot describe or conceive of a more comprehensive term, my bad, my apologies).
I do think it’s a little lacking in palm trees, though.
Amherst College vs. University of Massachusetts Amherst
Washington University in St. Louis
Washington University in St. Louis
Pennsylvania has both Indiana University of Pennsylvania (located in the town of Indiana, PA) and California University of Pennsylvania (in California, PA). Both were formally teachers colleges named after their respective towns.
It's pretty common to have very slight name differences for universities.
There's also San Francisco State University.
[deleted]
Based from another study:
>> Patients with high ENPP1 levels had low response to pembrolizumab and high chance of metastases. Those with low ENPP1 levels had a high response to pembrolizumab and no metastases. ENPP1 predicted both response to immunotherapy and likelihood of relapse.
Keytruda/PD-1 blocker:
https://en.wikipedia.org/wiki/Pembrolizumab
ENPP1 blockers already exist:
https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.e1...
>> Patients with high ENPP1 levels had low response to pembrolizumab and high chance of metastases. Those with low ENPP1 levels had a high response to pembrolizumab and no metastases. ENPP1 predicted both response to immunotherapy and likelihood of relapse.
Keytruda/PD-1 blocker:
https://en.wikipedia.org/wiki/Pembrolizumab
ENPP1 blockers already exist:
https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.e1...
At least one ENPP1 blocker appears to be in clinical trials already: https://clinicaltrials.gov/study/NCT05270213?term=RBS2418&ra.... It lists "advanced cancers" as being eligible.
I'm most interested in head and neck cancers, and pembrolizumab (Keytruda) is only effective in 20 - 30% of patients; see e.g. https://ascopubs.org/doi/full/10.1200/JCO.21.02198: "In the phase Ib KEYNOTE-012 study of pembrolizumab monotherapy in R/M HNSCC (N = 192), objective response rate (ORR) was higher in patients with PD-L1 CPS ≥ 1 than CPS < 1 (21% v 6%; one-sided P = .023)."
A lot of oncologists I've talked to also think PD-L1 expression is overrated as a marker of pembro effectiveness; obviously there's something going on, with higher PD-L1 expression being net better in terms of pembro utility overall, but the data are noisy and lots of exceptions abound. I'm also not sure how reliable PD-L1 expression tests are. My tumor was tested once by a well-known-in-the-field company called CARIS, and it showed a 20% Combined Positive Score (CPS). Another test done by the Mayo Clinic showed a 5% score. Who's right? Who knows. No one I've talked to. The attitude seems to be that no one is convinced the PD-L1 tests are highly accurate, and that once the CPS is above 1%, pembro's effectiveness is a crapshoot anyway. I got five doses of pembro and failed it, utterly.
I'm most interested in head and neck cancers, and pembrolizumab (Keytruda) is only effective in 20 - 30% of patients; see e.g. https://ascopubs.org/doi/full/10.1200/JCO.21.02198: "In the phase Ib KEYNOTE-012 study of pembrolizumab monotherapy in R/M HNSCC (N = 192), objective response rate (ORR) was higher in patients with PD-L1 CPS ≥ 1 than CPS < 1 (21% v 6%; one-sided P = .023)."
A lot of oncologists I've talked to also think PD-L1 expression is overrated as a marker of pembro effectiveness; obviously there's something going on, with higher PD-L1 expression being net better in terms of pembro utility overall, but the data are noisy and lots of exceptions abound. I'm also not sure how reliable PD-L1 expression tests are. My tumor was tested once by a well-known-in-the-field company called CARIS, and it showed a 20% Combined Positive Score (CPS). Another test done by the Mayo Clinic showed a 5% score. Who's right? Who knows. No one I've talked to. The attitude seems to be that no one is convinced the PD-L1 tests are highly accurate, and that once the CPS is above 1%, pembro's effectiveness is a crapshoot anyway. I got five doses of pembro and failed it, utterly.
This is the latest press release linked to the trial you have mentioned and their presentation at ESMO: https://www.riboscience.com/esmo-2023
From the article:
> This means that clinicians can use ENPP1 levels to better determine appropriate treatment for breast cancer patients. It also means that drugs that destroy the ENPP1 dam could make existing therapies more effective – and several ENPP1 inhibitors are already in clinical development.
To summarize --
They found a correlation between a protein (ENPP1) and breast cancer metastasis that they feel is a very strong signaler for pembrolizumab immunotherapy resistance. This would be helpful information to help get to the right dosage of medicine faster (or skip a class of drugs entirely), which might save weeks or months of taking a drug that effectively is neutralized by the resistance.
Additionally, hopefully new medicine will (after more research) go after this protein and see if attacking it allows the immune system to better resist cancer itself.
It's also worth noting that two of the researchers involved in this work own a company to try to utilize patents around this work.
They found a correlation between a protein (ENPP1) and breast cancer metastasis that they feel is a very strong signaler for pembrolizumab immunotherapy resistance. This would be helpful information to help get to the right dosage of medicine faster (or skip a class of drugs entirely), which might save weeks or months of taking a drug that effectively is neutralized by the resistance.
Additionally, hopefully new medicine will (after more research) go after this protein and see if attacking it allows the immune system to better resist cancer itself.
It's also worth noting that two of the researchers involved in this work own a company to try to utilize patents around this work.
> It's also worth noting that two of the researchers involved in this work own a company to try to utilize patents around this work.
Is the implication that there is bias, or are you implying there is reason to be hopeful that it makes it to market quickly?
Is the implication that there is bias, or are you implying there is reason to be hopeful that it makes it to market quickly?
Why not both?
I was stating a fact presented at the end of the article. The interpretation of that fact is up to the reader.
You said it was worth noting, which is more than just stating a fact.
Facts can be seen as important without implying any specific interpretation of them.
I consider the speed of light being 299,792 km per second as worth remembering even if I have no specific use in mind.
I consider the speed of light being 299,792 km per second as worth remembering even if I have no specific use in mind.
>Facts can be seen as important without implying any specific interpretation of them.
This isn't even true. In the example you gave, you clearly remember the speed of light because you think it may be useful someday.
When someone believes a fact is important or "worth noting", they used some reasoning to arrive at that conclusion. Whether or not that reasoning is flimsy is another matter.
This isn't even true. In the example you gave, you clearly remember the speed of light because you think it may be useful someday.
When someone believes a fact is important or "worth noting", they used some reasoning to arrive at that conclusion. Whether or not that reasoning is flimsy is another matter.
As an uninvolved bystander I can agree that the reason it is noteworthy can be separated from the fact of whether or not it is.
In this case I think there are a few reasons of note which were already alluded to, but I don't personally think it need call any questions about the validity of the experiments and the other reasons being around the potential future value of associated company, any opinions of which are for the individual and their financial advisors to consider.
I wasn't aware of the fact there was already a company created for it but it does say something about the confidence these researchers have placed in the results, even if that may not be noteworthy, per se, regarding the results.
In this case I think there are a few reasons of note which were already alluded to, but I don't personally think it need call any questions about the validity of the experiments and the other reasons being around the potential future value of associated company, any opinions of which are for the individual and their financial advisors to consider.
I wasn't aware of the fact there was already a company created for it but it does say something about the confidence these researchers have placed in the results, even if that may not be noteworthy, per se, regarding the results.
Right. And additionally, it provides at least a trace of possibility that there's some sort of a vested interest in the outcome of the research, although it shouldn't necessarily be held against them that they believe in their work and want to see applications from it.
>This isn't even true
Of course it is. This is one of those 'only on HN' moments. You absolutely can be cognizant that a fact may give rise to any number of competing interpretations, and you can understand those interpretations to be significant if true, while not endorsing them.
>When someone believes a fact is important or "worth noting", they used some reasoning to arrive at that conclusion
Again, you can understand that a fact gives rise to certain interpretations without endorsing those interpretations, and this could nevertheless be enough of a reason to merit sharing the fact.
Of course it is. This is one of those 'only on HN' moments. You absolutely can be cognizant that a fact may give rise to any number of competing interpretations, and you can understand those interpretations to be significant if true, while not endorsing them.
>When someone believes a fact is important or "worth noting", they used some reasoning to arrive at that conclusion
Again, you can understand that a fact gives rise to certain interpretations without endorsing those interpretations, and this could nevertheless be enough of a reason to merit sharing the fact.
So I think there may be some equivocation of the term "interpretation" in this thread--whether intentional or not--but I understand the point being made here.
My point is that when one determines that a fact is notable, there is an underlying reason for making that determination, whether it involves several "competing interpretations" or not. It is perfectly reasonable to ask for that underlying reason so I can assess the validity of the statement. If someone refuses to give it, as we've seen here, then its reasonable to dismiss their assertion. I'm not responsible for justifying their own argument for them.
As for the 'only on HN' remark, I think that was unnecessary. At any rate, this will be my last comment on the subject.
My point is that when one determines that a fact is notable, there is an underlying reason for making that determination, whether it involves several "competing interpretations" or not. It is perfectly reasonable to ask for that underlying reason so I can assess the validity of the statement. If someone refuses to give it, as we've seen here, then its reasonable to dismiss their assertion. I'm not responsible for justifying their own argument for them.
As for the 'only on HN' remark, I think that was unnecessary. At any rate, this will be my last comment on the subject.
I don’t think knowing c is going to particularly impact most people.
On one level it’s essentially random trivia you can easily lookup, but on another level it’s fundamental in a way that few things are. Individual mutations from random events wildly shaped human history making most facts people remember essentially happenstance. However, c is more closely tied to the underlying aspects of reality.
On one level it’s essentially random trivia you can easily lookup, but on another level it’s fundamental in a way that few things are. Individual mutations from random events wildly shaped human history making most facts people remember essentially happenstance. However, c is more closely tied to the underlying aspects of reality.
Oh great, you’re piling onto the obtuse pile
I let other people chime in, but to provide an answer myself:
I felt that it was worth noting because, depending on the viewpoint of the reader, that information could be seen as a positive or a negative, and could have an impact on their viewpoint.
1. The existence of the company suggests that there might be a meaningful or profitable future from what has already been learned.. commercialization of this information might be more readily possible.
2. Someone who's cynical might question the validity of the research and/or the motives of people involved.
I certainly have my own opinion, but I also have not deeply researched this subject, or the researchers involved. I was curious to get some high level information on this topic so I read the article. I felt it was hard to skim through so, after reading it, I wanted to provide the high level summary as I understood it for others here.
I felt that it was worth noting because, depending on the viewpoint of the reader, that information could be seen as a positive or a negative, and could have an impact on their viewpoint.
1. The existence of the company suggests that there might be a meaningful or profitable future from what has already been learned.. commercialization of this information might be more readily possible.
2. Someone who's cynical might question the validity of the research and/or the motives of people involved.
I certainly have my own opinion, but I also have not deeply researched this subject, or the researchers involved. I was curious to get some high level information on this topic so I read the article. I felt it was hard to skim through so, after reading it, I wanted to provide the high level summary as I understood it for others here.
> which is more than just stating a fact
Didn't seem like it to me (personally speaking).
Didn't seem like it to me (personally speaking).
[deleted]
Side issue:
Some people must have industrial scale production of mice to be used in
experiments.
How far are we from being able to model an entire mouse?
The last I heard was that someone could map all of a small worm, so a mouse is magnitudes more complicated than that. But compute power increases.
How far are we from being able to model an entire mouse?
The last I heard was that someone could map all of a small worm, so a mouse is magnitudes more complicated than that. But compute power increases.
If you're thinking we could test pharmaceuticals in a simulation I think thats a long way off. The worm model is not sufficient to model chemical reactions/lifecycles.
Link to the research article: https://www.pnas.org/doi/10.1073/pnas.2313693120
Also note that this isn't exactly news, it's been an ongoing research topic for a few years. Here is a research article from 2022: https://aacrjournals.org/cancerdiscovery/article/12/5/1356/6...
Also note that this isn't exactly news, it's been an ongoing research topic for a few years. Here is a research article from 2022: https://aacrjournals.org/cancerdiscovery/article/12/5/1356/6...
I'm going to go with "off". Thanks.
...in mice
Inmiced above. Thanks!
'Inmiced' lol! Thanks for keeping the titles accurate, so important especially with cancer research results. Happy holidays and I really enjoyed reading the quote on your profile https://news.ycombinator.com/user?id=dang
It's the least of your accomplishments but thanks for being such a great HN contributor over the years!
idk why I see so many comments like this on the medical threads of HN lately. Laboratory mice are close enough to us to do testing on and have provided reliable results throughout their use. A basic Wikipedia search shows references for all of those claims and more: https://en.wikipedia.org/wiki/Laboratory_mouse
That's because mouse models suck for many diseases. Cancer very much included, for two reasons:
1. Mice _love_ to get cancer naturally. If you have 100 mice, it's quite likely that around 20 of them will die within one year of cancer. This makes it difficult to extract useful signals. BTW, that's why if you see a study that a "chemical X results in cancer in mice", you should take that with a grain of salt.
2. Mice are small, so tumors are necessarily small too, with several orders of magnitude fewer cells than typical human tumors. So many drugs can just cure mice of cancer entirely, by killing cancerous cells too quickly to allow them to evolve resistance.
1. Mice _love_ to get cancer naturally. If you have 100 mice, it's quite likely that around 20 of them will die within one year of cancer. This makes it difficult to extract useful signals. BTW, that's why if you see a study that a "chemical X results in cancer in mice", you should take that with a grain of salt.
2. Mice are small, so tumors are necessarily small too, with several orders of magnitude fewer cells than typical human tumors. So many drugs can just cure mice of cancer entirely, by killing cancerous cells too quickly to allow them to evolve resistance.
> If you have 100 mice, it's quite likely that around 20 of them will die within one year of cancer.
If you have 100 people, about 40 of them will be diagnosed with cancer over their lifetime (39/100 females and 41/100 males). Note "diagnosed with" is very different from "die" and "over lifetime" is not the same as "within one year", but the probability of people getting cancer naturally is high as well.
If you have 100 people, about 40 of them will be diagnosed with cancer over their lifetime (39/100 females and 41/100 males). Note "diagnosed with" is very different from "die" and "over lifetime" is not the same as "within one year", but the probability of people getting cancer naturally is high as well.
Sure. But in general, cancer risk should scale with the number of cell divisions, which is fairly low for mice. And other small, short-lived mammals like weasels are not as susceptible to cancer. Naked mole rats (also rodents!) are downright cancer-proof.
This all means that mice don't have a good natural cancer-suppression machinery, and this in turn makes them somewhat awkward to use to discover new treatments.
This all means that mice don't have a good natural cancer-suppression machinery, and this in turn makes them somewhat awkward to use to discover new treatments.
I'm not sure it follows that high incidences of cancer means that it's unhelpful to use them for research to understand the mechanisms of cancer. And I'm not sure that either of your observations one or two are pertinent in this case as it applies to the on/off protein switch, as it is not about guaging the statistical frequency of cancers or about killing cancer cells.
Murine models are not unhelpful, just very tricky. Quite a few experimental data turned out to be incorrect because experiments were poorly conducted.
It’s a common trope in the field that we’ve already cured cancer in mice. They are similar enough to be a useful model for study. However, they are still quite different to the point where you never quite know how treatments will react… especially in cancer.
The biggest issue is that the mice we use for research typically have no or a highly depleted immune system. One of the biggest breakthroughs in the cancer field (IMO) is the development of humanized mice. These are mice that have had their immune system genes replaced with the human versions of these genes.
This is incredibly important for work like this where you’re studying cancer cell-immune cell interactions.
The biggest issue is that the mice we use for research typically have no or a highly depleted immune system. One of the biggest breakthroughs in the cancer field (IMO) is the development of humanized mice. These are mice that have had their immune system genes replaced with the human versions of these genes.
This is incredibly important for work like this where you’re studying cancer cell-immune cell interactions.
Have we actually cured cancer in mice?
What I'm really curious about is how many of these experiments and trials didn't work in mice but would work in humans.
it's plausible that some would: chocolate and coffee are toxic in mice but not humans.
unfortunately, we need mice models for safety for now.
hopefully, computational models and personalized medicine will change this in the future.
unfortunately, we need mice models for safety for now.
hopefully, computational models and personalized medicine will change this in the future.
One would hope that in vitro studies with human cell lines would identify those possibilities.
If we just experimented on and killed lots of humans we would be both further ahead and behind.
"In mice" is really hard to achieve.
You can order mice with specific cancer mutations: https://www.jax.org/strain/017835
ugh123(1)
Well then, I expect a therapy real soon now.
This is not an informed comment. New immunotherapies for cancers are real. It's just that they are very expensive. But it's not right to claim they are very far or imaginative.
But are there therapies for mice?
It'll be here any decade now.
While this particular treatment may go nowhere, cancer treatment has come a LONG way recently. Lots of theoretical “in mice” treatments I recall reading about 5-10 years ago are now actively being deployed clinically. By some measures we’ve had more than a 25% drop in age+health standardised cancer mortality over the last decade.
It’s easy to feel cynical when so many things seem like they get stuck for ages in trials and never make it to an actual treatment, but modern medicine is truly amazing. I have family who are sadly no longer with us, but who likely would have been cured completely if they had developed the same cancer today.
It’s easy to feel cynical when so many things seem like they get stuck for ages in trials and never make it to an actual treatment, but modern medicine is truly amazing. I have family who are sadly no longer with us, but who likely would have been cured completely if they had developed the same cancer today.
Looking at this graph of breast cancer mortality, the drop has been significant, steady, and showing no sign of leveling off. https://seer.cancer.gov/statistics-network/explorer/applicat...
A caveat for the rest of the world:
> our finding showed a significant increase in breast cancer mortality rate in the world during the past 25 years ... Statistical analysis showed a significant increase for breast cancer mortality rate in all super regions, except for High-income super region. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745227/
and for women under 40:
> Female breast cancer mortality rates have stopped declining in women younger than 40 years, ending a trend that existed from 1987 to 2010. Conversely, mortality rates have continued to decline in women aged 40–79 years. https://pubs.rsna.org/doi/full/10.1148/radiol.2021203476
> our finding showed a significant increase in breast cancer mortality rate in the world during the past 25 years ... Statistical analysis showed a significant increase for breast cancer mortality rate in all super regions, except for High-income super region. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745227/
and for women under 40:
> Female breast cancer mortality rates have stopped declining in women younger than 40 years, ending a trend that existed from 1987 to 2010. Conversely, mortality rates have continued to decline in women aged 40–79 years. https://pubs.rsna.org/doi/full/10.1148/radiol.2021203476
The conclusion I'd come to from those quotes is all these "amazing breakthroughs" might be in use sure, but not to the scale (and price) a layman would expect in order for it to be a properly viable solution for many sufferers.
My wife died from metastatic breast cancer, in 2011. Even then there were advancements. As much as I miss her and envy those who may get advances now, or a “cure”, I am excited to see progress. Maybe she’ll be one of the “last to pass” from this disease.
My sincere sympathies. I lost my kid sister to breast cancer about 6 years ago, much too young. I'm glad the fight continues.
I agree that there's been some progress in therapies and robot-assisted surgery, but the reason for the improvement in mortality seems more to do with early detection. Cancer deaths overall are also improving due to fewer smokers, but that should be accounted for by "health standardized" measurements.
I think this paper explains it: https://pubmed.ncbi.nlm.nih.gov/27175568/ "the major factors that accounted for these favorable trends were progress in tobacco control and improvements in early detection and treatment"
I feel like the treatment progress for most metastatic solid cancers have not significantly improved. A significant improvement wouldn't be just improving overall survival by a year or so. What seems possible to achieve (someday soon perhaps) is making cancer either a manageable condition, like HIV now is, or curable.
I think this paper explains it: https://pubmed.ncbi.nlm.nih.gov/27175568/ "the major factors that accounted for these favorable trends were progress in tobacco control and improvements in early detection and treatment"
I feel like the treatment progress for most metastatic solid cancers have not significantly improved. A significant improvement wouldn't be just improving overall survival by a year or so. What seems possible to achieve (someday soon perhaps) is making cancer either a manageable condition, like HIV now is, or curable.
ENPP1 is a known target that has been under active investigation for many years. This press release would like for you to think this Stanford lab discovered it, but it’s been known about for a while. We are just now starting to understand more about how it works in cancer (this work is a part of that). But treatments are already being worked on using this pathway.
I'm afraid I don't share your optimistic view. This being the US, I expect a bidding war on whether the switch should be set to "ON" or "OFF".
This is the dumbest conspiracy ever, stop propagating it.
These famous researchers are actually at UCSF, not University of San Francisco. UCSF is really a leader in breast cancer the world over, far more influential than Stanford's much smaller amount of faculty on the topic. So it's a bit weird to see such a basic mistake.