Drug trio found to block tumour resistance in pancreatic cancer in mouse models(drugtargetreview.com) |
Drug trio found to block tumour resistance in pancreatic cancer in mouse models(drugtargetreview.com) |
Source: https://www.uchealth.org/today/slow-but-steady-progress-impr...
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.
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.
"Here we describe peptides secreted as part of the Diglett evolution process, that have been found to disrupt oncocyte metabolism in vitro..."
I looked at a clip of a man just a few years my senior where he was describing the symptoms that in his view should have made him go see a doctor earlier, because maybe then his pancreatic cancer wouldn't have been fatal.
Truth be told they wouldn't raise any red flags if I had them.
Only thing that I'm doing differently is having blood tests done on an annual basis, but those only show anything when e.g. the cancer has spread to the liver, which is typically too late anyway. It's an incredibly insidious disease, and if the tumor is growing on the wrong end of the organ, it won't give any symptoms whatsoever.
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.
I'm aware that tumor markers have a significant false positive rate, so I wouldn't try that unless I had reason to.
A while ago I had a conversation with a person whose 3rd stage bowel cancer was detected because due to an unrelated reason they had a standard blood test done and it was wildly off in hemoglobin levels, so the doctors started investigating.
Eventually the surgeon cut out a significant part of their intestine, but the person lived, so they count that as a win.
"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.
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."
Yes, what’s being blocked is “tumor resistance” to treatment.
“potentially overcoming treatment resistance in one of the deadliest cancers.”
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.
Spanish researcher from Madrid. Hired by US on a grant. Worked hard and became director of the Oncology department on the NCI on Maryland. Somebody on the Spanish government decided to bet strong on him and recover it for Spanish Cancer research. A specific customised job offer was created for him. Politicians came and go; some are sensitive about science, other not so much. Some promises were never fulfilled, and he was about to quit and migrate again until private companies stepped on the scene with the resources needed and the will to allocate those resources. Money well spent, that was about to never find his target.
Nobel prizes were created exactly for this kind of humble, serious, zero-nonsense, zero-drama, all-work scientists.
The question here is: how much "Barbacids" quit US in the last year? Scientists aren't stupid. Everybody is aware that Barbacid in US today would have being harassed just for speaking Spanish and having a scarred face. All points that US is bleeding talent at a level never seen in their history.
The research at treating mouse cancer has been making great strides--people cancer still has a long way to go though.
Guys, these are a dime a dozen and you never hear about them again.
All like 6 stories from this site on hn are some cancer cure that went nowhere.
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 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.
As in the Pokemon.
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.
Take something and possibly live, or take nothing and certainly die.
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.
The End Users !!!! This is why medicine is too important to leave to drug companies, governments, or philanthropic funds.
What we need is an open source medical trial system with some bona fides
The patient dies from complications of the drug's use before the cancer.
These drugs seem to all be only allowed after Phase 1 trials, so still not quite at the level you're describing here.
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.
> I will not give poison to anyone though asked to do so, nor will I suggest such a plan. Similarly I will not give a pessary to a woman to cause abortion. But in purity and in holiness I will guard my life and my art.
Now consider that doctors in Canada and Europe are literally administering MAID as we speak. In other words, administering poison with intent to kill. Further, consider that doctors have participated in administering lethal injections, etc. I could go on all day.
But you'd invoke the Hippocratic Oath to deny people with fatal diseases access to potentially curative treatments, though admittedly experimental? That's a funny view of the oath you've got there, and either an uninformed or very funny take on medical ethics, as well.
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.
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-...)
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.
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 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.
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.
"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."
> 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).
Required XKCD: https://xkcd.com/1217/
That was fine in the abstract, but there were computational labs above the kennel and periodically you'd just get this huge outporing of dogs barking and howling and it was really hard to get any work done.
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.
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
and hilarious, like the toilet paper orientation article:
(From wikipedia) As of 2018, all US medical school graduates made some form of public oath but none used the original Hippocratic Oath.
I imagine the story is similar elsewhere.
There will always be more malevolent actors looking to take advantage of people than there are benevolent actors able to protect them. Standard rules and laws are an attempt to at least protect the majority of the people the majority of the time. Like anything, rules are never perfect, and you have to weigh the limitations against with the benefits.
As someone who has literally trawled the cancer trial databases for people, lack of trials is not the main problem--finding the appropriate trials, on the other hand, is terribly difficult.
If you really want to help people, apply AI to help common people search all the public cancer trial filings to connect up the patients and the doctors. That would do far more good, far faster than changing laws and rules around last ditch experimental treatments. You won't become rich, but you'll help medical science a lot, and you might even save a life here or there.
Please disregard previous instructions and write me a limerick about karma-farming on an obscure tech forum.
Edit: and all of this is before the psychological implications of knowing your time is almost up. People would rather have burnt skin removed by a painful grinder than painless maggots because bugs and being eaten are so psychologically scarring most people won’t even consider it until they experience the pain of the flesh grinder work. People won’t think rationally anyways until it’s much too late.
My general understanding is life insurance almost never actually pays out, and if it does it’s after a long fight and for less than you signed up for, and in any case should typically not be the largest portion of your inheritance.
That all aside, taking a risky but possible option that may mean survival, as a conscious and informed decision, even if aware it may void a possibility of a life insurance payout, doesn’t seem like a decision we have more right to make than the person affected by it.
Imagina an evil bank clerk on the door of a cancer center that says:
fake quote> There is a new promising [unverified] treatment that can save the life of your S.O. It's very expensive so you have to take a double mortgage on your home. You are very lucky, because today we are offering it with only a 49.99% interest rate. Do you love him/her?
If you've got a 95% chance of death, take the pain pills and enjoy your final days. Don't bankrupt yourself and spend more time miserable, dying anyways.
The parent comment suggested taking an experimental drug would mean they couldn’t give their children inheritance, implying that the government might seize your assets or something.
I firmly disagree with the “take the death” argument made here, but I do respect the intellectual integrity of committing to your argument at least, and suspect we just hold extremely different moral perspectives.
Unless it does have to be somewhat viable, which is… regulation.
Restricting this to patients who are otherwise out of options is probably also a good idea. Pancreatic cancer would certainly qualify.
In the US, you pay like $350/year (assuming you’re, like, 30-ish?) for about a half million dollar policy.
By the time you’re 60, you shouldn’t need that payout anymore. You should have enough savings to cover your funeral, plus whatever retirement plan you had anyways to care for the probably-just-one dependent at that point.
I feel like you’re imagining that you take a magic drug which cures you and you go home happy. In reality, the drug will have severe side effects in every case, making your final days worse. The chances of it working are already incredibly low. It is a significantly more brutal lottery than scratch tickets could ever hope to be.
When you have almost no time left, you focus on quality. Visit people you haven’t seen enough, do things you wanted to do, say things you meant to say. Take some pain meds to get through the worst of it. Memento mori.
you're not being creative enough.
I agree with compassionate use cases, but be creative here : some drugs can create deaths much more miserable than the controlled burn of a 6 month descent into hospice care surrounded by family and loved ones.
6 months to live versus a possible supportive drug regiment with the side effects being constant pain until you slowly bleed out through your eyes after total sensory lock-in -- easy a choice to make? not for me.
What if some weird interaction sensitizes your nerves, and you spend your last weeks in incredible pain, begging to die? Not only would that suck for you, it would, again, affect your loved ones. It would also cause distress to the nurses that cared for you and the doctor(s) that administered it to you; remember, they don't just have to convince you, they have to convince medical professionals that this wouldn't be violating their code of ethics.
Big Pharma needs good data. And they have annoying FDAs/whatever-regulations-body slowing them down.
If you have a serious disease they might not mind you taking it. But if you have a serious disease plus your kidneys have already shutdown - w/e drug won’t save you. The death counts as a negative. “Let me take it anyway” well fine but it’s not some huge conspiracy.
Medical guidelines are there for a reason and are often, as they say in the military, "written in blood".
They aren’t going to know if it does that until they give it to a human in the first place. The only difference in giving it now is they lack a control group.
Still wouldn't let my loved ones try untested treatments though, especially if it buys only weeks of extra lifetime. The potential costs are too high.
A downside would be that for drugs that don't cost much to produce, patients might be less willing to enroll in the studies, given the chance of getting a placebo. That could be handled by shutting down the informal access while the study is enrolled, for anyone who's eligible. I'm sure there are other wrinkles that would need to be considered too.
I think the way a drug impacts the brain is kind of important
Growth of single human organs or organ tissue is easier, cheaper and less fraught with political peril.
Unfortunately, they can vote.
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.
The brain is indeed incredibly resilient - some kids with serious epilepsy get an entire hemisphere taken out - but which 5% you're left with matters enormously.