It really is remarkable how far cancer treatment has progressed, even in the last few years. I'm one of the unfortunate people who, through a close family encounter with cancer, knows more about this stuff than anyone should have to. The oncologist told my relative that if they had presented with this particular cancer just a decade ago, his recommendation would have been to start hospice care.
However, in recent years, a very effective checkpoint inhibitor immunotherapy has been developed for the cancer in question. ~2x the success rates of traditional chemo, greatly increased overall survival statistics, and with massively reduced side effects. The results speak for themselves: this drug has granted my relative years of extra life in the worst case, and a path to a deep, long remission in the best case.
I think that as the technology develops, by 2040 we'll be looking back at the present state of the art with the same incredulity that we currently have for, like, bloodletting with leeches in the Middle Ages. I think they've been saying this for a long time now, but it's truer than ever that a real cure for cancer is right around the corner.
As a person who currently has stage IV NSCLC, I can add some context to this:
YMMV.
One thing to remember is that "Lung Cancer" is not just one thing. There are mutations of different genes, there are overexpressions of different genes. Each one has its own new medicines. Also, some peoples' cancers are more aggressive than others, and while for many they can find the right drug, for some nothing works.
Keytruda works wonders for some. It did not for me. I had 4 treatments of the CPP (carboplatin, pemetrexed, and pembrolizumab) triad, which had some success. They then put you on "maintenance," which is the PP without the carboplatin (which is the really old school platinum-based chemo). Maintenance did nothing for me. My main tumor grew more than 50% in 2 months.
Last summer I started 9 months on a chemo/immuno that was geared towards my specific mutation. It actually did wonders. It resulted in a 98% shrinkage of my main tumor before I ended up with pneumonitis from it and had to stop. But I've been able to be off treatment for the entire summer. I know there are others who have tried this, and it didn't work.
So yeah, I'm really, really glad your relative was able to get some relief from the Keytruda. But I also wish it were the wonder cure for everyone that it was for them.
I was diagnosed with stage III NSCLC February '21. Radiation, chemo, and a bilobectomy. I had the ALK+ morphology which meant I wasn't a candidate for immunotherapy but I've been on alectinib since my surgery in June '21 with no signs of recurrence so far.
The process is grueling in hindsight, but I'm glad to hear you're getting results. At first I would have said "if this is going to kill me, make it sooner rather than later" to avoid a drawn-out painful experience, but I'm starting to appreciate what the buying time really means. It's hard with all that's going on but get your head straight and make sure you enjoy it.
Thanks for sharing your story and treatment details. I should add that my relative's cancer has no particularly interesting mutations, but does have a high PD-L1 expression, which from what I can tell is the reason Keytruda was more likely to work for their situation.
> that was geared towards my specific mutation
This is actually one of the things that gives me hope for the future: genetic testing on a tissue sample of the patient's cancer is standard, and for many of the specific oncogenes that we know about, there exist therapies targeted to those specific mutations: https://www.cancer.org/cancer/lung-cancer/treating-non-small...
One thing I've learned is that even in the face of good news, cancer is a horrible time, and I wouldn't wish it on anyone. But I'm likewise glad to hear about your results from the latest treatment, and hope things stay as positive as they can for you.
I am hopeful we can move metastatic cancer (which is the true evil of cancer) to a controlled chronic condition.
BTW-- our oncology doctor believes in synergies between chemo and pembro, but I sometimes wonder if it's truly the chemo. Also, Pembro is not without its side-effects.
> in recent years, a very effective checkpoint inhibitor immunotherapy has been developed for the cancer in question. ~2x the success rates of traditional chemo
> I think they've been saying this for a long time now, but it's truer than ever that a real cure for cancer is right around the corner.
I think thats quite a leap. For prostate cancer( most common cancer among men), top line therapies are still androgen blockage that was discover 70 yrs ago, chemo and radiation. Keytruda failed to deliver any significant survival benefits[1].
Yes we've gotten better at slash, burn , poison methods. Radiation is more trageted and sophisticated. Diagnostics are more precise. Chemo drugs have better safety profiles.
But these are all marginal improvements. None of which indicate anything that we are close to a cure.
Only hope we still have is to catch it earlier and go ham on it. Most of the slash,burn, poison methods are being FDA approved for earlier use.
The other two things(one of which you've mentioned) are immune checkpoint blockade if you have MSI-hi/dMMR or PARP inhibition if you have BRCA2+. Even if you are lucky to have these mutations these drugs are a hit or miss[1].
I agree that my original comment is very optimistic--for what it's worth, Keytruda has thus far been very effective in the case I'm talking about, so I have some bias here. I concede that even in my "double the effectiveness" example, we're talking about doubling something like a 20% 5-year OS.
By "around the corner" I'm really talking about, like, 20-30 years out, which I think is fairly soon in terms of cancer treatment progress. You're right that it reads like a leap in the context of my comment.
Not to be too pessimistic, but 600,000 people died of cancer in 2019, so 20-30 years is hardly "round the corner" when you extrapolate to the, let's say conservatively, 10 million families in the US losing loved ones in that time period.
The history of cancer (The Emperor of All Maladies is a good book covering the history) is full of promising adjuvants, drugs, protocols that fail to generalize well. There are a lot of reasons for this. With drugs, one is that Phase 3 clinical trials often have patients who are selected on the basis of them being likely to be among the best responders. But once the drug is approved and made available to all patients within a given indication – a fundamentally different population – an overwhelming positive response may be significantly more modest. In many cases, this has to do with a patient's tolerance of the side effects or the interaction of the drug with known or underlying comorbidities.
While I'm encouraged by the research in this article and could see the drug being part of a combination protocol, I'm hesitant that it will be "universal". And the mechanism, candidly, is downright scary – if I were running a Phase 3 for this (seems the trial cited was a Phase 2 demonstrating baseline safety in humans), I would want a very detailed articulation of how the technology ensures with a high margin of safety that the drug delivery is targeted to the tumor and no other tissues. The permeability of blood vessels in tumors would not be sufficient (and also does not seem "universal").
On a more personal note, I'm actually a computational biologist and have done quite a bit of work in cancer research (masters thesis, portion of my dissertation). My Mother was also diagnosed with a highly aggressive cancer of unknown primary (CUP) origin in her lung late last year (estimated stage IIIb for NSCLC, stage 4 for CUP/melanoma). Its location and heart involvement made it inoperable. Turned out is was a melanoma, which to be frank I quickly recognized down to the subtype upon reviewing the pathology reports. The lung oncologists were much more conservative; given the location, they weren't especially well-versed in melanoma, and presumed it was an adenocarcinoma with a rare presentation despite the staining for carcinomas being negative across the board. Luckily, we managed to convince them to split the difference on the standard of care – CarboTaxol (carboplatin + taxol) combination and immunotherapy (nivolumab and ipilimumab), all at once. The immunotherapy surely saved her life; unlike with carcinomas, chemo is roughly 5% effective (as in, any response whatsoever) for melanomas. About 70% of melanoma diagnoses respond to combination immunotherapy with about 15% going into full remission (memory is shaky on that last number, may be slightly higher). With >95 PDL-1 expression, she was one of the lucky ones – she had a full response on both imaging and pathological endpoints. That also made her tumor (or what was left of it) operable. She's two lobes and a chunk of heart lighter, but she's alive, healthy, and recovering well. And while I cringed when he did it, one of her oncologists dropped the "c word" after surgery in discussing her case. Knowing the foe, I'm much more cautious in contemplating whether any of this represents a cure. Psychologically, the uncertainty around the future maintains a heavy burden over her and our family. A 70% response rate sounds really good, but it's a very different calculus when you're living it.
But as you said, her path towards a cure wouldn't have been possible not too long ago – in her case, 10-15 years; ipilimumab was approved in 2011 and nivolumab in 2014. But 30% of people with melanoma are still non-responders to combination immunotherapy. And, while a handful of other (generally less effective) options exist, non-responses in melanoma are deadly, often within a year or two of diagnosis, and for most all cancers have an incredibly high opportunity cost.
My Dad is currently battling a GBM. Do you have any advice for a web dev who wants to get his toe in the door of understanding the computational biology of gliomas?
I don't expect I'll be able to do much, but all of the treatments we've undertaken so far seem very dated (not able to resect, one round of radiation, temodar+avastin for the last year, just switched to CCNU+avastin). I'd love to know where the state of the art is at and know how to nudge/prompt his oncologists to be looking at it through that lens.
My email is in my profile, feel free to reach out privately.
Have you tried blood/tissue based comprehensive genomic profiling testing ? This might help understand the genomic determinants of the tumor, possibly helping the treating physician make an informed decision on treatment choice.
Part of this is because prostate cancer has such a high success rate. With treatment, the 5 year survival rate for early prostate cancer is over 99%, and is was close to 98% 20 years ago.
The current approach of regular prostate exams + treatment isn’t perfect but it’s extremely effective.
Prostate cancer is, from what I understand, one of the cancers with the least amount of genetic differences from normal tissue. That makes it harder to target. It also explains the general failure of checkpoint inhibitors.
> Prostate cancer is, from what I understand, one of the cancers with the least amount of genetic differences from normal tissue.
Would love to find any references for this.
FDA has only approved BRCA+ and few others like PALB2 for genetic targeting. It doesn't really matter how many others mutations that are found they won't be targeted with PARP.
So the question becomes is PC less likely to have target-able mutations compared to others ?
> At a broad glance, prostate tumors have, on average, fewer mutations (0.7 per Mb) than other common cancers, such as breast (1.2 per Mb), bladder (7.1 per Mb), colorectal (3.1 per Mb), and melanoma (12.1 per Mb)
I can't find the original article in which I saw it stated that PC has a lower mutational burden but the above might be sufficient.
As others have mentioned it depends. For instance the initial trials with pembrolizumab weren't the silver bullet the media makes them out to be today, until they identified what features might common among patients that did see a response, e.g. mismatch repair deficient cancers, because the tumor needs to be spitting out enough of these tumor-specific neoantigens to be targted by the immune system. That generally happens with highly mutated tumors such as those found in mismatch repair deficient tumors. The reason why the immune system was not targeting the tumors like it should have given the neoantigens until you take the drug is because the tumor cells presents the correct receptors that the immune system expects from healthy cells, which prevents the immune response. When you block that receptor as these drugs do, and also have many of these tumor specific neoantigens being expressed, then the immune system is able to target the tumor cells for death and the drug works well.
It's moving so fast even doctors(sans oncologists, perhaps?) can't keep up.
Brother's been a doctor about 15 years. Huge extended family is aging, and of course cancer creeps in. Of course family members call to get his opinion, and he's been wrong every single time(thankfully). Usually saying something like 'oh, she'll be dead within 2 years' and them living 6, or 8. And in one case calling something a death sentence that was actually, seemingly at least, cured.
It's entirely possible he's just a shit doctor, but I like to think it's that progress has moved a ton since he's studied up on it last.
Lucky you! When I see some recent projects using Spring, there is almost no Java code there, mostly very long YML files. The name remains the same, but it is a completely different programming language, if it may still be called so.
"their field" is a fuzzy concept. For example for a GP their field is "medicine". By definition they need to know just enough about everything to direct you to a specialist when needed, but it's simply impossible to be up to date with everything.
On the other hand, there's a huge number of consultants for enterprises which still write .net 4 like it's 2008 and they're both happy and productive. Unless they're sent to a training, why bother learning new stuff?
Would you be willing to share the type of cancer? Also, was the person you're referring to (can't tell if it was a relative) able to bypass traditional chemotherapy and go straight to the immunotherapy given the prognosis? Or did the oncologists require chemo first and only then your contact was able to receive the immunotherapy?
Thanks for sharing anything you can. If more comfortable sharing in private, I can be reached at asuela1 at yahoo's email service (it's my spam account, but I'll check it if you tell me you wrote back there).
Stage IIIC NSCLC, specifically a superior sulcus tumor, advanced enough to be considered inoperable. Standard of care in this case was induction radiotherapy, followed by a single course of combination chemotherapy consisting of carboplatin, pemetrexed, and pembrolizumab (the last of which is the cutting-edge immunotherapy I'm talking about; brand name Keytruda.) After that, patients are prescribed the pemetrexed and immunotherapy alone for a long 2-year "maintenance" course, at which point treatment options will be reassessed.
Surgery was not an option here because of the size and location of the mass, but after the initial course of chemo a PET-CT showed an 80% reduction in size. After some time on pembrolizumab, symptoms continue to improve and surgery may be back on the table soon.
(edited for a more accurate picture of maintenance treatment; thanks to borbulon for refreshing my memory)
Thank you for pointing out the standard of care in this case, given inability to resect, was the immunotherapy from the start. Obviously very specific for that type of lung cancer and the state of your contact's tumor, but I've been learning more and more about this and have been told by multiple oncologists that immunotherapy is typically only given after more conventional treatments are first attempted and fail to stop progression or shrink the mass(es). Needless to say that's far from categorical so in my next conversations I can be a bit more educated in my questioning.
And 80% reduction after that first course... Amazing. How long after the first course did they do the scan that showed that reduction?
Btw, very happy for you (and even moreso for your contact). Great news.
The scan that indicated the 80% reduction was after just a couple of weeks, if I recall correctly.
Since you're talking about immunotherapy not typically being a first-line treatment, I'll share a morbidly interesting fact that underscores some of the, er... quirks of the US medical system. The oncologist treating my relative initially staged my relative's cancer in the electronic health records as stage IV, despite no evidence of metastasis (the usual criterion)--he explained that he did this specifically in order to pursue first-line Keytruda (which is indicated for stage IV but not stage IIIC) and have it be covered by insurance.
I don't understand how medical insurance companies can choose what treatments can be applicable to what patients and yet not be as liable as a doctor for medical malpractice.
It’s not that they choose the treatment, you can get whatever treatment you want. They just say that they won’t pay for treatment other than X. This is unavoidable, really: if you look at countries with public healthcare system, like eg. UK, the (state) insurer there also makes decisions as to which treatments are covered, and which patients are eligible to get them. If anything, they are more conservative than private insurers in US: due to public nature, typically they do not offer higher range of treatments to customers who pay higher premiums. Instead, the coverage is “one size fits all”, and to limit costs, covered treatments options are seriously limited compared to what private insurers offer in US, especially in countries other than the wealthiest ones: in Poland, for example, cancer treatments available to patients on government healthcare are at least a decade or two behind the state of the art. Of course, the flip side is that you then get to see how cheap health care per capita is in Poland, and gripe about outrageous costs in US.
Thanks for the info on the timing. And that's my kind of oncologist. Risk in doing that on multiple levels, of course, but reassuring that some physicians are willing to do what's right vs what fits into into an insurance company's flow chart.
This. A close friend of mine was diagnosed with stage III stomach cancer. He lost massive amounts of weight and I almost thought he was not going to make it. And a year later he is back at work and doing pretty well.
It is not a single disease, but rather a result of several errant biological outcomes. The mortality rates have improved a lot with better treatments, and around 60% of the population will develop some form of the disease in their lifespan.
The most disturbing part is most people are unaware they are ill until relatively late stages of the disease.
If you live long enough, one will know many good people that go this way. It is a worthy area of research, as it improves the lives of many families. =)
Yes, my cancer was discovered pretty early by pure chance in a CT for an unrelated issue. I had zero symptoms, was really fit and pretty much never sick.
Who knows how long it would have had time to mutate and grow otherwise. Early detection is a really important issue for cancer treatments.
Looks as promising as any other promising cancer therapy in phase I trials!
There is a renaissance in cancer drug delivery at present, exemplified by antibody drug conjugates. The tech in the article is very interesting, and a superb bioengineering effort. A caveat is that complex multi-unit therapies don’t have a great track record. They are hard to manufacture reliably, and have a very large optimisation volume, so it’s difficult to increment the development as you only have finite resources for human trials. Contrast this with small molecules where there is a well defined process over various chemical and pharmacokinetic factors, prior to testing in humans. We also lack a good system for developing and trialing ‘platform’ tech like this - the current system is set up for single drugs/combos to be tested and eventually reimbursed in each cancer type separately. If you have a platform for delivering tailored therapies agnostic of cancer type, you will run into many barriers. There is currently only one drug I know of simultaneously approved across multiple cancer types (pembrolizumab in mismatch repair deficient tumours, a rare population). So many challenges ahead of the hype here.
I may be missing something but the article does not explain how the bacteria target is actually targeting the cancer cells. Of course, if you can design an ideal universal cancer targeting mechanism, the active ingredient itself is beside the point. Did anyone else catch this?
Stopping DNA replication across the body will be fatal. This is what eventually kills with radiation toxicity.
The article is missing lots of detail. They use antibodies to target receptors which are highly expressed by tumors, such as Epidermal growth factor receptor (EGFR).
"Given that the EDV surface is coated with lipopolysaccharide (LPS), single-chain bispecific antibodies were attached to the EDV surface where one arm of the antibody is directed to the O-polysaccharide epitopes and the other arm is directed to a tumour cell surface receptor for example Epidermal growth factor receptor (EGFR) which is found on the surface of over 70% of solid tumours"
and
"The EDVs being 400 nm rapidly fall out of these fenestrations and enter into the tumour microenvironment and since they carry the bispecific antibody on the EDV surface, the anti-EGFR component binds to EGFR on the tumour cell surface. This provokes macropinocytosis and the EDVs are taken into the early endosomes, followed by lysosomes and broken down in these organelles releasing the drug PNU-159682. The drug enters into the tumour cell cytoplasm and the nucleus and intercalates with the chromosomal DNA resulting in tumour cell apoptosis. In the event that a tumour type does not express EGFR for example liver cancer, which expresses asialoglycoprotein, then the bispecific antibody can be changed to anti-asialoglycoprotein while the anti-O-polysaccharide component remains constant. Similarly, HER-2 positive breast cancers can be targeted via anti-HER2/anti-O-polysaccharide bispecific antibody"
It does, from the article: "“Normally, our blood vessel walls are all sealed pipes,” Brahmbhatt says. “But around wherever the cancer is growing, the blood vessels are known to be very defective. They have got a lot of holes in them.”
Brahmbhatt and his collaborator Jennifer MacDiarmid devised a clever ploy. They would send a Trojan horse into malignant cells and turn cancer’s own trickery against it.
The Trojan horse, in this case, is a product of a harmless bacteria that’s been genetically engineered to have specific qualities. When this genetically engineered bacteria divides, it yields a tiny non-living cell of 400 nanometers in diameter—the right size to slip through the damaged vessels and mingle with the tumors."
I see. I do wonder how specific that is though. Potentially it could be toxic to other areas where vasculature could be "leaky". Like in the filtration mechanisms in the kidney.
Targeting the cancer's vascular supply is also a known anti-cancer mechanism of action (anti-angiogenics). How will this method not have the same toxicity as that one?
I loved Michael Levin's thoughts on solving cancer. Kind of similar to immunotherapy but on a level of reprogramming the cells back that got 'lost' from their big purpose in their organ.
I can't help but mention that there are two dominant schools of thought regarding cancer treatments:
1. The Somatic theory of cancer ('bad genes/out-of-control cellular replication')
2. The metabolic theory of cancer ('cancer cells ferment blood sugar for energy via an ancient emergency metabolic pathway')
Both have merit, but a complete occlusion of one would be bad.
I wrote an open letter, long ago, to a wealthy person who was on the board of a cancer research center, suggesting they read a book and fund the key research scientist:
I thought of the metabolic theory of cancer as I opened this page, because all cancers have a similar reliance upon certain energy generation pathways, which implies a corresponding vulnerability for treatment.
Some people find it interesting enough to click through, read the article, and to read the book.
Oncologist here.
You can think of drug development as an extremely wide funnel with a minuscule exit hole.
At any given time a medium sized pharmaceutical company has 300-500 drug candidates.
From this group 50 make it to phase 1 trials. 40 get slashed due to toxicity, company abandons them, gets bought by third party and sits in sleepy storage.
10 advance to phase 2 trials where 5-8 may not end up having enough efficacy/too toxic, does not improve survival.
The remaining 3-5 advance to phase 3 where they can suffer the above as well.
Tl:dr: Things usually work in the lab where all ideas start. Until a compound goes through thorough human experimentation believe little.
Phase 1 trials are used to determine drug toxicity. All that reault really says is that the new drug won't itself kill the patients. It still needs to be compared relative to the standard of care in larger phase 2 and 3 trials.
However, the article also describes patients in the trial having positive effects. Yes, it's not an efficacy trial, but if it was specifically used on patients who have exhausted all other clinical options, there were no significant adverse side-effects, and there were beneficial effects for some substantial number of patients, that sounds pretty hopeful to me. Of course it's possible issues will still be discovered, but this is a long way from a top-of-funnel lab result.
Thanks, that's an interesting insight into the dropoff rate for these ideas. Do you have an opinion on what the bottleneck is? Volume of ideas, length of testing, or perhaps flawed approach in general?
This is the bottleneck for one company. We have many companies this size doing the same thing.
The issue is large companies (novartis/BMS) sometimes sit on compounds and refuse to develop because they think it may not be worth it, may think a certain disease (read market) is saturated, or they may be waiting for the 'right time'. It can be frustrating.
Smaller companies have 2-3 compounds which they actively work to develop but most of them end up getting acquired by the big fish.
The extreme complexity of biology. There's no substitute to just trying things and seeing if they work, because you will never understand what's going on beforehand.
Thanks. I had read of success infecting tumors with virus, that the immune system will control only outside the tumor. But I didn't hear any more about it. What happened with that?
The universal cancer treatment will be full body transplant.
As long as the cancer isn't in the patient's brain, the patient's head could be removed and transplanted onto a donor (brain dead) body. This would render the patient a quadriplegic, but with repeated study over decades we might be able to repair the nervous system.
There isn't a large set of brain dead bodies to draw from, so if this process proves successful, perhaps we could one day start growing human bodies in labs from a monoclonal source. If we remove their ABO and MHC antigens, we might be able to lessen the need for an ongoing life-altering immunosuppressant regimen. These lab grown bodies would be headless/brainless from the outset via gene and surgical deactivation during development to remove any ethical issues. The bodies could be artificially innervated and pumped with the hormonal signals they need to grow until it's time to harvest them.
Cancer is thousands and thousands of different disease states, and it will remain a difficult landscape for the foreseeable future. A non-molecular approach of wholesale cancer tissue removal (via body replacement) seems like an out of the box solution that could work.
They genetically engineered a kind of bacteria that divides into non-living 'nanocells' that can't multiply further. These cells contain a special kind of RNA and a cell entry mechanism that lets them enter the cancer cells. The RNA interrupts the cell's ability to prepare for division. The article kind of implied that these nanocells follow the bloodstream pathways that cancer cells open when they metastasize.
The researchers main concern was whether those nanoncells would also enter healthy cells, but the tests seem to show healthy cells were not affected.
I think it was modified yeast bacteria produce a cell of exactly the right size to slip through the same blood vessels that the cancer did when it spread; unaffected blood vessels wouldn't let anything through.
Some quick thoughts.
This therapy uses a combination of methods that are already used in oncology. The usage of bacteria in oncology as part of immunotherapies has existed for decades via the use of BCG, although it is notably that these bacteria have genetic modifications to allow it to create a delivery vehicle as well. siRNAs have always been an attractive method but lacked proper delivery methods and initially had issues with degradation. The knockdown of DNA polymerases is new to me. Typically chemotherapeutics are anti-metabolites or seek to arrest mitosis (taxanes for example lock part of the cytoskeleton [microtubules] needed to move chromosomes). Targeting DNA polymerase makes fundamentally more sense because you would by and large avoid disrupting other cellular functions. Hopefully this represents another tool in the kit in regards to conjugate/combination therapies like Trastuzumab-deruxtecan.
Quick question: Based on this statements would these therapy work particularly well against metastatic disease given its moa for cell selectivity?
Money is absolutely an object. People are starting to do trials of early detection from circulating tumor DNA, and finding that the hit rate is alarmingly high. A decent portion of the population has some kind of malignancy, but most of these will either be cleared by the immune system, or be completely benign. Another problem is, if we detect this tumor DNA, it doesn't tell us where in the body the tumor might be. So then you're talking massive workups including while body CT scans and such for a problem that isn't going to be a problem for 99% of people. I'm not joking when I say that if rolled out as is, this has the potential to bankrupt the entire healthcare system with unnecessary procedures.
To be clear, I very much think that early detection of tumors will someday be an essential part of cancer treatment. We are not there yet.
>Another problem is, if we detect this tumor DNA, it doesn't tell us where in the body the tumor might be.
This isn't necessarily the case. A lot of CTCs have markers that are indicative of certain cancers or tissue types of origin. Different tissues have specific patterns of gene expression even if they all have the same underlying DNA, and there are databases with thousands of samples sequenced supporting these patterns.
Lots of clinics in Vancouver BC fully body MRI scans that are not super expensive. I really do think we should just make MRIs cheap and then get the whole world to do them.
I understand the cost, time, etc. but I still think if we can stop doing other useless stuff as humanity and do this it would be net positive.
I think the question being asked was "If money were no object, what is the best cancer detection method?", as opposed to stating that money wasn't an object.
"Mammograms are the best breast cancer screening tests we have at this time. But mammograms have their limits. For example, they aren’t 100% accurate in showing if a woman has breast cancer. They can miss some cancers, and sometimes they find things that turn out not to be cancer (but that still need further testing to be sure)."
https://xkcd.com/radiation/ lead me to believe that most x-rays only expose the person to a few days worth of background radiation. Is that accurate? And does it really matter?
Look at GRAIL therapeutics. Cancer sheds DNA that can be detected and amplified. We use this sometimes to try to tell if someone will have a recurrence before scans actually show it.
Sequencing is hard, and there are contaminants and difficulties calling a mutation/sequence cancerous, but I have had patients self-refer after a positive GRAIL test, no symptoms, and bam, biopsy from area of interest shows early cancer.
You can detect tumor cells circulating in blood for certain cancers. You can get the cost down by having these tests covered at regular intervals by insurance companies.
Does anyone know about updates on mRNA treatments for cancer? I had big hopes after the impressive corona-virus vaccines. I know BioNTech is investing heavily but not much has changed since then?
There are a few vaccines that try to 'make' your immune system recognize an abnormal (read cancerous) protein as foreign (Sipleucel T for prostate, GMCSF vaccine for melanoma). Minimal activity.
I'm far from an expert, but my Dad is currently battling a high-grade glioblastoma multiforme tumor in his brain. So I've learned a little.
> so this can put the breaks on cancer, but it can't fix cancer?
"Putting the brakes on cancer" is basically equivalent to "fixing cancer". For my Dad's GBM, he has an MRI from 13 years before his diagnosis that seems to show the early stages of his tumor. At the time, his neuro noted that it was mildly concerning, but then didn't order any follow-up testing. So the tumor lay "dormant" in my Dad's head for over a decade. Then it started rapidly growing last year, until he was losing his balance at work, started getting scans, and eventually found the brain tumor.
All of the standard of care around this is focused on mechanical or electromagnetic removal of large parts of the tumor, combined with throwing whatever chemotherapies you can at the body to stop the tumor from growing. Eventually, the tumor grows until it squeezes out all normal brain functionality. Anything that can arrest the tumor without killing you is good.
Someday soon they'll look at our insane chemotherapy with the same level of utter disbelief as we do about bloodletting and tapeworm diets
I mean untargeted chemotherapy kills -the one thing- that protects us since before we were born from cancer, our immune system.
Killing our immune system to kill cancer makes as much sense as shooting off the leg you lead with so to run faster.
Its idiotic, stupid and, yeah its basically trying to stop the copy errors in genes that cancer does, before all the massive amount of DNA errors kill the cancer victim ...
It's like a really really bad CRISPR process as I understand it, like the computer program SED was majorly crapping out and it made your program an utter mess.
Anyway, chemotherapy is DAMN foolish, and I for one will be glad when we're rid of it with better therapies
I'd argue that our future retrospective view of chemotherapy will be more of how we view hunting with a club rather than, say, a bow and arrow. Not optimal but, at least in many cases, proven to be better than nothing by multiple randomized clinical trials.
Invent something better if you know how. For many people chemo is their hope and in many cases does wonders by itself or in combination with other methods, either in parallel or in succession.
Watch all the funding dry up and the researcher get framed for some random, stupid crime, with just enough prison time to make sure he won't see the inside of a lab again before he's too senile to use it or dead.
Could also be a slip in the tub etc.
There's a lot of money in suffering, and if you think there aren't people sick enough out there to do real horrible shit to protect that income stream, you're kidding yourself.
How do you think this fucked up civilization was twisted into the giant pulsating tumor it currently is?
It really is remarkable how far cancer treatment has progressed, even in the last few years. I'm one of the unfortunate people who, through a close family encounter with cancer, knows more about this stuff than anyone should have to. The oncologist told my relative that if they had presented with this particular cancer just a decade ago, his recommendation would have been to start hospice care.
However, in recent years, a very effective checkpoint inhibitor immunotherapy has been developed for the cancer in question. ~2x the success rates of traditional chemo, greatly increased overall survival statistics, and with massively reduced side effects. The results speak for themselves: this drug has granted my relative years of extra life in the worst case, and a path to a deep, long remission in the best case.
I think that as the technology develops, by 2040 we'll be looking back at the present state of the art with the same incredulity that we currently have for, like, bloodletting with leeches in the Middle Ages. I think they've been saying this for a long time now, but it's truer than ever that a real cure for cancer is right around the corner.
As a person who currently has stage IV NSCLC, I can add some context to this:
YMMV.
One thing to remember is that "Lung Cancer" is not just one thing. There are mutations of different genes, there are overexpressions of different genes. Each one has its own new medicines. Also, some peoples' cancers are more aggressive than others, and while for many they can find the right drug, for some nothing works.
Keytruda works wonders for some. It did not for me. I had 4 treatments of the CPP (carboplatin, pemetrexed, and pembrolizumab) triad, which had some success. They then put you on "maintenance," which is the PP without the carboplatin (which is the really old school platinum-based chemo). Maintenance did nothing for me. My main tumor grew more than 50% in 2 months.
Last summer I started 9 months on a chemo/immuno that was geared towards my specific mutation. It actually did wonders. It resulted in a 98% shrinkage of my main tumor before I ended up with pneumonitis from it and had to stop. But I've been able to be off treatment for the entire summer. I know there are others who have tried this, and it didn't work.
So yeah, I'm really, really glad your relative was able to get some relief from the Keytruda. But I also wish it were the wonder cure for everyone that it was for them.
I was diagnosed with stage III NSCLC February '21. Radiation, chemo, and a bilobectomy. I had the ALK+ morphology which meant I wasn't a candidate for immunotherapy but I've been on alectinib since my surgery in June '21 with no signs of recurrence so far.
The process is grueling in hindsight, but I'm glad to hear you're getting results. At first I would have said "if this is going to kill me, make it sooner rather than later" to avoid a drawn-out painful experience, but I'm starting to appreciate what the buying time really means. It's hard with all that's going on but get your head straight and make sure you enjoy it.
Keep on keeping on.
Thanks for sharing your story and treatment details. I should add that my relative's cancer has no particularly interesting mutations, but does have a high PD-L1 expression, which from what I can tell is the reason Keytruda was more likely to work for their situation.
> that was geared towards my specific mutation
This is actually one of the things that gives me hope for the future: genetic testing on a tissue sample of the patient's cancer is standard, and for many of the specific oncogenes that we know about, there exist therapies targeted to those specific mutations: https://www.cancer.org/cancer/lung-cancer/treating-non-small...
One thing I've learned is that even in the face of good news, cancer is a horrible time, and I wouldn't wish it on anyone. But I'm likewise glad to hear about your results from the latest treatment, and hope things stay as positive as they can for you.
https://en.wikipedia.org/wiki/Sotorasib ?
I am hopeful we can move metastatic cancer (which is the true evil of cancer) to a controlled chronic condition.
BTW-- our oncology doctor believes in synergies between chemo and pembro, but I sometimes wonder if it's truly the chemo. Also, Pembro is not without its side-effects.
Shit. My best to you and yours. Thanks for sharing.
What are your thoughts on Dr. Seyfried and cancer as a metabolic disease?
> in recent years, a very effective checkpoint inhibitor immunotherapy has been developed for the cancer in question. ~2x the success rates of traditional chemo
> I think they've been saying this for a long time now, but it's truer than ever that a real cure for cancer is right around the corner.
I think thats quite a leap. For prostate cancer( most common cancer among men), top line therapies are still androgen blockage that was discover 70 yrs ago, chemo and radiation. Keytruda failed to deliver any significant survival benefits[1].
Yes we've gotten better at slash, burn , poison methods. Radiation is more trageted and sophisticated. Diagnostics are more precise. Chemo drugs have better safety profiles.
But these are all marginal improvements. None of which indicate anything that we are close to a cure.
Only hope we still have is to catch it earlier and go ham on it. Most of the slash,burn, poison methods are being FDA approved for earlier use.
The other two things(one of which you've mentioned) are immune checkpoint blockade if you have MSI-hi/dMMR or PARP inhibition if you have BRCA2+. Even if you are lucky to have these mutations these drugs are a hit or miss[1].
I don't feel optimistic about a cure at all.
1. https://www.businesswire.com/news/home/20220803005334/en/Mer...
I agree that my original comment is very optimistic--for what it's worth, Keytruda has thus far been very effective in the case I'm talking about, so I have some bias here. I concede that even in my "double the effectiveness" example, we're talking about doubling something like a 20% 5-year OS.
By "around the corner" I'm really talking about, like, 20-30 years out, which I think is fairly soon in terms of cancer treatment progress. You're right that it reads like a leap in the context of my comment.
Not to be too pessimistic, but 600,000 people died of cancer in 2019, so 20-30 years is hardly "round the corner" when you extrapolate to the, let's say conservatively, 10 million families in the US losing loved ones in that time period.
The history of cancer (The Emperor of All Maladies is a good book covering the history) is full of promising adjuvants, drugs, protocols that fail to generalize well. There are a lot of reasons for this. With drugs, one is that Phase 3 clinical trials often have patients who are selected on the basis of them being likely to be among the best responders. But once the drug is approved and made available to all patients within a given indication – a fundamentally different population – an overwhelming positive response may be significantly more modest. In many cases, this has to do with a patient's tolerance of the side effects or the interaction of the drug with known or underlying comorbidities.
While I'm encouraged by the research in this article and could see the drug being part of a combination protocol, I'm hesitant that it will be "universal". And the mechanism, candidly, is downright scary – if I were running a Phase 3 for this (seems the trial cited was a Phase 2 demonstrating baseline safety in humans), I would want a very detailed articulation of how the technology ensures with a high margin of safety that the drug delivery is targeted to the tumor and no other tissues. The permeability of blood vessels in tumors would not be sufficient (and also does not seem "universal").
On a more personal note, I'm actually a computational biologist and have done quite a bit of work in cancer research (masters thesis, portion of my dissertation). My Mother was also diagnosed with a highly aggressive cancer of unknown primary (CUP) origin in her lung late last year (estimated stage IIIb for NSCLC, stage 4 for CUP/melanoma). Its location and heart involvement made it inoperable. Turned out is was a melanoma, which to be frank I quickly recognized down to the subtype upon reviewing the pathology reports. The lung oncologists were much more conservative; given the location, they weren't especially well-versed in melanoma, and presumed it was an adenocarcinoma with a rare presentation despite the staining for carcinomas being negative across the board. Luckily, we managed to convince them to split the difference on the standard of care – CarboTaxol (carboplatin + taxol) combination and immunotherapy (nivolumab and ipilimumab), all at once. The immunotherapy surely saved her life; unlike with carcinomas, chemo is roughly 5% effective (as in, any response whatsoever) for melanomas. About 70% of melanoma diagnoses respond to combination immunotherapy with about 15% going into full remission (memory is shaky on that last number, may be slightly higher). With >95 PDL-1 expression, she was one of the lucky ones – she had a full response on both imaging and pathological endpoints. That also made her tumor (or what was left of it) operable. She's two lobes and a chunk of heart lighter, but she's alive, healthy, and recovering well. And while I cringed when he did it, one of her oncologists dropped the "c word" after surgery in discussing her case. Knowing the foe, I'm much more cautious in contemplating whether any of this represents a cure. Psychologically, the uncertainty around the future maintains a heavy burden over her and our family. A 70% response rate sounds really good, but it's a very different calculus when you're living it.
But as you said, her path towards a cure wouldn't have been possible not too long ago – in her case, 10-15 years; ipilimumab was approved in 2011 and nivolumab in 2014. But 30% of people with melanoma are still non-responders to combination immunotherapy. And, while a handful of other (generally less effective) options exist, non-responses in melanoma are deadly, often within a year or two of diagnosis, and for most all cancers have an incredibly high opportunity cost.
My Dad is currently battling a GBM. Do you have any advice for a web dev who wants to get his toe in the door of understanding the computational biology of gliomas?
I don't expect I'll be able to do much, but all of the treatments we've undertaken so far seem very dated (not able to resect, one round of radiation, temodar+avastin for the last year, just switched to CCNU+avastin). I'd love to know where the state of the art is at and know how to nudge/prompt his oncologists to be looking at it through that lens.
My email is in my profile, feel free to reach out privately.
Have you tried blood/tissue based comprehensive genomic profiling testing ? This might help understand the genomic determinants of the tumor, possibly helping the treating physician make an informed decision on treatment choice.
Part of this is because prostate cancer has such a high success rate. With treatment, the 5 year survival rate for early prostate cancer is over 99%, and is was close to 98% 20 years ago.
The current approach of regular prostate exams + treatment isn’t perfect but it’s extremely effective.
Prostate cancer is, from what I understand, one of the cancers with the least amount of genetic differences from normal tissue. That makes it harder to target. It also explains the general failure of checkpoint inhibitors.
> Prostate cancer is, from what I understand, one of the cancers with the least amount of genetic differences from normal tissue.
Would love to find any references for this.
FDA has only approved BRCA+ and few others like PALB2 for genetic targeting. It doesn't really matter how many others mutations that are found they won't be targeted with PARP.
So the question becomes is PC less likely to have target-able mutations compared to others ?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073096/
> At a broad glance, prostate tumors have, on average, fewer mutations (0.7 per Mb) than other common cancers, such as breast (1.2 per Mb), bladder (7.1 per Mb), colorectal (3.1 per Mb), and melanoma (12.1 per Mb)
I can't find the original article in which I saw it stated that PC has a lower mutational burden but the above might be sufficient.
Interestingly prostate cancer is a cancer many people die with and not from.
As others have mentioned it depends. For instance the initial trials with pembrolizumab weren't the silver bullet the media makes them out to be today, until they identified what features might common among patients that did see a response, e.g. mismatch repair deficient cancers, because the tumor needs to be spitting out enough of these tumor-specific neoantigens to be targted by the immune system. That generally happens with highly mutated tumors such as those found in mismatch repair deficient tumors. The reason why the immune system was not targeting the tumors like it should have given the neoantigens until you take the drug is because the tumor cells presents the correct receptors that the immune system expects from healthy cells, which prevents the immune response. When you block that receptor as these drugs do, and also have many of these tumor specific neoantigens being expressed, then the immune system is able to target the tumor cells for death and the drug works well.
It's moving so fast even doctors(sans oncologists, perhaps?) can't keep up.
Brother's been a doctor about 15 years. Huge extended family is aging, and of course cancer creeps in. Of course family members call to get his opinion, and he's been wrong every single time(thankfully). Usually saying something like 'oh, she'll be dead within 2 years' and them living 6, or 8. And in one case calling something a death sentence that was actually, seemingly at least, cured.
It's entirely possible he's just a shit doctor, but I like to think it's that progress has moved a ton since he's studied up on it last.
It is also notable how doctors can get away with not following the progress in their own field.
A programmer who would ignore the developments since 2007 would be unusable.
I'm still programming in Java like it's 2001. No problems here :)
Lucky you! When I see some recent projects using Spring, there is almost no Java code there, mostly very long YML files. The name remains the same, but it is a completely different programming language, if it may still be called so.
"their field" is a fuzzy concept. For example for a GP their field is "medicine". By definition they need to know just enough about everything to direct you to a specialist when needed, but it's simply impossible to be up to date with everything.
On the other hand, there's a huge number of consultants for enterprises which still write .net 4 like it's 2008 and they're both happy and productive. Unless they're sent to a training, why bother learning new stuff?
True, but a GP shouldn't declare death sentences on their relatives if he is out of his depth in oncology.
This 500x.
Would you be willing to share the type of cancer? Also, was the person you're referring to (can't tell if it was a relative) able to bypass traditional chemotherapy and go straight to the immunotherapy given the prognosis? Or did the oncologists require chemo first and only then your contact was able to receive the immunotherapy?
Thanks for sharing anything you can. If more comfortable sharing in private, I can be reached at asuela1 at yahoo's email service (it's my spam account, but I'll check it if you tell me you wrote back there).
Stage IIIC NSCLC, specifically a superior sulcus tumor, advanced enough to be considered inoperable. Standard of care in this case was induction radiotherapy, followed by a single course of combination chemotherapy consisting of carboplatin, pemetrexed, and pembrolizumab (the last of which is the cutting-edge immunotherapy I'm talking about; brand name Keytruda.) After that, patients are prescribed the pemetrexed and immunotherapy alone for a long 2-year "maintenance" course, at which point treatment options will be reassessed.
Surgery was not an option here because of the size and location of the mass, but after the initial course of chemo a PET-CT showed an 80% reduction in size. After some time on pembrolizumab, symptoms continue to improve and surgery may be back on the table soon.
(edited for a more accurate picture of maintenance treatment; thanks to borbulon for refreshing my memory)
Thank you for pointing out the standard of care in this case, given inability to resect, was the immunotherapy from the start. Obviously very specific for that type of lung cancer and the state of your contact's tumor, but I've been learning more and more about this and have been told by multiple oncologists that immunotherapy is typically only given after more conventional treatments are first attempted and fail to stop progression or shrink the mass(es). Needless to say that's far from categorical so in my next conversations I can be a bit more educated in my questioning.
And 80% reduction after that first course... Amazing. How long after the first course did they do the scan that showed that reduction?
Btw, very happy for you (and even moreso for your contact). Great news.
The scan that indicated the 80% reduction was after just a couple of weeks, if I recall correctly.
Since you're talking about immunotherapy not typically being a first-line treatment, I'll share a morbidly interesting fact that underscores some of the, er... quirks of the US medical system. The oncologist treating my relative initially staged my relative's cancer in the electronic health records as stage IV, despite no evidence of metastasis (the usual criterion)--he explained that he did this specifically in order to pursue first-line Keytruda (which is indicated for stage IV but not stage IIIC) and have it be covered by insurance.
I don't understand how medical insurance companies can choose what treatments can be applicable to what patients and yet not be as liable as a doctor for medical malpractice.
It’s not that they choose the treatment, you can get whatever treatment you want. They just say that they won’t pay for treatment other than X. This is unavoidable, really: if you look at countries with public healthcare system, like eg. UK, the (state) insurer there also makes decisions as to which treatments are covered, and which patients are eligible to get them. If anything, they are more conservative than private insurers in US: due to public nature, typically they do not offer higher range of treatments to customers who pay higher premiums. Instead, the coverage is “one size fits all”, and to limit costs, covered treatments options are seriously limited compared to what private insurers offer in US, especially in countries other than the wealthiest ones: in Poland, for example, cancer treatments available to patients on government healthcare are at least a decade or two behind the state of the art. Of course, the flip side is that you then get to see how cheap health care per capita is in Poland, and gripe about outrageous costs in US.
Thanks for the info on the timing. And that's my kind of oncologist. Risk in doing that on multiple levels, of course, but reassuring that some physicians are willing to do what's right vs what fits into into an insurance company's flow chart.
Not sure about lung cancer, but there's positive results in other cancers for earlier immunotherapy !
https://oncologypro.esmo.org/meeting-resources/esmo-congress...
Of course it varies by cancer. Look up "adjuvant immunotherapy".
It is now standard of care for melanoma, for one, but it isn't successful for all cancers, (or even all melanoma mutations).
This. A close friend of mine was diagnosed with stage III stomach cancer. He lost massive amounts of weight and I almost thought he was not going to make it. And a year later he is back at work and doing pretty well.
It is not a single disease, but rather a result of several errant biological outcomes. The mortality rates have improved a lot with better treatments, and around 60% of the population will develop some form of the disease in their lifespan.
The most disturbing part is most people are unaware they are ill until relatively late stages of the disease.
If you live long enough, one will know many good people that go this way. It is a worthy area of research, as it improves the lives of many families. =)
Yes, my cancer was discovered pretty early by pure chance in a CT for an unrelated issue. I had zero symptoms, was really fit and pretty much never sick.
Who knows how long it would have had time to mutate and grow otherwise. Early detection is a really important issue for cancer treatments.
Screenings allowed my family members to catch cancer early when they still had chances for good prognoses, so don't skip out on regular checkups.
liquid biopsy seems promising in early detection.
Here is the only clinical data: https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.46...
Looks as promising as any other promising cancer therapy in phase I trials!
There is a renaissance in cancer drug delivery at present, exemplified by antibody drug conjugates. The tech in the article is very interesting, and a superb bioengineering effort. A caveat is that complex multi-unit therapies don’t have a great track record. They are hard to manufacture reliably, and have a very large optimisation volume, so it’s difficult to increment the development as you only have finite resources for human trials. Contrast this with small molecules where there is a well defined process over various chemical and pharmacokinetic factors, prior to testing in humans. We also lack a good system for developing and trialing ‘platform’ tech like this - the current system is set up for single drugs/combos to be tested and eventually reimbursed in each cancer type separately. If you have a platform for delivering tailored therapies agnostic of cancer type, you will run into many barriers. There is currently only one drug I know of simultaneously approved across multiple cancer types (pembrolizumab in mismatch repair deficient tumours, a rare population). So many challenges ahead of the hype here.
I may be missing something but the article does not explain how the bacteria target is actually targeting the cancer cells. Of course, if you can design an ideal universal cancer targeting mechanism, the active ingredient itself is beside the point. Did anyone else catch this?
Stopping DNA replication across the body will be fatal. This is what eventually kills with radiation toxicity.
The article is missing lots of detail. They use antibodies to target receptors which are highly expressed by tumors, such as Epidermal growth factor receptor (EGFR).
"Given that the EDV surface is coated with lipopolysaccharide (LPS), single-chain bispecific antibodies were attached to the EDV surface where one arm of the antibody is directed to the O-polysaccharide epitopes and the other arm is directed to a tumour cell surface receptor for example Epidermal growth factor receptor (EGFR) which is found on the surface of over 70% of solid tumours"
and
"The EDVs being 400 nm rapidly fall out of these fenestrations and enter into the tumour microenvironment and since they carry the bispecific antibody on the EDV surface, the anti-EGFR component binds to EGFR on the tumour cell surface. This provokes macropinocytosis and the EDVs are taken into the early endosomes, followed by lysosomes and broken down in these organelles releasing the drug PNU-159682. The drug enters into the tumour cell cytoplasm and the nucleus and intercalates with the chromosomal DNA resulting in tumour cell apoptosis. In the event that a tumour type does not express EGFR for example liver cancer, which expresses asialoglycoprotein, then the bispecific antibody can be changed to anti-asialoglycoprotein while the anti-O-polysaccharide component remains constant. Similarly, HER-2 positive breast cancers can be targeted via anti-HER2/anti-O-polysaccharide bispecific antibody"
https://sfamjournals.onlinelibrary.wiley.com/doi/full/10.111...
I don't think this particular therapeutic automatically homes to all cancer cells. However, certain bacteria have been found to home to cancer cells, so maybe that helps too. https://wis-wander.weizmann.ac.il/life-sciences/cells-inside...
Ah. Thanks for finding this. That makes more sense. Bacteria that are attracted to cancer cells are a fascinating concept.
It is very exciting to see another tool in the toolbox to achieve higher cancer cell therapeutic specificity.
It does, from the article: "“Normally, our blood vessel walls are all sealed pipes,” Brahmbhatt says. “But around wherever the cancer is growing, the blood vessels are known to be very defective. They have got a lot of holes in them.”
Brahmbhatt and his collaborator Jennifer MacDiarmid devised a clever ploy. They would send a Trojan horse into malignant cells and turn cancer’s own trickery against it.
The Trojan horse, in this case, is a product of a harmless bacteria that’s been genetically engineered to have specific qualities. When this genetically engineered bacteria divides, it yields a tiny non-living cell of 400 nanometers in diameter—the right size to slip through the damaged vessels and mingle with the tumors."
I see. I do wonder how specific that is though. Potentially it could be toxic to other areas where vasculature could be "leaky". Like in the filtration mechanisms in the kidney.
Targeting the cancer's vascular supply is also a known anti-cancer mechanism of action (anti-angiogenics). How will this method not have the same toxicity as that one?
Presumably that 400nm size is important for specificity as well
I loved Michael Levin's thoughts on solving cancer. Kind of similar to immunotherapy but on a level of reprogramming the cells back that got 'lost' from their big purpose in their organ.
https://www.youtube.com/watch?v=p3lsYlod5OU&t=8653s
Michael Levin is an astonishing breath of fresh air.
I can't help but mention that there are two dominant schools of thought regarding cancer treatments:
1. The Somatic theory of cancer ('bad genes/out-of-control cellular replication')
2. The metabolic theory of cancer ('cancer cells ferment blood sugar for energy via an ancient emergency metabolic pathway')
Both have merit, but a complete occlusion of one would be bad.
I wrote an open letter, long ago, to a wealthy person who was on the board of a cancer research center, suggesting they read a book and fund the key research scientist:
https://josh.works/mike-clayville-can-have-a-huge-impact-on-...
I thought of the metabolic theory of cancer as I opened this page, because all cancers have a similar reliance upon certain energy generation pathways, which implies a corresponding vulnerability for treatment.
Some people find it interesting enough to click through, read the article, and to read the book.
> cancer cells ferment blood sugar
oh boy
They do.
Eg https://www.cancer.gov/research/key-initiatives/ras/ras-cent...
Obviously not usually considered cause, but rather effect.
It's why PET scans work well on cancer patients, they inject you with a glucose analog that has a radioactive marker.
Oncologist here. You can think of drug development as an extremely wide funnel with a minuscule exit hole. At any given time a medium sized pharmaceutical company has 300-500 drug candidates. From this group 50 make it to phase 1 trials. 40 get slashed due to toxicity, company abandons them, gets bought by third party and sits in sleepy storage. 10 advance to phase 2 trials where 5-8 may not end up having enough efficacy/too toxic, does not improve survival. The remaining 3-5 advance to phase 3 where they can suffer the above as well.
Tl:dr: Things usually work in the lab where all ideas start. Until a compound goes through thorough human experimentation believe little.
Sounds like this one is pretty advanced down the funnel, having successfully passed phase 1 human trials, or am I missing something?
Phase 1 trials are used to determine drug toxicity. All that reault really says is that the new drug won't itself kill the patients. It still needs to be compared relative to the standard of care in larger phase 2 and 3 trials.
However, the article also describes patients in the trial having positive effects. Yes, it's not an efficacy trial, but if it was specifically used on patients who have exhausted all other clinical options, there were no significant adverse side-effects, and there were beneficial effects for some substantial number of patients, that sounds pretty hopeful to me. Of course it's possible issues will still be discovered, but this is a long way from a top-of-funnel lab result.
Thanks, that's an interesting insight into the dropoff rate for these ideas. Do you have an opinion on what the bottleneck is? Volume of ideas, length of testing, or perhaps flawed approach in general?
This is the bottleneck for one company. We have many companies this size doing the same thing.
The issue is large companies (novartis/BMS) sometimes sit on compounds and refuse to develop because they think it may not be worth it, may think a certain disease (read market) is saturated, or they may be waiting for the 'right time'. It can be frustrating.
Smaller companies have 2-3 compounds which they actively work to develop but most of them end up getting acquired by the big fish.
The extreme complexity of biology. There's no substitute to just trying things and seeing if they work, because you will never understand what's going on beforehand.
funny how many of blockebuster drugs were discovered by accident.
And for some that were designed to hit a specific target, it was discovered afterwards that they work by a completely different mechanism.
Glad to see another oncologist on HN!
Thanks. I had read of success infecting tumors with virus, that the immune system will control only outside the tumor. But I didn't hear any more about it. What happened with that?
The universal cancer treatment will be full body transplant.
As long as the cancer isn't in the patient's brain, the patient's head could be removed and transplanted onto a donor (brain dead) body. This would render the patient a quadriplegic, but with repeated study over decades we might be able to repair the nervous system.
There isn't a large set of brain dead bodies to draw from, so if this process proves successful, perhaps we could one day start growing human bodies in labs from a monoclonal source. If we remove their ABO and MHC antigens, we might be able to lessen the need for an ongoing life-altering immunosuppressant regimen. These lab grown bodies would be headless/brainless from the outset via gene and surgical deactivation during development to remove any ethical issues. The bodies could be artificially innervated and pumped with the hormonal signals they need to grow until it's time to harvest them.
Cancer is thousands and thousands of different disease states, and it will remain a difficult landscape for the foreseeable future. A non-molecular approach of wholesale cancer tissue removal (via body replacement) seems like an out of the box solution that could work.
Did I miss it or was the delivery mechanism not really mentioned? I suppose that might be the secret sauce?
What happens once they stop the growth of cancer, say in the case of a tumour? Will it break down over time or does it need to be surgically removed?
They genetically engineered a kind of bacteria that divides into non-living 'nanocells' that can't multiply further. These cells contain a special kind of RNA and a cell entry mechanism that lets them enter the cancer cells. The RNA interrupts the cell's ability to prepare for division. The article kind of implied that these nanocells follow the bloodstream pathways that cancer cells open when they metastasize.
The researchers main concern was whether those nanoncells would also enter healthy cells, but the tests seem to show healthy cells were not affected.
I think it was modified yeast bacteria produce a cell of exactly the right size to slip through the same blood vessels that the cancer did when it spread; unaffected blood vessels wouldn't let anything through.
Some quick thoughts. This therapy uses a combination of methods that are already used in oncology. The usage of bacteria in oncology as part of immunotherapies has existed for decades via the use of BCG, although it is notably that these bacteria have genetic modifications to allow it to create a delivery vehicle as well. siRNAs have always been an attractive method but lacked proper delivery methods and initially had issues with degradation. The knockdown of DNA polymerases is new to me. Typically chemotherapeutics are anti-metabolites or seek to arrest mitosis (taxanes for example lock part of the cytoskeleton [microtubules] needed to move chromosomes). Targeting DNA polymerase makes fundamentally more sense because you would by and large avoid disrupting other cellular functions. Hopefully this represents another tool in the kit in regards to conjugate/combination therapies like Trastuzumab-deruxtecan.
Quick question: Based on this statements would these therapy work particularly well against metastatic disease given its moa for cell selectivity?
Early detection?
Whats the best way to detect cancer (money is no object) and how do we get that cost down 10x and get everyone to participate?
Money is absolutely an object. People are starting to do trials of early detection from circulating tumor DNA, and finding that the hit rate is alarmingly high. A decent portion of the population has some kind of malignancy, but most of these will either be cleared by the immune system, or be completely benign. Another problem is, if we detect this tumor DNA, it doesn't tell us where in the body the tumor might be. So then you're talking massive workups including while body CT scans and such for a problem that isn't going to be a problem for 99% of people. I'm not joking when I say that if rolled out as is, this has the potential to bankrupt the entire healthcare system with unnecessary procedures.
To be clear, I very much think that early detection of tumors will someday be an essential part of cancer treatment. We are not there yet.
>Another problem is, if we detect this tumor DNA, it doesn't tell us where in the body the tumor might be.
This isn't necessarily the case. A lot of CTCs have markers that are indicative of certain cancers or tissue types of origin. Different tissues have specific patterns of gene expression even if they all have the same underlying DNA, and there are databases with thousands of samples sequenced supporting these patterns.
Lots of clinics in Vancouver BC fully body MRI scans that are not super expensive. I really do think we should just make MRIs cheap and then get the whole world to do them.
I understand the cost, time, etc. but I still think if we can stop doing other useless stuff as humanity and do this it would be net positive.
I think the question being asked was "If money were no object, what is the best cancer detection method?", as opposed to stating that money wasn't an object.
Very interesting comment, nonetheless.
problems:
- False-positive results
- False-negative results
"Mammograms are the best breast cancer screening tests we have at this time. But mammograms have their limits. For example, they aren’t 100% accurate in showing if a woman has breast cancer. They can miss some cancers, and sometimes they find things that turn out not to be cancer (but that still need further testing to be sure)."
https://www.cancer.org/cancer/breast-cancer/screening-tests-...
Furthermore the detection method used (x-rays) cause cancer in and of themselves.
https://xkcd.com/radiation/ lead me to believe that most x-rays only expose the person to a few days worth of background radiation. Is that accurate? And does it really matter?
Look at GRAIL therapeutics. Cancer sheds DNA that can be detected and amplified. We use this sometimes to try to tell if someone will have a recurrence before scans actually show it. Sequencing is hard, and there are contaminants and difficulties calling a mutation/sequence cancerous, but I have had patients self-refer after a positive GRAIL test, no symptoms, and bam, biopsy from area of interest shows early cancer.
You can detect tumor cells circulating in blood for certain cancers. You can get the cost down by having these tests covered at regular intervals by insurance companies.
Or make it over the counter and pay the $500.
The article reminds me of the cowpea mosaic virus, a similar hope that seems to force the immune system to attack the cancer:
https://www.dartmouth-hitchcock.org/stories/article/norris-c...
https://www.bloomberg.com/press-releases/2022-02-02/newly-pu...
Has this been written up in some respected journal? (No, not Nature.)
Their research was published in Cancer Cell.
https://www.prnewswire.com/news-releases/engeneic-announces-...
https://engeneic.com/
Othes by Stillman : https://scholar.google.com/citations?user=ANthHuAAAAAJ&hl=en...
Does anyone know about updates on mRNA treatments for cancer? I had big hopes after the impressive corona-virus vaccines. I know BioNTech is investing heavily but not much has changed since then?
There are a few vaccines that try to 'make' your immune system recognize an abnormal (read cancerous) protein as foreign (Sipleucel T for prostate, GMCSF vaccine for melanoma). Minimal activity.
When could we realistically see this solution for someone with prostate cancer?
https://engeneic.com/intellectual-property/
It's a scam.
so this can put the breaks on cancer, but it can't fix cancer?
I'm far from an expert, but my Dad is currently battling a high-grade glioblastoma multiforme tumor in his brain. So I've learned a little.
> so this can put the breaks on cancer, but it can't fix cancer?
"Putting the brakes on cancer" is basically equivalent to "fixing cancer". For my Dad's GBM, he has an MRI from 13 years before his diagnosis that seems to show the early stages of his tumor. At the time, his neuro noted that it was mildly concerning, but then didn't order any follow-up testing. So the tumor lay "dormant" in my Dad's head for over a decade. Then it started rapidly growing last year, until he was losing his balance at work, started getting scans, and eventually found the brain tumor.
All of the standard of care around this is focused on mechanical or electromagnetic removal of large parts of the tumor, combined with throwing whatever chemotherapies you can at the body to stop the tumor from growing. Eventually, the tumor grows until it squeezes out all normal brain functionality. Anything that can arrest the tumor without killing you is good.
Paper from a peer reviewed repo, not press releases please
I ctrl+f for "patent" and got no hits, so forwarded it to someone on our team to dive in to further.
Someday soon they'll look at our insane chemotherapy with the same level of utter disbelief as we do about bloodletting and tapeworm diets
I mean untargeted chemotherapy kills -the one thing- that protects us since before we were born from cancer, our immune system.
Killing our immune system to kill cancer makes as much sense as shooting off the leg you lead with so to run faster.
Its idiotic, stupid and, yeah its basically trying to stop the copy errors in genes that cancer does, before all the massive amount of DNA errors kill the cancer victim ...
It's like a really really bad CRISPR process as I understand it, like the computer program SED was majorly crapping out and it made your program an utter mess.
Anyway, chemotherapy is DAMN foolish, and I for one will be glad when we're rid of it with better therapies
I'd argue that our future retrospective view of chemotherapy will be more of how we view hunting with a club rather than, say, a bow and arrow. Not optimal but, at least in many cases, proven to be better than nothing by multiple randomized clinical trials.
If you got cancer and the onclogist recommended chemo, would you refuse it?
Invent something better if you know how. For many people chemo is their hope and in many cases does wonders by itself or in combination with other methods, either in parallel or in succession.
Nanoparticle-delivered chemotherapy could also be a potential solution, and is actively researched.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357073/
Watch all the funding dry up and the researcher get framed for some random, stupid crime, with just enough prison time to make sure he won't see the inside of a lab again before he's too senile to use it or dead. Could also be a slip in the tub etc.
There's a lot of money in suffering, and if you think there aren't people sick enough out there to do real horrible shit to protect that income stream, you're kidding yourself.
How do you think this fucked up civilization was twisted into the giant pulsating tumor it currently is?