1. Cancer cells are human cells and behave very similar to human cells compared to foreign bacteria or viruses which have a vastly different metabolism.
2. Cancer is not a single disease but a gazillion different mutations which may have vastly different characteristics.
Point 1 most of the time prevents cures such as "kill the human cells" from working effectively without killing the patient, too. Successufull cancer cells look so "human" that even the immune system doesn't see the difference. Point 2 means that the "cure for cancer" may be found for some kinds of cancer but there are thousands more. If we cure all cancers known today we will find new ones when the patients are just a few years older. Remember that the death rate increases exponentially with age and so will diseases like cancer.
3. Cancer cells can be hard to get to with drug therapy. Even if we have a drug that kills the cell in question we can't always get therapeutic concentrations into the core of solid tumors, and we can't get many drugs past the blood brain barrier.
4. Cancer cells can be highly unstable, genetically, depending on what part of the DNA got mangled. Unstable cells that mutate rapidly follow the same Darwinian logic you see in microbes. A single tumor can contain thousands of different mutations of the original cell type, and if your therapy kills 99% of them the 1% that come roaring back will be highly resistant to whatever strategy you used the first time around.
This is not far off from what much traditional chemotherapy actually does. The approach is to literally poison yourself, and hope that as a whole you can take more of it than the cancerous cells can.
One of the approaches used in chemotherapy is drugs which disrupt cell division or associated processes. Which means the cells dividing most frequently (i.e., cancerous cells) are the ones hardest hit by the drug.
Though this does affect other cell types which divide frequently, which is why chemotherapy patients lose their hair (hair follicles need rapid cell division) have digestive problems (digestive cells divide rapidly) and can suffer immune-related issues (bone marrow divides rapidly).
Do you study biochemistry or medicine? Because it would seem that your first point is completely true but technically an oversimplification when it comes to treatment of common cancers.
Those are classic success stories mainly because they were the low-hanging fruit for targeted cancer treatment. For blood-cell cancers like leukemia and lymphoma, treatment has come a long way due to advances like the ones you mentioned.
For "solid" tumor cancers like breast, pancreatic, prostate, and skin cancer, we're still struggling to make a dent in the death rate.
> For "solid" tumor cancers like breast, pancreatic, prostate, and skin cancer, we're still struggling to make a dent in the death rate.
Actually, we are not "struggling" on breast cancer. The death rate comes down a reasonable percentage each year.
It's just that a small percentage compounds slower and slower once you take out the low hanging fruit.
As you point out, the problem is that cancer isn't just one disease with one mechanism. Even "breast" cancer isn't just one disease with one mechanism.
So, it's not terribly profitable to go after say "cancer X with mutations P, D, and Q". This really needs government funding.
We'd have been far better off with a governmental "War on Cancer" than on any of the other "War on X" that they've done.
>So, it's not terribly profitable to go after say "cancer X with mutations P, D, and Q". This really needs government funding.
This is one of the key problems. The effective size of most true cancers types is so small that pharmaceutical companies can’t make a profit developing a drug that targets these cancers. Imagine you identify a new drug that 100% cures people with a cancer that has three specific mutations. Now lets assume that out of the millions of people who get cancer each year only 500 have this particular combinations of mutations. This drug will cost the same as any other drug to develop (lets assume $1 billion), but you can only sell it to 500 people per year. Even if you set the price at $100,000 per person you don’t come close to earning enough money to pay back the development costs. Add in the fact that very few drugs make it through the whole development process you can see why we have a problem.
If it costs $1 billion for private companies to develop a drug, why wouldn't it cost $1 billion for government to develop it? Spending $1 billion to save 500 people will bankrupt the country one way or another, if you keep going after cures for 500 people groups, whether government funds it or not.
A more effective approach would be to find ways to reduce the cost of new drug development.
I'm skeptical it's as bad as that. We classify cancers by the type of cell that went bad, i.e. lung cancer if it occurs in the lung, liver cancer if it occurs in the liver, brain cancer if it occurs in the brain, etc. But you can have, say, lung and liver cancers that result from the same mutation, and there's a chance, at least, they'll respond to the same therapy.
And sometimes there are other diseases caused by problems in whatever pathway you're messing with. Tamoxifen, for example, can be used to treat two relatively rare non-cancer diseases.
Classify cancers by the tissue origin is only of partial help in treating. A cancer may arise in the liver, but be totally refractory to one treatment, but respond to another.
One way to workout how many different cancers there are when classified by treatment response is to look at the true cure rate to when a cancer is treated using a treatment. Since the treatments we have are biased in targeting the most common sub-types this can only give us a lower bound, but even this number is huge since the cancer cure rate is not that high for the most common cancers (I am not talking about 5 year survival, but real cure). My rough guess is there are 10,000s of different cancers when classified by treatment response.
>Classify cancers by the tissue origin is only of partial help in treating. A cancer may arise in the liver, but be totally refractory to one treatment, but respond to another.
Well, sure. That's my point, though. Cancers that arise indifferent parts of the body may be treatable with the same drug.
>One way to workout how many different cancers there are when classified by treatment response is to look at the true cure rate to when a cancer is treated using a treatment.
That's the current situation as it stands today. It's not necessarily what we'll see in five or ten years.
The problem is that we don’t have the range of treatment types to target all the the different mutation types. Most of the drugs we have target the same basic pathways like DNA damage repair - we have dozens of these drugs, but very few targeting specific mutations. We need a lot more diversity of action in our drugs if we have a chance to cure cancer.
Having said this the most hopeful area is the immunotherapies. Scaled out to their full potential we could have a very powerful set of drugs to go after the cancer diversity problem.
Well these two problems are technical problems that can only occur if the key economic problem can be overcome. You can only have issues with enrolling people in a trial if the trial is at least attempted.
The current thinking is that cancers are not evolving for resistance during treatment, but that there are a sub-population of cells present in the tumour mass that are being selected for by treatment (i.e. we kill 99% of the tumour that is sensitive and the 1% that is resistant grows back).
We know how to solve this problem from HIV. HIV evolves resistance to drugs faster than any cancer yet we can treat patients for years by using HAART (i.e. give lots of drugs at once that target different key components). We need to do this with cancer, but this will require developing new drugs that are less lethal since you can't just give a patient a dozen standard anti-cancer drugs and expect them to live.
>The current thinking is that cancers are not evolving for resistance during treatment, but that there are a sub-population of cells present in the tumour mass that are being selected for by treatment (i.e. we kill 99% of the tumour that is sensitive and the 1% that is resistant grows back).
No, the cancer evolves resistance during treatment. Evolution is change in allele frequency in a population over time, not the emergence of new mutation. It does not matter whether the mutation was a rare, preexisting mutation or it occurred after treatment; both likely happen. The "evolution" part is the outgrowth as a result of a fitness differential produced by the new environment (therapy).
>We know how to solve this problem from HIV. HIV evolves resistance to drugs faster than any cancer yet we can treat patients for years by using HAART (i.e. give lots of drugs at once that target different key components). We need to do this with cancer, but this will require developing new drugs that are less lethal since you can't just give a patient a dozen standard anti-cancer drugs and expect them to live.
We will never be able to do this with cancer. HIV has only nine proteins in its genome. This means any resistance mutation it develops must be on-target and will tend to operate through specific bottleneck points. This is not true with cancer - there is on-target resistance, of course, but this is easily overcome through better drug design. We can develop drugs that get around EGFR T790M, but in a cancer there are a dozen different new mutations in other genes that can emerge to produce resistance. Drugging all of these targets in advance is impossible - we can barely drug one gene with patients tolerating it. We'll lose this game of whack-a-mole.
This is a losing game in general. The tumor has too much space to adapt - it's not limited to a tiny genomic space like HIV, it has the whole human genome to work with.
This is why I think successful strategies are going to result from not inhibiting particular genes but treating the tumor as a tissue and modulating the host/tumor interactions. Immunotherapy acts on this axis, and it's already looking more promising in this regard (responders don't tend to become resistant).
I think we are in agreement, but you did say "2. Evolved resistance with an entirely new set of mutations”. I was pointing out that evolution is not coming about from the selection of new mutations, but the selection of pre-existing mutations present with the tumour before treatment.
>Drugging all of these targets in advance is impossible - we can barely drug one gene with patients tolerating it. We'll lose this game of whack-a-mole.
It is not impossible, just difficult. It will certainly be impossible if we keep trying to develop new treatments the way we have for the last 50 years. We need to change the entire way we screen and test new cancer treatments if we are going to be able to use the HAART approach in human cancer.
I agree with you that immunotherapy is looking the most promising approach right now, but done right chemotherapy has a lot of potential too. I would not rule one or the other out.
Lets distinguish between diagnosis and treatment. Many cancers can be identified by the over-expression of genes or other genetic material. This knowledge is immediately useful to clinical staff. Although its hard to use this information to target specific cells, it hints at mechanisms that are of interest to academic research.
Everytime the line takes a step down, at least one person has died. The only happy ending is that less people die, and a really happy ending is when significantly less people die in the treatment group than the control group. Really puts things into perspective.
Unfortunately the comic missed the reason why such research continues: people will pay most of their money for a cure for (or even a temporary reprieve from) _their_ cancer. This becomes "all of their money" rather than "most..." if their child has cancer.
Cancer centers are enormous money-generating systems. Most of their research is useless but the doctors running them get rich, the corporations who own them get rich, all of their patients die and in the end nobody cares so the process continues.
I actually agree with you up until the last sentence. Many researchers and doctors care quite a bit and are excited to finally be moving toward curative treatments (rather than chemo treadmills).
I especially like how it explains the meaning behind the oft repeated mantra that cancer is not a single disease, or that cancer is not a single disease therefore there will never be a cure for cancer. Both these statements reflect true facts about the nature of cancer, but out of context they sound like weird illogical platitudes.
I'd argue that progress is slow because the research community is spending too little time on lines of work that can address many or all types of cancer. If you look at most cancer research it is highly specific to the molecular biochemistry of one subtype of cancer with a tiny percentage of overall patients. Yet that work is rarely any less costly than any of the possible paths forward to broad cancer therapies.
Examples:
1) Telomere extension interdiction, either via disabling telomerase in some way, or more cleverly disabling the effects of telomerase in a targeted fashion in cancer cells only, as has been demonstrated in early stage research.
2) ALT disruption, for the minority of cancers that abuse ALT to extend telomeres rather than telomerase.
3) Chimeric antibody receptor based immunotherapies. Still to soon to tell how broad these might be in their application.
4) CD47 targeting coupled to any discriminating cell destruction system. CD47 seems to be a very broad marker for many types of cancer.
But disruption of telomere lengthening is definitely at the top of this list. It should be possible to suppress it globally (both telomerase and ALT) in a patient in the worst case and wait out the cancer's withering before turning it back on. This would be considerably less harmful than chemotherapy and much more effective. It would require no targeting, no cancer specificity, and just work. A number of research groups are working on slices of this technology, but by no means enough.
A few comments: Firstly early detection has gotten way better than the 90's. PET/CT's are standard in the USA now which is awesome for staging and diagnostics - still scarce in the rest of the World. Early diagnosis is huge in treating the big C.
Drugs that aren't chemotherapy but are biotherapies (or immunotherapies) like Rituximab (Rituxin) are available now which have improved prognosis in some cancers by 15% which is a big deal.
Pathology labs are doing a much better job now of identifying genetic subtypes which help target therapies. Right now they use staining techniques to figure out which subtype you have based on a known subtype looking the same way when stained. Hopefully one day they'll be able to sequence each pathology sample.
Also just responding to a few comments about the economics: Cancer drugs and treatment are insanely expensive in the USA and much of the rest of the World. So the economic incentive is very much there for companies like Genentech to develop drugs like Rituxin (at $5K a dose).
So my sense is that this isn't a cure or no cure disease. Instead we're accelerating towards improving outcomes by either putting the disease into remission in a lot of patients and delivering in some cases decades more life - or actually curing them.
The biggest difference, as of 2015, is that we now have an extremely promising and more coherent research direction in the form of immunotherapy: (1) activating and disinhibiting adaptive immune cells (2) engineering highly active immune cells that target known tumor markers, and mostly recently, (3) personalized therapeutic vaccination against a patient's specific cancer. The first two approaches have already shown significant improvements in survival for several cancer types and there are literally hundreds, if not thousands, of combinations and variations worth trying that might extend efficacy to most cancer types.
Specifically, for metastatic melanoma, the "asymptote" of trial survival curves used to be around 0-10% long-term survivors. The first successful immune checkpoint agent, ipilimumab, brought the survival asymptote up to ~15-20%. The next agents, nivolumab & pembrolizumab, brought the survival asymptote up to ~40-60%. The combination of both approaches seems to result in long-term survival for ~60-85% of patients (at the cost of more extreme side effects). That's a tremendous improvement that we've seen over just ~8 years, and in a disease that was previously thought to be intractable.
A question for people in the know - if there's a research/treatment that can not be patented/monetized due to its generic nature, but it still requires millions of dollars in trials - is it doomed to never be done?
I think that not too many folks have tried that hard, really. But whatever, I'm giving it a shot. (Setting up and running a fun experiment today). I got 60k in funding from crowd funding, which is great for a startup nonprofit with no reputation. This is enough to do a mouse equivalent of the kaplan-meier curve.... But not enough to pay myself (I variously drive for Lyft and contract code to make ends meet).
Worth noting the salk and Sabin polio vaccines were not patented.
I would say a real breakthrough would still get done through gov't or non-profit support. It just might take a lot longer than a drug with clear financial upside.
DCA - dichloroactate comes to mind. It was promising but unpatentable. It got lots of funding.
There are a lot of research chemicals that have potential but are discarded for various reason. Usually the reasons revolve around efficacy. A lot of them can be bought off Alibaba. Something to think about if you're desperate.
Myo-inositol trispyrophosphate has a lot of potential for cancer treatment. And its use in sports doping has decreased the price.
Heh. What I read there is "Even more widespread doping is sports will lead to a cure for cancer". Sounds like a reason to encourage doping rather than trying to stamp it out.
Unless the therapy you envision requires simply isolation of unchanged DNA and injection of that DNA back into a person without any modification whatsoever, it's likely that you could obtain a patent on a novel therapy.
I don't believe that the answer to this is "because the task is difficult".
I actually think the answer is simply - because the life sciences are in their infancy. It's like asking a medieval astronomer why it's so difficult to fly to the moon.
At the end of the day we do science with our brains, and our brains are not built to understand biology. How could they be? To really be able to understand even the simplest, isolated biological process, you probably need to hold at least a thousand bits of data in working memory. You can build a model on a computer, but we still don't know what the important bits of data are out of many millions, we don't know when they are missing, and we don't know when our model begins to be valid and ceases to be valid.
In contrast, a physicist can gain deep insight about the ENTIRE universe while sitting under a tree with a pen and paper and some cogent abstractions. Furthermore, this insight is valid backwards and forwards in time except in clearly obvious extreme conditions.
This is actually completely amazing when you think about it. We would like to think the same about biology, and scientists act this way, but we would be mistaken. Abstractions fail in biology. Even the most basic and obvious abstractions made by humans, like the concept of a gene, are too simple to act as a foundation for ongoing discovery. And we don't have any alternative framework.
There are several reasons why cancer is so difficult to treat, but the main one is simply that cancer cells is the patients own cells that have a couple of mutations, so most things that kill cancer cells also kill healthy cells. Thus successful cancer treatments are those who kills the cancer cells, but only almost kill the patient.
The other main reason why cancer treatment is difficult is that there are many different combinations of genes that can mutate and cause cancer, so that even the same cell type can get cancer several different ways. There are at least six different kinds of breast cancer for example, where a drug effective against one can be totally ineffective against another, and this is the case for a lot of cancer types. Thus cancer is not one decease, but hundreds of different deceases, each requiring different treatment. It is quite amazing that more than half of those getting cancer treatment actually get cured today.
It's amazing to read an article about cancer drug development which doesn't talk about the successful immunotherapies. I know that checkpoint blockade and cellular therapies weren't as widely known in 2010, but it shows how shockingly far research has moved in a relatively short period of time.
That's been true as long as treatments for cancer have ever been researched (reaching back to the 1800s). Only recently have immunotherapies started yielding significant clinical results for common cancer types. I think the change in efficacy has a lot more to do with the accumulation of scientific knowledge about the immune system (it hasn't been long since we even discovered T-cells or dendritic cells), along with huge improvements in genetic sequence & editing.
It seems to be the shared assumption of the Internet age that somewhere out there is a powerful "them" controlling everything. All the worlds problems are due to "them" acting in their own interests, and everything would be fine if only "we" could put ourselves in charge instead.
I think much progress will come in the form of early diagnostics. It's easy to spot developing cancers by looking for free DNA in blood. Cheap and non-invasive.
This works particularly well for cancers with recurring mutational patterns (like KRAS mutations in pancreatic cancer), since that lets you affordably do ultra-deep sequencing of small regions of the genome. If you had to deep (>5000x coverage) sequencing of many megabases then (with currently available platforms) the diagnostic wouldn't be affordable.
early detection is great, if you're being specifically checked for cancer. the problem is that you can have tumors growing inside you for years, and during that time, the effects of those tumors may lead your doctor to misdiagnose the problem. And by the time those tumors make themselves painfully obvious, you've got Stage 4 cancer which is pretty much a death sentence.
In the US you can order your doctor to arrange a cancer screening for you (scan or blood test), if you are worried you may have cancer. It's your money, after all. In other countries such as Canada, that's not so easily done. You're at the mercy of whatever doctor you've ended up with, and that doctor is not going to do anything for you unless it makes sense to him.
This has basically been my experience, anyhow. Thanks to my doctor's inaction I have maybe 6 months to live.
I had to look up what immunotherapy is... not sure if it would do much good in my case, because I don't have much of an immune system at this point. I've already quit chemotherapy.. think I went 6 rounds before 'throwing in the towel'. Seems pointless to postpone what is inevitable, but I can understand how some might want to hang on.. particularly if one is married and with children.
How do you tell the difference between slow growing cancers and fast growing cancers?
EG: for many men the treatment for prostate cancer has severe side effects and their cancer is something they would have died with, not of. Being able tell which cancers are slow or fast would improve many lives.
One idea: if you have a biomarker you can track via CTCs or ctDNA, then you could watch the rate at which that marker's availability increases.
The PSA doubling time for indolent prostate cancers can often be measured in years, whereas CA 19-9 doubling time for pancreatic cancer is more often measured in days or months.
Honestly, 2010 is now quite a long time ago in cancer research. I would not read any article from then and hope to understand the current state of knowledge. Not that it isn't interesting, but it's almost more from a historical perspective at this point.
Cancer is hard for lots of reasons, but the main reason we have not made the progress we should have is the way we are going about looking for new treatments. Our animal models don't reflect natural human disease, we use the wrong way of classifying cancers (by tissue of origin rather than sensitivity), and we require that all new treatment provide a rapid response in terminal patients (stage I/II trials). If you made me cancer dictator with an NIH sized budget and an ability to set the rules I could provide very rapid progress.
Edit. I normally don't care about being down voted, but on a serious topic like this it really does everyone a disservice. If you disagree with something I have written then please reply rather than mindless reaching for the down arrow.
This is really deserving of a blog post/essay, but the main thing to get right is the discovery process. We have millions of pre-existing drugs (the NIH has looked at millions on its own), the problem is the way we go about selecting possible treatments from them. In brief what I would do is:
1. Demand we use animal models that reflect actual human disease (natural occurrence in old age). No more sticking human cancers cell lines into SCID mice.
2. Genome sequence all human cancers so that we classify them by genetic defects. We should not care which tissue a cancer arose in, but by which drugs it is selectively sensitive to.
3. Test new treatments in patients that reflect actual patients - ie newly diagnosed patients, not patients that are weeks away from dying and who have failed everything else.
4. Go all out on the immune approach with an emphasis on developing treatments with minimal side-effects that can be given to healthy people as a preventative treatment. We need to think about cancer as something we prevent rather than cure.
1) Aside from significant increase in cost and experiment turn-around time, there's a more basic question: if you don't use a replicable and scalable model of the disease, how do you induce the cancer you're interested in studying? Wait around for one of ~5000 mice to develop pancreatic cancer?
2) There's already significant efforts underway to sequence many thousands of human tumors (e.g. you probably know about TCGA). Once the cost drops a bit more, then it might be feasible to sequence all tumors. However, a pathologist can still tell you quite a bit that's hard to reverse-engineer from sequencing (e.g. does the cell look like a melanocyte?). Classifying by tissue of origin (+ the ontology of cancer subtypes) does actually capture a lot of the variation between cancers. Sequencing adds a little on top of that, but surprisingly not as much as people hoped. For example, how often can you predict actionable drug sensitivity from RNAseq or WES? In my experience so far, there's only even the possibility of clinical benefit in a small number of special cases (e.g. BRAF V600E).
3) Newly diagnosed patients often have great treatment options! Do you really want to RCTs with placebo arms on stage I breast cancer patients?
4)
"Go all out on the immune approach" there's been a huge boost of funding in that direction (by the NCI/NIH and private donors like Sean Parker).
"with an emphasis on developing treatments with minimal side-effects that can be given to healthy people as a preventative treatment." That's an interesting idea and I don't know who's working on it. Write it up as a grant proposal and send it to the CRI?
Glad to be getting some thoughtful responses rather than idiotic down votes.
1. Basically yes, although I would centralise the breeding of mice and then farm them out to researchers as they developed each of the different cancers. Another option that we are not making as much use of as we can is natural cancer in human pets. We have millions of dogs and cats developing natural cancers that we could use.
2. Yes sequencing has not shown the promise for treatment that we hoped, but that is because the treatments we have were not developed with genomic data. It doesn't matter how much you know about a cancer if you don't have any tools to actually attack the weaknesses identified. We need to use the genomic data to indentify weaknesses, then use these identified weaknesses to screen for new treatments.
The best targets will be those genes that are not normally expressed in adult tissue that are expressed in cancer tissue. When I was an academic I had a student look into this area and there are literally hundreds of genes that are regularly expressed in cancer that are not expressed in adults. These are perfect targets for immune treatments provided you have enough of them to draw on.
3. Actually most newly diagnosed patients have deceptively great treatment options. For most cancers most of our treatments are just delaying tactics, not curative. Anyway for those few cancers where we have great curative cancers treatments are not the areas that I would start on.
4. Many people have tried to get funding in this area without success. You appear to know something about the funding process so you would know that any such grant would fail to get funded. Because of the needs for a proper animal model infrustucture it would not be possible to do anyway. I would rather concentrate on getting the animal models right before working on any new treatments.
People downvote because you come across as either a dummy, or a snake oil peddler. Based on your blog, you know about PHP, Windows... That is great, but does not exactly qualify you to be NHS czar. If you think it does, well... good luck.
I am actually a former tenured academic scientist in the School of Pharmacy and Applied Science at Latrobe University here in Australia. I currently run a genomics software company (Nucleics). Cancer is one area I have had an active research interest in over the years and have thought a lot about these questions. While I may be wrong I hope I am not a dummy.
You say that one key is experimenting on pets(which will have huge barriers in the west). In china, eating dogs is legal.So why haven't we seen such research coming from china, and especially successful drugs from there?
Actually there has been some research into cancer treatment using pets in the west, just not as much as we should be doing [1].
We really need to organise all the pets into clinical trials of new treatments. People have done surveys of pet owners and most people are happy for their pet to participate in such trials especially if they know that they are helping human research and other pets. We just need to start using this amazing resource rather than giving mice artificial cancers.
As for why more research has not come out of China, a lot of really interesting research is going on right now in China, it will just take a little time to filter out to us in the west. Drug development is a 15 to 20 year journey and China has only recently entered this domain.
1. Cancer cells are human cells and behave very similar to human cells compared to foreign bacteria or viruses which have a vastly different metabolism.
2. Cancer is not a single disease but a gazillion different mutations which may have vastly different characteristics.
Point 1 most of the time prevents cures such as "kill the human cells" from working effectively without killing the patient, too. Successufull cancer cells look so "human" that even the immune system doesn't see the difference. Point 2 means that the "cure for cancer" may be found for some kinds of cancer but there are thousands more. If we cure all cancers known today we will find new ones when the patients are just a few years older. Remember that the death rate increases exponentially with age and so will diseases like cancer.