
Why Is It So Difficult to Develop Drugs for Cancer? (2010) - valhalla
http://www.newyorker.com/magazine/2010/05/17/the-treatment-2
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static_noise
Two things come to mind immediately:

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.

~~~
hhjj
Can't we just kill half the cells periodically until there is no more
cancerous cells ?

~~~
carterehsmith
We can, but that kills the patient.

~~~
ubernostrum
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).

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pvnick
This is the kind of statistics that really tugs at your heart strings. This is
a Kaplan–Meier chart: [http://oncology101.net/wp-
content/uploads/2013/04/OPTMAL_sur...](http://oncology101.net/wp-
content/uploads/2013/04/OPTMAL_survival-curve1.jpg)

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.

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Eric_WVGG
This comic is a pretty great summation:
[http://www.phdcomics.com/comics/archive.php?comicid=1162](http://www.phdcomics.com/comics/archive.php?comicid=1162)

~~~
giardini
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.

~~~
iskander
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).

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reasonattlm
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.

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mmaunder
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.

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BorisMelnik
Very informative, is there some sort of 2015 updated version of this to show
how far we've come in regards to the Kaplan-Meier curve?

~~~
iskander
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.

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Myrth
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?

~~~
refurb
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.

~~~
atomical
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.

~~~
J_Darnley
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.

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Gatsky
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.

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alephnil
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.

~~~
raarts
Spelling 'disease' correctly would add a lot of credibility to your arguments.

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iskander
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.

~~~
venomsnake
You will be surprised how fast research can move when the generation holding
the power are nearing their old age

~~~
iskander
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.

~~~
venomsnake
Yeah but baby boomers are and exceptional generation. The generation behind
them is smaller (the Gen-X ers)

------
known
Editing DNA should cure Cancer;
[http://www.bbc.com/news/health-34200029](http://www.bbc.com/news/health-34200029)

------
nextos
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.

~~~
easter6
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.

~~~
nextos
I am extremely sorry to hear :(

Have you thought about trying an immunotherapy? I've seen some impressive
outcomes.

~~~
easter6
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.

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zmmmmm
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.

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blazespin
cancer is the halting problem:
[https://en.wikipedia.org/wiki/Halting_problem](https://en.wikipedia.org/wiki/Halting_problem)

~~~
danieltillett
No need to be that pessimistic.

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iskander
The article is paywalled for me, is there an alternative link?

~~~
agumonkey
Try this
[http://www.printfriendly.com/print/?source=homepage&url=http...](http://www.printfriendly.com/print/?source=homepage&url=http%3A%2F%2Fwww.newyorker.com%2Fmagazine%2F2010%2F05%2F17%2Fthe-
treatment-2)

~~~
iskander
Thanks!

------
danieltillett
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.

~~~
iskander
>If you made me cancer dictator with an NIH budget and an ability to set the
rules I could provide very rapid progress.

What would you change?

~~~
danieltillett
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.

~~~
iskander
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?

~~~
danieltillett
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.

~~~
carterehsmith
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.

~~~
danieltillett
I actually know about a lot of things :)

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.

