
An unexpected twist in cancer metabolism - J3L2404
http://web.mit.edu/newsoffice/2010/cancer-metabolism-0917.html
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carbocation
It is always delightful to me when people look more closely at well-understood
pathways and make new discoveries that change our understanding. This is one
such occasion.

Basically, it appears that they discovered a feed-forward loop in the
synthesis of phosphoenolpyruvate, the penultimate product of glycolysis.
Though this wasn't mentioned in the news article, I wonder if this helps to
explain the Warburg effect.

Anyways, this doesn't exactly jump out to me with applications since the
research seems so early stage. True, discovery of novel pathways implies that
inhibition of these pathways could be useful for treating cancer. But until
some research is actually done in that vein, I'm hesitant to read too deeply.
I'll review the manuscript itself, but I don't think we know for sure that
this "cancer-only" pathway is not at play in important, rapidly-growing non-
cancerous tissues, which would be my main concern.

~~~
carbocation
OK, I've read the manuscript now. Very interesting work. I didn't realize this
initially, but they are also saying that the transient phosphorylation of
PGAM1 is a mechanism by which PEP is converted to pyruvate at a meaningful
rate!

Reason for the exclamation point: the conversion of PEP -> pyruvate is is
considered the last of 3 rate-limiting steps in glycolysis. They propose an
end-run around this rate-limiting step. In their model, PEP donates its
phosphate to PGAM1. Thus, PEP becomes pyruvate. Normally I wouldn't expect
this to be a meaningful way to produce pyruvate--but their data appear to
support the notion that PGAM1 becomes dephosphorylated at a high enough rate
that this process can repeat itself fast enough to sustain pyruvate
production. Oh, and phosphorylated PGAM1 isn't just a temporary phosphate
holder--they hypothesize (relying on other studies) that it helps shunt
carbons into biosynthetic pathways (which you need if you are a proliferating
cancer).

It's not every day that someone figures out how living cells bypass a
canonical rate-limiting step in the fundamental metabolic process shared by
all living things.

~~~
noonespecial
It took me about 20 minutes to google all of the terms in your response and
figure out why this is really important, but I feel like I might actually get
some of this this now and feel the excitement.

Thanks for this as the paper itself was more or less unapproachable for me.
Biohacking still seems to me like this great big unexplored space filled with
new terms and exciting ideas that I'm just beginning to get acquainted with.

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bitdiddle
Having just spent 3 days at an annual NCI meeting this article sort of made
sense to me. What's fascinating is that the state of the art is moving so fast
in this field that many are predicting within a few years we'll be able to
deliver individualized chemo-therapies. General internists and even
oncologists can't keep up with the rate of progress.

As an aside, it's also a space where fast moving small startups could make a
big difference

~~~
carbocation
The key is to individualize to the level of the specific cancer, not
necessarily to the patient with the cancer (Osler would punch me for saying
this).

I say this because, for example, leukemia is not one cancer; it is a
constellation of cancers with similar features. However, if you take one
specific cancer from this group (chronic myelogenous leukemia of the Bcr/abl
type), you can treat it with imatinib. The survival at 5 years with imatinib
is 89%--an incredible success. I'm saying this to point out that we _already
have_ individualized treatments for (a vanishing minority of) cancers.

As we grow to understand the molecular and genetic basis for each individual
cancer, we will, one by one, be able to target these and turn them into
chronic diseases like hypertension or hypercholesterolemia. Perhaps, one day,
we will even cure them. The current article being discussed actually hints at
a more global phenomenon, and may produce tools that we can use _as add-ons
to_ the individualized cancer treatments that we will be giving patients.

I'll just repeat the two things that I always like to say in this type of
discussion:

1: We need to target the molecular basis for disease.

2: We need to remember the HAART model when treating cancer, which involves
targeting multiple enzymes necessary for tumor growth and proliferation (or at
least target different parts of the same enzymes) in order to fight drug
resistance.

~~~
bitdiddle
Well as a programmer I won't dispute your assertion, but what I heard at a
keynote from a very prestigious scientist is that we will actually start
targeting the patient, not just the specific cancer. He cited some examples
where certain known therapies that starve tumors are disastrous in a very
small percentage of patients due to certain genetic differences. It was like
hearing science fiction. This is certainly a great time to be in this field.

~~~
carbocation
The scientist and I don't disagree; I think we just have a semantic
difference. If the cancer is genetically different from the expectation, then
it requires a different treatment. So if you have a disease that looks just
like CML but doesn't have a Bcr/Abl fusion tyrosine kinase, imatinib is
probably not what we'd want to use. I would call that molecule-centric, and
s/he might call it patient-centric. Either way, the wording doesn't matter so
long as you're treating the patient with the most appropriate therapy.

~~~
bitdiddle
I see, well I'll certainly take your word for it. I really need to read more
of this literature as I've been working with these folks quite a bit, and
hardly know the difference between a gene and a protein.

~~~
carbocation
Are you doing bioinformatics? If so, it's a great excuse to learn more about
the field, and learning more about the field will make you care more about the
work you're doing--a feed-forward loop. At least, when I started doing medical
genetic research, that's how things worked for me.

~~~
bitdiddle
sort of, I work in description logics, they are used to build medical
terminologies. NCI has used them over the years in cancer genomics. A good
amount has rubbed off just hanging out with these folks but recently I've
become keen to learn more.

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etal
Here's the original article/abstract:

<http://www.sciencemag.org/cgi/content/abstract/329/5998/1492>

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stcredzero
Only a layman here, but it wounds like this could inhibit tumor growth in a
broad spectrum of cancers. I wonder, if a drug inhibiting this alternative
metabolic pathway were developed, would cancers simply evolve a different
pathway?

~~~
etal
Maybe (I don't study this) but at least some of this pathway is also used in
embryonic cells, so it's pretty fundamental. More often, cancer cells will
evolve resistance to whatever inhibitor molecule is targeting them, i.e.
mutate so the ligand doesn't bind as well.

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StavrosK
50 minutes and no doctor/researcher has rained on this parade yet? Where is
everybody?

