AndDownstreamEffectorsVille
In the last post I mentioned that I worked with the powerful K-Ras oncogene to make experimental tumours a long, long time ago, back in the days when our then Canadian prime minister (i.e. the guy with the really big chin) was making the very, very best of all possible non-dodgy, pasta consultant-assisted deals to buy a whole bunch of jet planes from Europa.
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Hey!
How's that for a lede!
Anyway, to recap....
When I was mucking about with K-Ras in the lab way back in the late 1980's and early 1990's, it was already becoming abundantly clear that its oncoprotein it codes for drives the formation of a whole bunch of real tumours in actual people one example of which is the hard to treat, and often deadly, pancreatic ductal adenocarcinoma (PDAC).
Which brings us to the big breakthrough that was announced recently - a novel drug treatment that significantly lengthens the lifespan of folks with PDAC in a mid-stage clinical trial.
So, how does this breakthrough drug work?
Well, as you might have guessed given the set up, it blocks the activity of the K-Ras oncoprotein.
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People were trying to block the activity of K-Ras, which lurks inside tumor cells and does its dastardly deed by jacking up cell division and survival, way before I started working on it.
So why has it taken forty years, plus, to get there?
Well...
Back in the day, one of the ways to do this was to use something called 'scrape loading' wherein cells in a culture dish are scraped to poke holes in their membranes so that you can load them up with big, honking neutralizing antibodies that bind to the K-ras protein. However, this approach doesn't work in people because poking holes in the membranes of cells inside your body is not a good thing (i.e. it's super toxic).
But people kept trying.
The thing is, K-Ras is really hard to drug. First of all, to turn K-Ras 'off' you actually have to activate an enzymatic activity that is built-into the oncoprotein. This is tough, because designing a drug that messes up an enzyme is way easier than designing a drug that revs up (i.e. activates) said enzyme. Luckily, in the case of oncoproteins that have enzymic activity, inhibiting that activity turns the majority of them off. Thus, a whole bunch of the new class of 'rational' chemotherapeutic drugs work by inhibiting the enzymatic activity of the oncoprotein. Thus, these inhibitor drugs and usually have names that end in 'ib'. A good example of this is Imatinib a drug that inhibits the activity of an oncoprotein called Bcr-Abl that drives cell division in a sub-type of leukaemia cells.
You can also use antibodies as drugs that bind to oncoproteins to mess them up and ultimately turn them off, but these work best when they first bind to the oncoproteins that have bits that stick out of the tumor cell. These antibody-based drugs often end 'ab'. A good example of this is Trastuzumab, an inhibitory antibody that first binds to an oncoprotein called Her2 on the cell surface of one of the now treatable sub-types of breast cancer.
The other difficulty with trying to drug K-Ras is that molecule itself is slippery and smooth which makes it difficult to find, or build, a small molecule that can bind and stick to it.
So, given all these issues, people kept trying to make K-Ras inhibitors and they kept failing. This was such a problem that by the 2000's many smart folks started saying that K-Ras was 'undruggable'. Lucky for us, some even smarter people didn't quit and started thinking that, instead of trying to turn K-Ras itself 'off' that they would instead try to block the its ability to interact with and turn on the 'downstream effectors' of the oncoprotein that actually drive uncontrolled cell division.
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By now your eyes are probably starting to glaze over with all the weird nomenclature and terminology that keeps creeping into this post no matter how hard I try to keep it out.
So.
Let's take a little break and I'll deal with all of that next time when I get down to explaining precisely how and why the new K-Ras drug is such a blockbuster.
Talk to you all then!
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Speaking of weird nomenclature, you may have been wondering where the name 'K-Ras' comes from...Well, remember that virus I was telling you about that we used way back in the olden days (i.e. the 1980's) to get the oncoprotein expressed in cells to make experimental tumours?....Well it was first isolated by a pathologist named Werner Kirsten way back in the year of Canada's centennial based on its ability, as a cell-free extract, to cause Rats to form soft tissue tumours called sarcomas...Thus the name K-Ras...Which just goes to so that, unlike, say, fruit fly geneticists who come up with crazy gene names like Sonic Hedgehog, Armadillo and Big-Brain, cancer biologists tend to come up with pretty boring derivative gene monikers.
Image at the top of the post?....These are cells isolated from the outermost part of the adrenal cortex that are being grown in a culture dish...They have been infected with the Kirsten sarcoma virus and thus the viral genome has started to make the K-Ras oncoprotein inside them...The bright white bits you can see inside the elongated cultured cells actually represent those K-Ras oncoproteins which have been fluorescently tagged by that antibody I wrote about in the post, above...As for the big donut holes in the middle of each elongated cell that have very little of the white stuff...Those are nuclei...K-Ras oncoproteins hate to be in the nucleus and instead they hangout out in the cell's cytoplasm where they bind to membranes to become functional such that they can interact with upstream signals and downstream effectors...But more about all that next time.
As for those jet planes that were first foisted upon us by the big chinned guy way back when...As much as I hate to admit it, I far prefer flying in a relatively roomy Airbus rather than the overly cramped cigar tubes that the super-fine folks down in Seattle are building these days.
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