Friday Rambling

Finally DONE with counting cells. The new definiens software for cell counting came but the sad thing is, my supervisor came up with the theory that tumor necrosis may effect our results and started making me keep track of dead cells, which are hard for the software to recognize since they have fragmented nuclear contents that screw up the cell count, so I ended up having to spend most of monday-thursday counting images by hand again -.- but it's all done now... and I get Friday to relax/write/stalk all of your blogs ^^.

I'm starting to enjoy pharmacy, at least the biology behind it if not the labwork and image analysis. So I thought I'd write about the project we've been working on for the last two months. If biology bores you, stop reading now.

The main candidate drug of our company is tivozanib and it's an inhibitor of VEGF receptors and without going into detail about the specifics of the mechanism, the VEGF pathway basically induces angiogenesis (growth of microvessels) in tumors. So treatment of tivozanib inhibits angiogenesis, triggers hypoxia and stops the delivery of nutrients and oxygen to the tumor region. The company has created an almost complete human-in-mice archive and the bioinformatics department have been working on a gene expression profile for each kind of tumors they have in the archive. An interesting thing they discovered was that the tumors resistant to tivozanib generally shows a significantly higher expression of myeloid genes associated with macrophage activation. So a hypothesis that someone came up with is that macrophage activity plays an angiogenic role in these resistant tumor types. In the project I'm involved in, we want to see if depleting macrophage count will turn tivo-resistant tumors into tivo-sensitive tumors. We've tested a couple of *what we thought* was macrophage inhibiting molecules in combination with tivozanib to see if there is a greater tumor inhibition. One of the molecules that showed promising results was xeloda. It's a chemo drug that's already been approved and studies have shown that it's effective in treating bone marrow diseases such as leukemia. So from my basic understanding of the rationale behind picking this molecule to target the macrophage: leukemia is a cancer of white blood cells, therefore macrophages are involved and if xeloda treats leukemia, it kills macrophages? Whatever the rationale is, we got very surprising results. Treatment of tivo-xeloda combo works much better than the additive effect of tivo only, or xeloda only in terms of reducing tumor volume, which, so far, is to be expected based on our hypothesis. However, when I looked at the images of IHC, the macrophage count on the xeloda and xeloda+tivo seems to be actually greater than the vehicle (control) and tivo only treatment arms, which completely contradicts the xeloda-kills-macrophage-theory. Since scientists are a bunch of skeptics they used three other methods to confirm the IHC, still getting the same results, AND made the group repeat the whole experiment, getting the same results again (a whole month work put to waste, gah). So in the end, we found a combo that works great and could translate into useful clinical information, but our initial understanding of the mechanism behind it turned out to be completely wrong. Accidental result based on bullshit reasoning, lol. We're still working out ways to explain the synergistic effect of xeloda and tivo. The most simple explanation is that tivo targets blood vessels and xeloda directly kills tumor cells, but we're still unsure whether macrophage activity contributes to this effect. Yesterday our group called an emergency meeting and talked about the results/future directions, it was very confusing to follow, especially since my direct supervior and his supervisor get into heated arguments all the time, but pretty exciting nevertheless.

I think for the next month we'll be focusing more on a Tivo-Avastin comparison project. Avastin is the frontline drug that's on the shelves for the type of cancers we're interested in treating. Based on our phase one and two clinical results, Tivo not only work better but shows less side effects for patients. Now, it's just a matter of organizing more presentable results and marketing big time, and hoping Tivo gets through phase III of clinical trials.

This morning we had a biweekly presentation, I had a hard time paying attention due to the lack of sleep (slept at 3:30 yesterday and woke up at 7, fudge), but there was one thing that I got a laugh out of. So the presenter today showed a slide from a tumor efficacy study done in Japan, there was a graph of tumor volumes vs number of days after treatment, and a few of the treatment arms went up to as high as 9000 mm^3 (that's about as big as the mouse itself). Wow Japan, so much for animal health regulation. So AVEO was originally planning on using this data in an upcoming conference, but they don't want people to question it and then have to deal with complications. So, one person proposed (as a joke, or maybe not...) that we should change the numbers into percent increase, to hide the actual values, which I find very clever, but very sad. I'm sure they'll end up settling this in a more professional way, but it makes me question just much of the data from the scientific community is really trustworthy...