The Polarized Postdoc

Posts Tagged ‘cancer

Resistance

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The fight with cancer is a battle of endurance, and persistence. In the end, for each individual and for the science community, the last one standing will be the winner. Until then, all tricks, dirty and otherwise, are justified.

The same way that wars can be studied as strategic games by compartimentalizing away all their horror, it is sometimes fascinating to be at the front lines and get a glimpse of the progress of the cancer battle, in real time. A good example is this book about the development of herceptin, a novel about the process of developing a successful drug against breast cancer. Far from an sterilized science report, it is an enthralling tale of hope and human bravery. But wait, don´t run out to buy the book just yet, please, first finish reading the post!

The basis of any anti-cancer attack lies on the fact that cancer cells don´t form an isolated army, but instead hide guerrilla-style amongst the normal cells in your body. So we have to identify them, and get rid of them either by resecting the tumor mass or by applying somehow selective chemical weapons.

Not so long ago, we witnessed the raise of targeted therapies as effective chemical treatments of many tumor types. The rationale of this approach resides in classifying tumors according to their molecular profile, instead of organ or histological type, and targeting the underlying genetic lesions that generates or sustains tumor growth.

There are different ways to do this, such as using small molecule inhibitors (TKIs) that stop the pernicious activity of the oncogenic kinases. Antibodies that block the proteins responsible for the aberrant properties (uncontrolled growth, invasion, dedifferentiation) are currently effective therapies against breast cancer too. Wider in scope, anti mitotic agents kill cells when they try to divide and expand. Normal cells are usual quiescent so they can dodge the killer drug, except from the parts of our bodies that undergo active turnover such as our hair, mucosas, and immune systems. Which explains the sometimes terrible side effects.

Recently, yet another smart gun has been devised, taking advantage of the unique aspects of cancer biology. Once of the reasons why tumor cells roam free and divide in a fast and uncontrolled manner is the fact that they have over-ridden part of the exquisite control mechanisms that ensure genetic integrity during cell division. These mechanisms are like will executors, making sure that the daughter cells receive one each an accurate and faithful copy of their mother genetic material. Then they can read and interpret it to build all their cellular structures in their progenitor´s image. This is of utter importance for the survival and correct function of the organism and is often the bottom line alteration triggering carcinogenic events. For this reason, many redundant mechanisms simultaneously oversee cell division in this manner and although loss of one of them can be tolerated, and even beneficial for cancer cells, complete lost is programmed to inevitably lead to system failure and death. Tumor cells live on the edge, escaping surveillance to be able to divide even if they carry severe genetic aberrations, just barely enough to avoid programmed cell death.

Researchers have just released a new drug, olaparib, that inhibits the function of one of the control mechanisms that dictates if cells survive aberrant division or commit suicide, and have shown that it can be used to selectively kill tumor cells. Now, other concerns regarding short-term and long-term toxicity will have to be addressed, but this does not obscure this brilliant victory for our side.

Sadly, even in the midst of success, there is a fast turnaround for the good news, and no long after some these drugs prove efficiency, the first signs of resistance are reported. The rough, fast-paced tumor cells have a high rate of mutation that allows them to adapt to adverse environments. So soon after seemingly succumbing to the TKI drugs, tumors resprout having developed new ways of surviving and thriving that lend the pathways targeted by the drugs obsolete.

Seldom prey of discouragement, there you find the scientists again, running back to their labs to design and test new drugs. The next battle starts studying how the resistance appears, following the process in the test tubes or tissue culture plates. Many great researchers like Dr. Sordella are currently working on coming up with new strategies that will kill the resistant tumors, and eventually unravel the basis of resistance itself to stop it before it develops.

The urgency, relevance and exciting nature of this type of work can be strongly addictive, as I can personally atest. Sometimes it is hard to find a reason to leave the lab, at all, which is dangerous enough for obvious reasons. But to keep the fight alive we need more motivated researchers, more inventive minds and brave patients, and if you are neither of those, you can still go ahead and chip in some money for the many fundraising initiatives.

But no matter how neatly and thoroughly we swim over it, the horror is still there. The crude reality of the cancer disease is everywhere around us. A few days ago I learned of the terrible disease affecting a dear professor of mine. He is fighting lung cancer with erlotinib, the same drug whose improvement I was just helping write a grant to fund. I wish him all the best, with all my heart. But my mind also knows the side effects, the probabilities, the uncertain waiting time and the failure rate he is facing.

My thoughts also go to the many people proud to be working hard to give, if not him, other future patients a better chance. One of them, another dear friend, has gotten sick as well, cause cancer spares nobody. And takes down civilians and enemy soldiers alike.

Sometimes the implications of this job just sneak up on you, sometimes they make you choke, reminding you of just how impotent we are when facing the enemy one on one. That is why we need an army, and a well-equipped one at that.

I promise I will stop bothering you with gloomy posts, and put up soon more joyful and delicious experiments, but I had to say that I can´t think of much better ways to put your money to good use than throwing some bucks here and there to help cancer research, or any research for that matter. We will try to use it wisely, and will be thankful for it. Because in the end, statistics non-withstanding, every day that we are still standing is a triumph against the disease.

To all those fighting, know that even if everything else fails you will still have our love and support. We will be rooting for you. Resist, my braves!

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Written by polarizedpostdoc

July 23, 2009 at 12:59

Posted in personal, science

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Evolutionary noise

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This year I celebrated America´s birthday in style, sitting around with my friends in our beer and burger filled bellies playing the evolution game. Basically, a hand-waving exercise to entertain ourselves whilst fireworks do their natural selection bit around the neighborhood. It consists in picking a natural feature or trait around you (from blue eyes to curved finches), and by applying simple evolutionary rules decide how and why it was preserved to be witnessed by us today. When asked about the rules by the significant non-scientist present, we were able to distill all the beauty and wisdom of Darwin´s theory in a few simple parameters: traits are selected-for, in a given environment, if they confer an advantage for either survival or procreation.

Everything else that comes along for the ride can be considered evolutionary noise. The term defines seemingly useless traits such as the ability to twist your tongue or move your ears. Unless you can do either in a really sexy way that can help guarantee your reproductive success, that is. Unfortunately for me, when I think about evolutionary noise I can not dodge this mental thumbnail of a low deep humming caused by our tail bones retracting and our skulls expanding. But I still love the game.

Of course, when played on a 4th of July evening, fireflies are the first thing to come up.

caught in mid-courtship by the National Geographic

caught in mid-courtship by the National Geographic

We were all pretty close to accurate in speculating that light production, in all its refinement and uniqueness, cannot be a by-product of insect species divergence. The green sparks are, far from noise, a well-tuned performance by the summer dusk orchestra. Our best, almost-educated guess was that flashes play a role in mating and/or prey attraction. This turned out to be true, albeit in a sleek and refined way: flash patterns actually differ from one firefly species to another, allowing the similar looking bugs to recognize a suitable partner. Which is definitely useful, and could even come in handy in some dark human shindigs I know. Moreover, some firefly females use their flash patterns to attract males from other species and eat them. Much like in the aforementioned shindigs, romance is a risky business in the mid summer nights.

From the evolution perspective, firefly light is all quiet, except from the smooching and chewing. The firefly take on “better living through chemistry” fits the profile of a selected-for advantageous adaptation. So maybe to hear the noise one has to come closer, and stare at recent evolution instead of long-hauled characteristics. For that I proposed an example recently learned from population genetics, one of the coolest scientific disciplines. Some weeks ago I had the pleasure to become acquainted with the work of GS Atwal. Simply put, Dr. Atwal uses overly complex statistical tools to dissect the distribution of genetic variants (aka allelles or SNPs in their multiple forms) in different human populations.

It has been known for a while that the genetic background determines susceptibility to certain diseases, including cancer. Population genetic studies are aimed at describing how the different variants appear, often linked to more trackable traits. The population distribution of some faulty variants of tumor suppressor genes correlates with the respective incidence of cancers that stem from the malfunction of the protein encoded by those defective genes. Confronted with this, the question that Atwal asked to climb to the next level of knowledge was how and why, even if they are obviously harmful, do these variants get fixed and stay in the population. Sort of a formal version of the evolution game, without fireworks or fireflies.

At a glance, it would seem like those cancer-prone variants (polymorphisms) are just lousy evolutionary noise. If you apply the rules, these variants do not affect survival of the individual until well after the peak of reproductive age (which is still in the prime of our twenties, biologically speaking). But in collaboration with some eminent geneticists and systems biology experts, Atwal determined that in some cases, the cancerous polymorphisms correlated with a better reproductive success, by increasing fertility rates and facilitating embryonic implantation. These studies in mice reveal an interesting aspect of cancer genetics, the antagonistic pleitropy of some of the genes involved in cancer protection pathways. This concept, while extremely stimulating for future cancer research purposes, is definitely not indicative of evolutionary noise, but of a complex symphony of form and function, shaping the way we perceive natural selection as we grow able to interfere with it. So even when cancer is in play, in the end is Evolution 1, Noise 0.

The score remained tight as well around the dinner table, as we continued to seek out other examples in the warmth of the quieting darkness, and together we lengthy discussed biological sounds of the kind of thumbs and tears and hair and appendixes, with moderate success and plenty of laughter, feeling loved, amused and content. And looking around to capture that moment of sheer perfection, I wondered at the unlikeness of it all, the infinite permutations along the invisible road that led to here, now. It occurred to me right there that the noise might be part of the music of change, entwined with the melody, and that only if they are inextricably blended chance can have a direction.

And I could not help but whisper, trying to entreat the swift moment,

Tarry a while! You are so fair!

Happy 4th of July, everybody.

Written by polarizedpostdoc

July 6, 2009 at 15:15

Posted in personal, science

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Know your enemy

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Contrary to what the buzz says, new developments in the war against cancer are not that hard to come by, or that minor. Those important characteristics in anti-cancer advances (speed, abundance and relevance) are in direct correlation to the money and effort invested in research. Which is why we need to keep committing both to an unfaltering fight. Because even the smallest victory saves countless lives, present and future.

It is my personal experience that usually cancer research elicits respect, and often encouragement, from lay audiences understanding the fierceness of the fight on both sides. But for some reason, lately cancer research is under a heavy flak of criticism based on lack of progress and innovativeness.

I disagree with both claims as strongly and biasedly as I possibly can. And I could use my insider´s view to go on a really righteous and uptight diatribe about why and how, exactly, but in my best scientist behavior I am going to just let the facts speak for themselves.

Just recently, two new therapies have been announced, one of them stemming from a pretty revolutionary and novel approach called synthetic lethality. In an agile leap from ideas to cures, this new concept has already provided effective therapies for one of the most aggressive and poorly understood forms of breast cancer, the so-called triple negative tumors. This positive response represents not only a victory, but a spearhead propelling us ahead in the game, opening new possibilities for treating other forms of the disease.

Because contrary to the rules of engagement proposed initially when we declared this war against cancer, the enemy is neither one, nor static. Cancer is an ample term that fits in solid armies of tumors growing silent and morphing in many different organs, guerrillas of circulating tumor cells ready to invade new territories, dormant mutations that act like secret agents turning normal cells to the dark side, collaborationist immune system components, and many more wicked weapons yet to be uncovered.

It has been clear for a while that the most effective way of winning is by getting to know your enemies, in every terrific form they take, and fight them to the ground one by one. This logic is simple and powerful enough, on top of tried and true, and I am perplexed as to why mass media can´t seem to accept it. There is not going to be a single bullet solution for cancer, but we are sure going to keep winning battles, if only they let us fight in peace.

One of the most poignant ones is the ongoing quest to discover how tumor cells can leave their niche and, evading several layers of surveillance, infiltrate other organs spreading the disease and making it impossible to control by surgical methods. Last week I had the privilege to witness an outstanding scientist describing how his group has devised a novel system to observe in real time the sly tricks of invasive tumor cells, shedding some light about the initial steps of this deadly process called metastasis.

The group of John Condeelis managed to put a microscope video camera inside a mouse breast tumor, and monitored the movements of tumor cells. In their recordings, we are able to witness in awe the showdown between immune cells (the vigilant macrophages) and tumor cells, as they chase each other´s chemical scent while sliding down the tumor´s scaffold of collagen fibers. The tumor cells swiftly follow the macrophage signal, EGF, to the blood vessels, where they can extend cellular protrusions to break into the blood stream. Hence, the first step towards invasion has happened, silently and far from the tightly surveilled edges of the tumor.

tumor cells ambush a blood vessel, ready to go on a invasion mission

green tumor cells ambush a red blood vessel, ready to go on a invasion mission

Once they had gathered this valuable recon intel, the researchers were able to capture some of these rogue tumor cells, simply by luring them with the same chemical whiff into a trap, a collagen coated steel tube. The prisoners were subjected to exhaustive interrogation of their genomes, which allowed for the identification of the potent weapons they were using to dig into the blood vessel and escape.
One of the proteins thus identified, dubbed Mena invasion isoform, is a unique variant found in cancer cells that enables for efficient movement and rearrangement of the cytoskeleton when the cell is reaching and carving the vessel wall. Sort of like claws and fangs, except more scary.
This finding is of outstanding importance and lasting relevance, and it makes me proud to be a scientist working on cancer. For the skeptics out there, yes, it is still too early, but surely the identification of both the mechanism and the molecular player responsible will in time allow for the development of drugs that stop either, or both. Just like with anti-angiogenesis therapies that cut enemy supply lines, limiting tumor cell mobility may not kill the disease completely, but it blows a severe hit on its progression. And sometimes that is all you need to maintain people alive, so we can all keep fighting.

Written by polarizedpostdoc

July 2, 2009 at 15:57

Posted in science

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