Meditations of an oncology geek

Archive for January, 2013

Is the cancer stem cell model obsolete?

without comments

28 January 2013

It is widely accepted (appreciated?) that tumors are tantalizingly heterogeneous; they are not just a ball of cancer cells. A proverbial mountain of research has emerged characterizing most solid tumors as a hierarchy of different cell types that contribute to what might be best viewed as a pseudo-organ with its own perverse “homeostasis.” There has emerged the model of the “Cancer Stem Cell” (CSC) in which a small population of tumor cells can give rise to an entire (heterogeneous) tumor.

The CSC model is attractive for several reasons:
1) It provides a model of carcinogenesis in which the long-lived stem cells in tissues are the ones that acquire mutations and go awry; already containing some of the hallmarks of cancer (self-renewal, resistance to apoptosis)
2) It provides a mechanism for how tumors can become heterogeneous, as stem cells are capable of giving rise to more than one cell type.
3) It would explain how tumors become resistant to chemotherapy, and suggests a means fight target tumors with much less side-effects!

I will not delve into reason #1 here, but reason #3 is of great personal interest (I admit I’m a sucker for things that could greatly improve cancer therapy). The approach is this: target the CSC’s so the tumor cannot renew itself! (illustrated above, courtesy: wiki commons)

However, a recent phenomenon reported by Robert Weinberg’s group suggests that this process is not unidirectional, and that a small population of non-CSC’s can convert back to CSC’s. At his talk last week, Weinberg presented even more compelling data than was shown in the PNAS paper.

Confusing? You bet. (I would show the actual data in the paper, but I’m pretty sure I’d be violating copyright laws for that one) Apparently, one would need to design drugs to both kill CSC’s, and prevent the spontaneous de-differentiation into CSC’s…

At this point, I’m left wondering about the entire “Cancer Stem Cell” or “Cancer Progenitor Cell” label. It could be that ALL tumor cells are capable of reverting back to CSC’s. Weinberg assumes this is not so in follow-up reviews in the literature, and proposes a third population of “non-CSC” or “dormant-CSC” with little evidence to suggest that such a population exists.

Unidirectional differentiation is central to the CSC model, and how we would use the theory to design therapeutic approaches. Perhaps it’s time to take a step back and re-draw the model from scratch in light of the new data? This is something I’ll spend more time thinking about myself.

I wish I could end this post with a concise story and model. Unfortunately, I only have ambiguity of rapidly changing models of cancer metastasis for the time being. I’m willing to bet other research groups are working on this as I type this, and I will re-visit this topic in the future as more research comes to light.

Ryon

Written by Ryon

January 27th, 2013 at 8:34 pm

Posted in Science Blog

The godfather himself: Robert Weinberg visits the Moores Cancer Center

without comments

24 January 2013

Yesterday I had the pleasure of attending a talk by Robert Weinberg, perhaps one of the most influential scientists to ever tackle cancer. Weinberg pioneered research on oncogenes and tumor suppressor genes, and his 2000 review paper The Hallmarks of Cancer carries the distinction as the most cited paper in Cell and even has its own wikipedia page.

These days Weinberg is still at it, and his group at MIT is no less prolific in their publishing. His lab today works on two (somewhat converging) areas of cancer biology that are both highly contentious and controversial: cancer stem cells (CSC) and “epithelial to mesenchymal transition” (EMT).

As I’ve stressed time and time again in my blog: the vast majority of cancer mortality and debilitating effects of the disease are caused by metastasis, or the spread of cancer to vital organs. The leading theory on HOW cancer cells are able to spread and seed distant organs is EMT. The theory essentially proposes that cancer cells in a primary (epithelial) tumor are able to de-differentiate into a (mesenchymal) state, allowing them to change shape and turn from cellular bricks to contortionists, enabling them to weave their way through tissues to blood vessels, and after a ride through the blood stream, exit by slipping between endothelial cells lining capillaries, then re-differentiating from contortionists (mesenchymal) to cellular bricks (epithelial) again. See image.

The evidence for this process occurring in (human engineered) mouse models of cancer is pretty good. However, this theory has come under fire due to the utter lack of histological evidence from hundreds of thousands of human patient biopsies every year. Granted, EMT is theorized to be a transient event, and not all pathologists are really looking for evidence of EMT all the time; they’re usually looking at other clues in the tumor for how to best treat an individual patient. However, in science the onus is to prove that something exists, not that something does not exist. Does EMT really occur in humans? Would this mechanism be of use to cancer therapeutic strategies? At the time of this writing, these questions remain open-ended.

My problem with EMT is that the definition changes from researcher to researcher, and can at times even be contradicting. It’s become a scientific buzzword often used to make new research appear concise and consistent when in fact valuable nuances might be glossed over in the process. Granted, theories can change over time with new data and observations, and it is possible that not everyone is on the same page. I was really hoping that Weinberg would have provided a concise definition of EMT in his talk. Instead, problems with the phenomena were pseudo-discussed in terms of “partial EMT” or “limited EMT.”

I will discuss the evolution of the cancer stem cell hypothesis (and how this is affecting therapeutic approach and drug investment) when I have more time, but for the moment I must step away from the keyboard and attend to my cell cultures!

Ryon

Written by Ryon

January 24th, 2013 at 11:20 am

Posted in Science Blog

Tumor heterogeneity: The fly in the ointment of cancer genomics-driven therapy?

without comments

9 January 2012

As I mentioned in my last post, I’m maybe just a little bit excited about the UCSD Moores Cancer Center’s shift in focus toward genomics based cancer therapy: My Answer to Cancer.

Dr. Scott Lippman is the new director of the Moores Cancer Center, and summarized the project:

Until now, cancer treatment has been a one-size-fits-all approach. Recent technological advances have made it possible to generate a profile of all the abnormalities in the genetic code of a tumor. By gathering enough data, we can identify profiles that will allow us to tailor cancer treatments to individual patients. In other words, we will open up a whole new world of cancer treatment that could lead to saving many patients who never had a chance before.

Dr. Lippman continues:

We will implement genomic sequencing and personalized care for all of our patients. To fund this bold new approach to cancer treatment, we are looking to all of you, our donors, to help us raise an initial $5 million to provide personalized cancer treatment for the first 1,000 patients.

New targeted cancer therapies coming into the clinic have a lot of promise, so long as they are given to the correct patients; most will work extremely well with minimal side effects… for a small fraction of cancers. For instance, maybe 10% of patients’ breast cancer will have the correct genetic profile to respond to a new monoclonal antibody or enzyme inhibitor. Cancer genomics promises to make these profiles much clearer, and to much more quickly refine use of new therapeutic tools in the clinic.

In my last post I portrayed fighting cancer as analogous to a medieval siege of a fortified city. The potential of personalized cancer treatment through cancer genomics would be like knowing in advance where the weaknesses are in the walls of the fortified city. Sort of.

Cancer is not a fortified city; it’s hundreds of millions of them. To add to this, they’re not all the same, and do not have the same weak points, even within an individual patient. The Emperor of All Maladies earns this distinction not only from the horrible complications of advanced disease, but the uncanny ability to grow resistant to therapy and come back stronger and more deadly than before.

Cancer is evolution on steroids. Most cancers are genetically unstable to begin with, and as a tumor grows (and begins to spread) it becomes more and more heterogeneous; the same weakness will not work for every fortification. Or worse, using the same strategy against all fortified cancer cells will leave only the resistant cells remaining, which then re-populate the patient (not good!). There is also the conundrum of current therapeutic side effects weakening the patient, making treatment of a second or third wave of cancer resistance even more difficult to treat.

Could cancer genomics be that expert battlefield intelligence to bring down the fortresses? I’ve previous written about another complication with this approach: intratumor heterogeneity and the need to sequence multiple regions of an individual tumor. Simply put, unless multiple regions of an individual tumor are sequenced to give a good idea of the essential and non-essential (“driver” vs. “non-driver”) mutations, there’s a good possibility that even the most directed therapies will no match (after the first or second round) for the Emperor of all Maladies.

According to a genomics expert at the UCSD School of Medicine, with the current technology the costs of genomic sequencing is between $2000 to $4000 per genome. Dr. Lippman’s proposed fundraising would theoretically cover the cost of one or two sequences per patient among the 1000 patients, but that assumption is void of administrative costs, or other sources of funding (grants, etc).

Will that be enough sampling to overcome hurdles of tumor heterogeneity? How many sequences from how many tumor biopsies per patient are needed to breach the fortresses? Do we have he tools to exploit the weaknesses we identify? Do we know enough about cancer biology to recognize a weakness when we see it? These are open-ended questions that I (and quite possibly no one else) have the answers to… yet. It is my hope that this new initiative will successfully answer some of these questions.

Ryon

Written by Ryon

January 9th, 2013 at 10:50 am

Posted in Science Blog

No longer science fiction: cancer genomics is coming to the UCSD Moores Cancer Center

without comments

7 January 2012

Curing cancer is hard. Perhaps that’s a gross understatement? I was once sat next to a lovely businesswoman on a plane who asked: “You know, we’ve put men on the moon. Why haven’t we cured cancer?” I just shrugged my shoulders and replied “Because curing cancer is harder than putting men on the moon?”

There’s a pervasive dark humor among cancer researchers and cancer clinicians. It’s a field that sees infrequent, small progressions compared to to many other endeavors to a problem that has strong emotional resonance to dire needs of patients fighting what Siddhartha Mukherjee correctly called “The Emperor of all Maladies.”

So, when I occasionally see something uplifting in my field it really sticks. The UCSD Moores Cancer Center recently hired Dr. Scott Lippman as our new director, and he recently gave a lunchtime talk to an overcrowded commons room filled with scientists, students, clinicians, directors, and everything in between. The initiative My Answer to Cancer is audacious: to set up many, many new clinical trials to pioneer the use of cancer genomics for the individualized treatment of cancer.

Image: The Moores Cancer Center will be pioneering new clinical trials using cancer genomics as a tour de force. My lab is upstairs. I’m only a little proud…

What is this cancer genomics thing, and why is this goofy scientific apprentice so excited about it? In cancer research circles it’s a borderline mythical tactic previously confined to science-fiction, the type that researchers dream about, but the dark sarcasm of the field prevents anyone from getting too excited. It would be like commanding a medieval siege against a heavily fortified city, but knowing ahead of time that under the east wall is a secret access tunnel that can be exploited with the right tools. Cancer genomics has always had that aura of potential to be exactly that; the filter that makes the enemy’s weaknesses painfully visible for exploitation.

A genome is the sum of all sequences of all genes in an individual. It’s a mind-boggling amount of information; in the second decade of the 21st century genomes are commonly communicated between researchers by hard discs in physical mail to save time because of the amount of bandwidth otherwise required.

Until recently, it was prohibitively expensive to do this for anyone. Not anymore. In fact, it’s within reach for one to consider doing this for both a patient’s genome AND their cancer. It would literally single out how the cancer differs from the patient, knowledge that was previously unthinkable, and immediately imply the correct tools (therapeutics, weapons?) to cripple an individual’s cancer with minimal side effects to the patient.

Dr. Lippman wants to do exactly this. It’s audacious, but the unique private sector and industry collaborations immediately available to the MCC here in San Diego make this vision much less opaque, if not readily feasible, despite my dark sarcasm.

2013 is looking to be a big year for the Moores Cancer Center. I’m really excited to see what comes of this.

Though I do have reservations and criticisms about current technological and methological limitations, I will outline these in a future post and not damper the sunny glimmers of progression and hope that I wish to share with you, dear reader!

Ryon

claimtoken-50ecb55790666

Written by Ryon

January 7th, 2013 at 4:25 pm

Posted in Science Blog

Squeezing Boobs and Breast Cancer

without comments

2 January 2013

Nappy New Year! I hope you had a great time with friends and family, dear reader. If your New Year’s celebration was anything like mine, it might have involved get-togethers, cocktails, and tangental (illuminating?) conversations. As the token science nerd in the room I was often bombarded questions regarding a recent report that ricocheted around the Web:

As reported in the reputable Nature NewsBlog: “Breast cancer behaviour: more than mutations
and ScienceNews: “Pressure keeps cancer cells in check” to the more common type of attention-grabbing science-ish journalism “Squeezing breasts ‘can stop cancer’ ” which, by the time it got to me at a party sounded like “Dude, so I heard that squeezing boobs prevents cancer?!? Awesome!” followed up with ideas for crude pickup lines that could only seem appropriate given the (not so) mild influence of alcohol.

While I admit such reporting did generate a fair amount of humorous discourse, I would like to point out something that I feel has been under-reported about the study: This science has not been published yet. All good science goes through rigorous peer-review to weed out poor controls and flawed logic, among other things. As a scientist, it’s hard to take these reports seriously without the actual paper in hand, and I must suspend judgement until it has gone through those rigors (as should everyone else).

This phenomenon was reported in an annual meeting of the American Society for Cell Biology. Though undeniably a prestigious symposium, it is not a surrogate for peer-review. However, some of the comments made by the researchers made me raise an eyebrow:

“People have known for centuries that physical force can influence our bodies,” said Gautham Venugopalan, a leading member of the research team at the University of California in Berkeley. “When we lift weights our muscles get bigger. The force of gravity is essential to keeping our bones strong. Here we show that physical force can play a role in the growth – and reversion – of cancer cells.”

While those statements are not overtly fallacious, it leads one to believe that cancer can be treated with physical force. Ok, so what kind of physical force? Is the force always a good thing? Could it harm? How much? Does this change with age? Does this work for cancer metastases too? What about bone metastases? Does this work as a preventive measure?

From what I can gather some of the research seems both plausible and insightful, IF it survives peer-review, which it has not yet.

Once published, I will do a follow-up. Until then, I do not endorse use of this study for anything more than cheesy sarcastic pickup lines.

Ryon

Written by Ryon

January 2nd, 2013 at 1:27 pm

Posted in Science Blog