One Drug to Shrink All Tumors | Hacker News Reader

One Drug to Shrink All Tumors

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187 pointsph0rque51 comments

Wow. Extraordinary claims require extraordinary evidence, but Irv Weissman and his lab are the real deal. Here's the original article (which is open access): http://www.pnas.org/content/early/2012/03/20/1121623109

Of course, this isn't the first time we've seen such promising initial results only to hit roadblocks in translation, but here's to hoping it's a real effect, even if it eventually turns out to be less than a true "cure"!

Edit: looks like this is follow-up work from Weissman's research on Leukemia, which is considered influential: http://www.cell.com/abstract/S0092-8674(09)00650-3

The trouble is that there are many, many different ways that a cancerous cell is able to be cancerous.

A malignant cancer cell has generally had upwards of 7 mutational events that directly enable it to replicate itself enough times to form a tumor and become damaging.

These mutations includes things like breaking programmed cell death (apoptosis) pathways (e.g. P53 mutations), increases in anaerobic glycolysis (due to lack of oxygen within the micro-environment of a tumor), increasing production of angiogenesis related proteins (to create new blood vessels to the tumor so that it can continue to grow).

Cancer cells even acquire mutations to the pathways that regulate DNA damage repair and replication so that further mutations happen more easily, providing more variation in the clonal colony of cancerous cells making the "cancer" more able to withstand changes in the tumors environment (e.g. the introduction of chemotherapy, hypoxia, etc). Essentially the cancer evolves over relatively short periods of time.

In other words, this is just one pathway that there is a chance we may be able to disrupt, but it may very well be a crucial one. If we can build up enough drugs to target the specific mutations that make some cancers so aggressive, then we stand a good chance at significantly reducing the mortality of cancer.

Excellent research, but we have a long way to go still.

Yes, however, the "drug" described (it's more of an idea for a drug at this stage, really) does not aim to disrupt the tumor cell itself. Instead it's based on the observation that many (maybe most?) cancerous cells over-express the protein CD47 on their surfaces as a survival mechanism in order to prevent macrophages and dendrites from taking them out.

If successful - and that's a big if, because I'd be willing to wager this treatment will never see the light of day - if successful, the drug would break the CD47 recognition mechanism by blocking the protein with antibodies, thereby allowing the patient's immune system to attack the malfunctioning cells. In a way this would be more elegant than aiming at re-starting apoptosis pathways or blocking the expression of angiogenesis factors because the specific mechanisms employed by cancer cells to do so seem to vary greatly as you said.

Unfortunately, evolution is evolution, and if there is any way that cancer cells can trick the immune system that does not require CD47, trust me we'll know about it after the first few months using this drug. We've probably learned more about the intricate inner workings of cells by studying the ways in which cancers can evade treatments than by any other method. Still, I don't doubt this will be another tool in the oncologists tool belt and likely a useful one at that.

Is cancer cured? Not by a long shot!

What I find mildly disappointing is that cancer is an evolutionary process, but it is still treated primarily as a cell signaling disease. That is, everyone is studying how to attack individual cells. What we really need is a better understanding of the evolutionary process as a whole. Combination treatments are likely the correct solution, but which ones? in what doses? with what timing? Those are questions we need to answer.

  Unfortunately, evolution is evolution, and if there is any way that 
  cancer cells can trick the immune system that does not require CD47, 
  trust me we'll know about it after the first few months using this drug.

I totally agree. Also, I'm skeptical about side effects. We'll see. As I said, I don't believe this will come out as an actual drug.

  What I find mildly disappointing is that cancer is an evolutionary 
  process, but it is still treated primarily as a cell signaling disease.

Absolutely. We spend a lot of time figuring out the biochemical intricacies of very specialized tumor cells with, predictably, not a lot to show for it. My guess is we'll be making inroads this way as far as pre-cancerous and early stage disease is concerned but we simply lack the technology to deal with the phenomenon itself. To speculate further, I don't think this will be solved by micro-advancements in pharmaceuticals (even quite well-targeted ones), I believe we need a new class of active agent that can go in there and make decisions on a cell-by-cell basis if necessary.

Isn't the evolution of cancer cells rather more constrained than your average pathogen? A normal pathogen can infect many thousands or millions of hosts, and can evolve immunities over many years, decades or centuries. A cancer is limited to a single host, and cannot pass on any of its tricks; it must start from scratch each time.

If we had medicine as potent as penicillin that could attack or inhibit certain cancer cells, it might be that the cancer simply wouldn't have the time to fight back before it's removed entirely.

Cancer cells are rather more difficult to distinguish from normal cells than bacteria, of course, but it seems reasonable to assume we'd have less problems with cancer cells evolving defences.

One big difference between typical pathogens and cancer cells is that cancer cells have much more unstable genomes. Cancer cells divide rapidly and when they do, all sorts of mutations occur.

Even for someone with a diagnosed cancer (i.e. ovarian cancer), there are typically hundreds if not thousands of different types of cancer cells. This is what makes treating cancer so difficult. A drug may knock down 95% of your cancer, but the cells it didn't kill have no problem coming back and are now treatment-resistant.

There are plenty of drugs that work for cancer type A, B, C etc. Unfortunately, there are billions of people in the world all randomly generating Cancer's so all possible mutations are going to show up eventually in somebody.

Which presents the problem, let's say the most common 50% of all cancers are easily cured by drug X. Well the other 50% are all less common and moving to 100% is only going to get harder as you progress.

>>>Which presents the problem, let's say the most common 50% of all cancers are easily cured by drug X. Well the other 50% are all less common and moving to 100% is only going to get harder as you progress.

But for those who are in the 50% who can be cured in the first wave...

... and maybe one of them will go on to develop the cure that helps the remaining 50%.

But keep in mind each of those cancers is developing and evolving independently. Wiping out one type of cancer doesn't make it more likely for the other to proliferate on a population-wide scale. Sure, this treatment might not end up working for everyone, because some people's cancers might have developed chance resistance, but a whole bunch of people are going to be helped and cured without any ill evolutionary consequences.

Wait, how is this claim extraordinary? There's a proposed mechanism that doesn't seem to contradict anything we had previously thought we knew about biology, its not like researcher is claiming that he's found evidence for Lamarkian evolution or something.

We ask for extraordinary evidence for claims that are in and of themselves extraordinary. Simply having extraordinary implications doesn't warrant needing extraordinary evidence, though we should always be hesitant to rely on one person's experiments whether their claims are ordinary or not.

Why is it that I've read maybe a dozen articles like this in the past couple of years but still don't see much change in the way cancer is being treated in the wild? Will there be a year in the not-too-distant future when all of these breakthroughs finally hit the shelves?

I realize the answer is "clinical trials take time and don't always work" but can someone please explain the process to me?

First, there's a lot of bad science out there. A large part of this is due to the fact that animal models are almost uniformly terrible at modeling real human disease. Second, a therapy may be highly effective but also highly toxic or have other severe risks or side effects, which are hard to tell in preclinical research. The bar here is very high, and trials can easily be pulled over a few "adverse events." Third, it's rare that investigational drugs are used as first-line therapies; so, the patients getting them are usually the ones in worst shape. This can lead to all kinds of problems in demonstrating efficacy. Also, if your drug does get through trials, the FDA looks very hard at who the drug was tested on and can narrowly limit the indications it receives. So, if you develop "promising drug X", and it's trialled on Stage IV glioblastoma patients who express marker Y and are (for whatever reason) over the age of 45 and mostly female, then you're going to be limited to > 45 year old females with Stage IV glioblastoma expressing marker Y, until you can prove safety and efficacy in another population. But the vast majority of drugs never get anywhere near here: they mostly fail in safety or fail to demonstrate effectiveness early on. (An interesting side note here is that many of the signals you look for to estimate your "effectiveness", like size of tumor, don't always correlate to long-term survival. You can have a drug that appears to shrink tumors and patients still dying. It's really common to see good indicators of progress with little or no impact on survival.)

TL;DR: animal models of disease mostly suck.

Wasn't too long, read and extremely interesting. A sincere thank you.

Cancer itself is such a rollercoaster of emotions for everyone involved and these promises and failures of breakthroughs are a sad and ironic parallel.

I agree with most of what you said, but for cancer drugs the adverse events are usually less critical for the development than for other drugs. Usually you conduct Ph1 in cancer patients instead of healthy volunteers for other therapeutic areas. Survival is the endpoint that matters, and adverse events are more regarded as a balance between risk and benefit for oncology. You would not accept the same kind of risks for a central nervous system drug, for example.

> you're going to be limited to > 45 year old females with Stage IV glioblastoma expressing marker Y

If the drug is approved for a specific use in a specific demographic, then doctors can choose to prescribe it for other uses and to other demographics. Apparently 50% of cancer patients receive an "off-label" drug: http://en.wikipedia.org/wiki/Off-label_use#Frequency_of_off-...

Cancer is a difficult biological problem. It is probably the most difficult biological problem I can think of, being both microscopic and inscrutable but also sharing features of population-scale problems. We use cancer as an analogy, but what is an analogy for cancer, apart from humanity itself?

It is easy to forget that most cancers develop through an evolutionary process that takes 15 - 20 years. During this time they are under constant selection pressure by the immune system.

It is not surprising therefore, that to turn up at the very end of the process when a patient has a civillization of heterogenous, optimised cancer growing in them that trying to eradicate the whole thing with a single approach, however elegant, is likely to fail. Cancer therapies in general provide an incremental benefit.

< 5% of therapies make it out of the lab into something a doctor can use on a patient who needs it.

There is just one more difficult biological problem; namely, death.

Most of these grandiose announcements are composed in a way to secure funding for the research group releasing the paper in question. They are almost always entirely based on idealized animal models that have no hope of ever working in the real world. A very small percentage of these research ideas is viable and does make its way to clinical trials, after which these ideas are almost certainly buried never to be seen again due to a crushing load of patent concerns, hedging of liabilities, conflicts with corporate strategies, and general cultural resistance.

Pharmaceutical companies are doing a difficult tight rope walk here. On the one hand, they have a nice status quo, in essence a license to print money. On the other hand, they are subject to a number of threatening forces such as the expiry of patents or the ever-present danger of a rogue competitor making a disruptive discovery. This means there has to be a certain amount of innovation, and that innovation has to cost a lot of money, but ideally the improvements would be minimal. A lot of times, it makes way more sense to kill an idea and keep it under wraps. All big companies have to make these kinds of decisions, it's just good business sense.

You read many articles like this because the press likes to latch onto every research finding and shout "Drug X / Prof Y cures cancer!"

In reality, cancer is many, many different diseases. About the only thing that cancers share is the property of uncontrolled (and unwanted) growth. Some of these cancers we already know how to cure, others remain incurable to date.

The reality is probably that there is no "cure for cancer", rather there are many, many individual treatments for specific cancers. Eventually, we may be able to tailor treatments to individual cancers but that's a long way away at the moment as I understand things.

"The Emperor of All Maladies" is a good read on the subject.

I used to think that, until I watched the TED talk by William Li [1]. The process of angiogenesis can be found as the catalyst in every cancer and medicine/food already work to reverse or halt angiogenesis. Doxycycline, for example, is a broad-spectrum anti-biotic that has been around for decades, is cheap and readily available and has been successful at slowing or regressing tumors. [2]

[1] http://www.ted.com/talks/william_li.html

[2] http://www.sunridgemedical.com/ResearchArticles/DoxycyclineC... (PDF)

Silver bullets usually aren't. (Sadly.)

Yeah, these drugs appear to improve survival times somewhat, but at extortionate expense.

Avastin for instance has been something of a disappointment: yes, it appears to delay mortality but that's about it & the FDA has pulled its approval for use in breast cancer because there was no evidence that it actually helped. The side effects can also be difficult, as you might expect for a drug that targets a process like blood vessel growth.

If dietary changes could have profound effects on cancer progression then a controlled trial would be simple (and ethically straightforward). In reality, eating a decent diet is known to reduce the rates of cancer & improve survival rates of those who are diagnosed with cancer, but it isn't a cure & it probably never will be.

There's a lot to be said for getting to the cancer before it takes off. Silver bullets are easy to dismiss, but what we're really talking about is stopping a simple process with a simple process. It would be hard to stop a missile once it's off the ground, but from the silo it's a matter of turning off a few switches - or rather, not allowing them to be turned on.

I don't claim to know medicine, but I am familiar with simple measures equating to great results when acting on initial factors. An ounce of prevention equals a pound of cure in this case.

> You read many articles like this because the press likes to latch onto every research finding and shout "Drug X / Prof Y cures cancer!"

http://www.phdcomics.com/comics.php?f=1174

Why hurry things up when the cancer treatment industry is making billions with the status quo?

I'm sure the industry (and by extension, the government regulatory and funding agencies) would rather this research was never funded in the first place.

"Weissman's team has received a $20 million grant from the California Institute for Regenerative Medicine"

It's heartening to see this being properly funded.

I attended Dr Weisssman present this work a few years back at Dana-Farber. The somewhat long tl;dr is that while immune cells kill foreign material, normal cells have "don't eat me" signal, CD47, a cell surface marker. Cancer cells also have CD47, the "don't eat me" signal, which helps them evade the immune system. So, blocking CD47 would cause the immune system to naturally target the cancer cells, with minimal side effect.

Weissman's lab has an excellent scientific record so this is as good as it is going to get. The challenge now is to see if these dynamics work the same way in humans.

Anyone familiar with these could share some estimate of in about how much time can we expect to hear the results from human trials?

Before even starting human trials they would need to do a bunch of pre-clinical work (pharmacokinetics, toxicology, etc). They could then get permission from the FDA to start phase I trials, which, depending on the type of cancer tested on, would probably take a couple years to turn around and get data on.

My guess? 4-5 years?

Thought HN might be interested in this very nice explanation on Cancer and some ways to prevent (to some extent) is shared by a redditor biochemist http://www.reddit.com/r/funny/comments/kb39j/scumbag_telomer...

I'm not familiar enough with CD47 to know where else it is expressed, but I'm wondering what the "regular" use of CD47 is. Since it's over-expressed in cancers, I'm assuming the cancer is somehow mucking up the regulation pathway for CD47 and there are regular non-cancer related functions for CD47.

The trick to making this work will be hoping that blocking CD47 on healthy cells isn't particularly lethal (in humans), or getting the antibody to target ONLY cancerous cells.

edit: From the paper, it looks like the mice weren't unhappy with the antibody floating around -

"Importantly, the therapeutic anti-mCD47 [antibody] produced no unacceptable toxicity over the course of the experiment, despite having spread systemically. These experiments were analyzed at the end of the therapeutic regimen; acute infusion of these antibodies led to a short-term anemia."

Here you go: http://www.ncbi.nlm.nih.gov/protein?db=protein&cmd=link&...

GenBank for CD47: http://www.ncbi.nlm.nih.gov/protein/AAH37306.1

(Should be obvious, but this is woefully incomplete in terms of where CD47 probably actually appears. But can be a good first place to start.)

It turns out the first paragraph in the paper gives a good indication for me – it's pretty much all over the shop, which makes the lack of toxicity here pretty interesting.

This is basically a neat hack - Cancerous cells use a certain Chemical marker to stop being attacked. This researcher blocks this marker from being used thus allowing the body's immune system to attack and destroy the Cancerous cells.

This is very promising research indeed but while they have shown Human Tumor Cells in mice shrinking, they have yet to show Human cells in Humans shrinking. Should make for a very cool Phase-1 human trial.

Isn't this marker also used by healthy cells? So what is to stop your system basically attacking itself massively?

I think the key is that Cancerous cells expressed a higher level of this marker leading the Immune cells to destroy them specifically.

However there is also this line "Although macrophages also attacked blood cells expressing CD47 when mice were given the antibody, the researchers found that the decrease in blood cells was short-lived; the animals turned up production of new blood cells to replace those they lost from the treatment," so this seems like a very valid concern.

Good question. I'm an author on both of the new CD47 studies, so I'll try to answer this for you:

1. CD47 appears to be higher on tumor cells than on normal cells. In general, the higher the expression of a marker on a diseased cell versus a healthy cell, the more of a therapeutic window/index [1] that is available for a treatment to specifically target diseased cells.

2. Inhibiting the anti-phagocytosis (i.e., "don't eat me") signal is only half of the equation. There are also pro-phagocytosis (i.e., "eat me") signal(s) that also are present [2] and that play a role in whether, and how well, macrophages, and other phagocytes, can phagocytose a cell. "Eat me" signal(s) also differ between normal and cancer cells, adding more nuance to the situation.

[1] Therapeutic index: http://en.wikipedia.org/wiki/Therapeutic_index

[2] A paper examining a putative "eat me" signal, as it relates to CD47: http://stm.sciencemag.org/content/2/63/63ra94.abstract

It does sound like a very promising avenue, but I imagine that this route could still be a problem for people already pre-disposed to autoimmune diseases. Still, most of those aren't as bad as the alternative here. Any drug based on this doesn't have to not have side effects, it just has to be better than normal chemotherapy.

You raise another good point here, that the allowable side effect profiles for cancer drugs are much less stringent than for drugs indicated for less life-threatening diseases.

Impressive with what kind of research and development scientist come up! Hope it works or at least helps.

The real cancer cure is white blood cell transfusion. Check with LEF for more info (they are funding the trial). Certain Chinese doctors in China will perform it (under the cover), for those in need.

How do I like short comments like this. One cure and your cancer will go away. Yeah, right. And people actually might believe things like that with the result that they don't get proven treatment in time. Cancer is really serious, it can kill you you know, and since there are promising developments (as far as I can tell as not being a doctor), we are still far away from a definite cure to that. You would realy do everyone a favor by keeping comments like that for yourself.

I'm going to ignore the HN guidelines and not be civil for a moment...You're an arsehole. Once you lose someone close to you from cancer you'll understand why.

Here is my take on curing cancer from a programmers perspective. Extract a healthy strain of DNA from the patient, insert the healthy DNA into a virus that will be targeted to attack all cells of a certain type, which will include the cancerous cells. The erroneous/ cancerous will be replaced with the healthy DNA, while healthy cells get the DNA they already had. It's kinda like reformatting a hard drive. Has anyone heard of a custom treatment like this?

If you make enough simplifying assumptions anything is trivial.

Kill the cancer. Leave the normal tissue alone. C'mon scientists how hard can that be.

Surely we could just eventually breed microscopic dogs, and, you know, train them to sniff out and destroy the cancers?

> The erroneous/ cancerous will be replaced with the healthy DNA

Human DNA, weighing in at gigabases, is too large to fit into viruses. Also, 'replacement' implies getting rid of the bad stuff, which isn't really explicitly contemplated here.

Finally, if you are good enough at identifying cancer cells from the outside that you can target them for DNA replacement, you'll probably be better off by just killing that cell.

> ... a virus that will be targeted to attack all cells of a certain type ...

The trouble is that living things are basically made of fancy Jello. There is no programmable interface to say "go here".

Actually, look up a company called Oncolytics. It's based around a technology that you can create viruses that only infect cancer cells. There is a lot of work going on in this area.

As much as I hate to do this: http://xkcd.com/793/

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