Steve Mirsky: Welcome to the Scientific American podcast Science Talk, posted on January 24, 2014. I am Steve Mirsky. On this episode—
Rakesh Jain: Our thinking is that the exocellular matrix of collagen in these tumors, the abundant collagen in tumors is a major contributor to this problem.
Steve Mirsky: That’s Rakesh Jain, and this problem is the difficulty of getting drugs to the interior of certain tumors. Jain is the director of the Edwin L. Steele Laboratory for Tumor Biology in the radiation oncology department of Massachusetts General Hospital and Harvard Medical School. He is one of only 20 people ever to be elected a member of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine, and he’s the author of an article in the February issue of Scientific American about using physics to fight cancer, called An Indirect Way to Tame Cancer. I spoke to him by phone.
Cancer therapy is almost always looked at as a molecular issue. When we hear about a new cancer drug it’s usually a molecule. And your attempts to deal with cancer obviously are molecular in nature, but they’re within a context of structural considerations and physics.
Rakesh Jain: That’s correct. Our thinking is that physical forces play an important role in the progression of tumor as well as its response of tumor to various treatments.
Steve Mirsky: And these physical forces are manifested in what’s called the extracellular matrix.
Rakesh Jain: Yes. So the extracellular matrix is the material that’s between cells, and this is made out of a variety of proteins, such as collagen and a gel-like substance such as hyaluronan. These components of the matrix generate forces as well as they store forces.
Steve Mirsky: Everybody’s familiar with collagen because it’s basically what’s in Jell-O.
Rakesh Jain: Yes. Yes.
Steve Mirsky: But the other substance is a little more out of peoples’ everyday experience.
Rakesh Jain: It is. And this is the substance which would be, for example, inside our eye. That’s the jelly that’s made out of hyaluronan. And every tissue in our body, almost every tissue in our body has collagen, which provides this sort of structural and mechanical support, so to speak. And in between this is this jelly, which is made out of hyaluronan and other molecules as well.
Steve Mirsky: Right. So these are proteins and other kinds of molecules that actually give us our structure.
Rakesh Jain: Absolutely. Absolutely. So if you are to remove collagen completely from us we would all turn into Silly Putty.
Steve Mirsky: But we might not have as much cancer.
Rakesh Jain: [Laughter] That’s right. We really don’t often think about the consequences of that.
Steve Mirsky: Right. Right. So talk about the extracellular matrix and how the physical forces that act upon it might be related to our cancer problem.
Rakesh Jain: So as the cancer cells grow they usually grow in a confined environment. And this environment is confined by the surrounding normal tissue, normal cells, as well as confined by the matrix. So when the cancer cells proliferate they push this and then this matrix pushes things back, and this is how you generate forces. And as the cancer cells continue to grow they require blood vessels, and these blood vessels bring nutrients and waste products. So one would think that a tumor, when it is growing it will continue to acquire blood vessels, and it does. But what happens is as the tumor grows and the space is limited and these forces that are being generated, the blood vessels that form are squished or are compressed by these forces. And this compression lowers the amount of oxygen available to tumors. And this low level of oxygen is known as hypoxia.
Now we have known from various retrospective studies; studies of clinical data done by many people that tumors that are very hypoxic have a very poor prognosis. The patients in those tumors do not survive as long as patients where there’s an adequate amount of oxygen in their tumors. So this is very counterintuitive; one would think that the tumors would like more oxygen so they could grow, and yet the most hypoxic tumors are the ones which are most lethal.
Steve Mirsky: Right. So what’s going on there? Why do the tumors like that oxygen deprivation so much?
Rakesh Jain: This oxygen deprivation, or hypoxia, it affects tumor growth and metastasis in so many different ways. So let me give you some examples. So when you have hypoxia, that’s low level of oxygen, it creates genomic instability. That means it helps cancer create more mutations. So that’s the very simple thing it does. And when cancer cells make certain proteins they do not fall properly when there’s hypoxia. That also helps cancer to become more malignant. And hypoxia also selects for cancer cells that are more malignant. Usually in a normal cell commit suicide when there is hypoxia, but tumor cells do not commit suicide under hypoxia; those are the ones which are more malignant. And hypoxia also forces cancer cells and normal cells which are in the surrounding tissue to make certain proteins that makes these cancer cells more motile, so they become more metastatic; they metastasize.
And more importantly, cancer cells decreases the effectiveness of the immune system. So even if immune cells go inside the tumor, if they see low levels of oxygen they stop functioning. And in our body there are two types of immune cells in the tumor, known as macrophages. One are what are known as pro-tumor macrophages, they help tumor growth, and others are known as anti-tumor macrophages. And what hypoxia does is it converts the anti-tumor macrophages, the tumor-fighting macrophages into tumor-promoting macrophages.
Steve Mirsky: And it also interferes, when you send a medication through the blood stream to try to get at the tumor, this situation also interferes with the medicine getting where it needs to go.
Rakesh Jain: Absolutely. So when you have a poor – the blood vessels are crushed or squeezed by the tumor, the blood stops flowing to that, so they cannot bring drugs into the different regions of the tumor. And it just doesn’t end it there. The regions where the drugs do not get in are also the regions where there’s low level of oxygen, and a number of investigators have shown that these regions, hypoxic regions harbor the so-called cancer stem cells. Now cancer stem cells are the type of cancer cells that can form a whole new tumor, and they like to sit in these regions which are hypoxic. And so the drugs don’t access the most dangerous cancer cells because they are sitting in this hypoxic region. But in addition, even if the drugs get into the hypoxic region, somehow you could do that, they stop functioning there, because a lot of the drugs, for them to function they require oxygen.
Same thing for radiation; radiation therapy is the most common therapy for cancer, and that requires oxygen. Because what radiation does is it converts oxygen to what is known as oxygen radical, and that is what causes damage to the DNA and the DNA replication, of course then the cell dies. So that’s how hypoxia affects not only facilitates tumor growth and metastasis, but hypoxia also increases resistance to every form of therapy, where you give drugs; radiation therapy, where you use radiation; and immunotherapy. So tumors seem to exploit this microenvironment or this abnormality or this abnormal microenvironment, hypoxic microenvironment to aid their growth and resist treatment.
Steve Mirsky: So you thought because the exocellular matrix is a player in this entire scenario, with the forces that are being exerted, that if you could interfere with the collagen structure it might improve the possibility of getting the drugs where they need to go.
Rakesh Jain: Absolutely. We have been worrying about hypoxia for quite some time, but we realized the importance of matrix in this whole problem of drug delivery about 14 years ago, in the year 2000. One of my post-doctoral fellows, Dr. Paul Ornetti from Italy, what he showed, what he discovered was that the tumors which were very stiff, it was very hard for drugs to penetrate into them. So what he did is he looked at why are these tumors stiff, why are they so rigid, and what he found out is they had a very high level of collagen in them. So the experiment he did was he gave a bacterial collagenase, an enzyme that destroys collagen, just injected right into the tumor. And that made the tumor softer and at the same time the drugs which you are studying, they penetrated deeper, they had a better diffusion.
So that is how we got into this in the year 2000. That was very exciting and totally unexpected at that time, that that matrix was playing a role in blocking the delivery of macro molecules. For his work he used particles of the size in 100 to 150 nanometers.
Steve Mirsky: Those represented a possible molecular drug that you would try?
Rakesh Jain: Exactly. So for example, the drugs that are used for giving gene therapy are all nano medicine, all nanoparticles which are given to cancer patients right now. They have the size of 100 nanometers. So that’s why he was interested in looking at these large particles.
Steve Mirsky: And this work was done in mice?
Rakesh Jain: It was done in mice.
Steve Mirsky: Okay.
Rakesh Jain: With that discovery the next question was, well, you cannot give bacterial collagenase.
Steve Mirsky: No, because you don’t want to turn everybody into Silly Putty.
Rakesh Jain: You got it. Exactly. Exactly. Especially in a metastatic setting, where the tumor is throughout the body. So you need an agent which will modify collagen or dissolve it, but this drug has to be given systemically, so it can reach all regions of the body, wherever the tumors have metastasized. So that began – that started a search for molecule sand drugs in our laboratory. And we decided to work with in the year 2002 with a hormone called relaxin that women make towards the end of their pregnancy. It reorganizes the collagen in the cervix of the women and that allows the baby to come out easily. And then the hormone level of relaxin begins to go down, back to normal, and everything is back to normal.
So we said, “Okay, why don’t we try this, because this is a natural substance.” And we did, and indeed, we treated our mice for about two weeks with the relaxin. And as we had suspected, it indeed reorganized collagen, made the matrix very pliable and permeable, and when we injected molecules of different sizes they were able to penetrate much deeper into those tumors, much more easily. And so we are very excited about this discovery and it was published in 2003 in a journal called Nature of Medicine.
What happened is after we published this work we started thinking about if we could, you know, try this, do a clinical trial with this. Except we found some publications that in some animals that have prostate cancer relaxin can increase metastasis. Now even though that did not happen in our own study, the fact that there are some studies showing that, we just said, “Okay, we cannot proceed with this, so we need to look for some alternate molecules that will accomplish the same goal that is of modifying the collagen matrix and allowing the drugs to penetrate deeper into the tumor.” And what we did then, we looked for various FDA-approved drugs that might have the potential to do that, because if they did we could move to the clinical trial pretty rapidly.
Steve Mirsky: Right. It would be basically using the drug off-label.
Rakesh Jain: You got it. Yes, using the drug off label.
Steve Mirsky: So you don’t have to create a new drug from scratch; you check to see what’s already out there that might have a secondary function.
Rakesh Jain: Absolutely. And that is known as repurposing a drug. And repurposing a drug has a lot of advantages; cost is just one of them. and the second one is speed, because you can move very rapidly to the clinic; you don’t have to wait 10 to 15 years, which is what it usually takes when you make a discovery in your laboratory to all the way to getting a drug approved. So that’s why we decided to look at a variety of FDA-approved drugs, which were either off patent or still in use, under patent. So what we found out, that the commonly prescribed drugs to lower blood pressure, also known as anti-hypertensives, actually have the ability to do that. And the idea behind that came as follows. We said – we asked the questions what molecules in our body control the production of collagen, and the growth factor that is the master regulator of collagen is known as TGF beta, transforming growth factor beta. So we began to look in the literature what FDA-approved drugs block the activity of TGF beta, and indeed these anti-hypertensive drugs do that. And what is even more remarkable, that these drugs are given to patients that have cardiac fibrosis, for example, an excess amount of matrix in their various organs, such as heart, such as the heart. And these patients take these drugs for many, many years.
So we looked in the literature to find out if anybody has actually tried to do this, to reduce fibrosis with these drugs in tumors and to see if it improves the delivery of drugs or if it opens up blood vessels. And guess what; there was no such data, no publication. So we were very excited about pursuing this, and that’s when another graduate student in my laboratory gave one of the most commonly prescribed anti-hypertensive drugs, known as losartin, to animals that have tumors which are highly fibrotic. And he found out that two weeks after giving losartin to the animals the collagen levels decreased dramatically. And not only did the collagen level decrease, but when he gave various nanoparticles of 100 nanometer size, either intratumorally, that means injecting them right into the tumor – or systemically, that means injecting in the blood stream – their delivery to the tumor improved dramatically.
Steve Mirsky: And that’s really the key thing, because if you loosen up the collagen but you don’t get penetration by the drug you haven’t gotten anywhere.
Rakesh Jain: Exactly. So that’s the asset test, does it improve the penetration of the drug, and it did. And not only that, what we did then is we combined losartin with a viral therapy, it’s called HSV, and these viruses replicate in the tumor and they kill tumor cells. And they are large, they’re about 150 nanometers in diameter. And when you inject these particles systemically they don’t penetrate the tumor very well. But when we combined with losartin they penetrated and then they also reduced the tumor growth much more than when these viral particles were given out alone. So this was very exciting, that this therapy was doing what we had suspected based on our work we started in the year 2000.
But that still doesn’t answer the question which we started in the beginning of this conversation, that is does it have any effect on hypoxia. So then what we said is, “Okay, let’s see if you can increase the dose of losartin,” because what we found was that the decrease in collagen was very much dose-dependent, that means the higher the dose of losartin, there as more reduction in collagen. And when you begin to reduce collagen you reach a point suddenly where the blood vessels begin to open up. And that’s exactly what we found, that when we doubled the dose of losartin and we looked at the blood vessels in the tumor, prior to losartin most of the blood vessels in this very fibrotic tumor were collapsed, but when we treated these animals with losartin these blood vessels reopened, they became decompressed and you could see blood flow through these vessels where it did not exist before.
So what this suggests to us is that if we give the right dose of losartin not only can you improve the blood supply, not only can you alleviate hypoxia, but you can also improve the penetration. So there’s so many benefits there. And when we did this not only did the tumors respond to these various therapies, but also the animals survived longer.
Steve Mirsky: And ultimately that’s the real acid test.
Rakesh Jain: That’s the acid test, exactly. So the animal survival went up. But I should make a little side point here, and that is the tumors that are most deadly right now, that have the worst prognosis are a type of pancreatic cancers known as pancreatic ductal adenocarcinomas.
Steve Mirsky: Very low five-year survival rates.
Rakesh Jain: Exactly. Their five-year survival is like 5 to 6-percent and the survival has not increased in the last 20 to 30 years beyond this. The most recent drug approved by the FDA this year was a combination of two drugs called Gemcitabine and another drug is known as Abraxane. And that combination, elegant study published in the New England Journal of Medicine by Dr. Dan Van Hoff, if you look at that picture the survival advantage with this regimen is about two months. But the five-year survival still has not budged. So this is one of the most deadly disease and our thinking is that the extracellular matrix of collagen in these tumors, the abundant collagen in tumors is a major contributor to this problem. In many ways one is by collapsing blood vessels, so it creates hypoxia, and second, this amount of collagen would also hinder the delivery of therapeutics into the tumor.
So based on our preclinical studies, a team of clinicians at Mass. General Hospital has actually now started a clinical trial using losartin and a cocktail of cancer therapeutic drugs, which is now a standard of care for these pancreatic ductal adenocarcinoma patients. So the trial just started just middle of last year and hopefully in the next several years we will know the outcome.
Steve Mirsky: Now there is some evidence, an unplanned experiment has been done with cancer patients who also had high blood pressure, where many cancer patients with high blood pressure were receiving cancer medication and an anti-hypertensive at the same time, and in looking through the literature you did find that there’s some evidence through that unplanned experiment that this root has some promise.
Rakesh Jain: Absolutely. So these kinds of studies are known as retrospective studies, Steve, and a group in Japan published a retrospective study showing that pancreatic ductal adenocarcinoma patients who had hypertension, high blood pressure, when they received losartin they survived approximately six months longer than the patients who had received some other kind of blood pressure medications that do not change collagen. And not only that, Steve, there are two other similar retrospective studies published; one with lung cancer patients, non small-cell lung cancer patients. When they get these kinds of drugs in combination with chemotherapy they live longer. And finally, the kidney cancer patients, when they receive these anti-hypertensive drugs along with their standard of care, an anti-angionetic drug, these patients also live six to nine months longer.
These retrospective studies are very encouraging and they also provided the motivation for the Mass. General Hospital clinicians to initiate a clinical trial here.
Steve Mirsky: Again, when do you hope to get some results that you can analyze from the clinical trial?
Rakesh Jain: So, Steve, I am not involved with that clinical trial because of the conflict of interest issues, but I have the feeling that within a couple of years we should have an answer.
Steve Mirsky: And you’re not involved because you have a stake in a biotech company that would be creating these drugs.
Rakesh Jain: Exactly.
Steve Mirsky: Right. So you can’t be involved in the trial that analyzes the drug.
Rakesh Jain: No. So once you have a financial conflict of interest then you cannot be involved in a clinical trial. Those are the rules at Mass. General Hospital.
Steve Mirsky: Well, some very interesting stuff.
Rakesh Jain: Well thank you very much, Steve.
Steve Mirsky: We were just talking about conflict of interest rules, so I want to read the disclosure at the end of the article in the magazine. “Rakesh K. Jain cofounded, has equity in, and sits on the board of directors of Extuit, a company that is developing anti-cancer therapies. Extuit and Mass. General Hospital have applied for drug patents based on the work summarized in this article. Jain also receives grants and consulting fees from and advises several other companies involved in cancer research.”
Also at the end of the article there is info about the clinical trial based on the concepts we discussed. You’ll find it on a link to it on the web page for the podcast, but I’ll also read it now. “Find more on the matrix depleting clinical trial being carried out by cancer specialists at Massachusetts General Hospital at clinicaltrials.gov/show/NCT01821729.
That’s it for this episode. Get your science news at our website www.scientificamerican.com, where you can read the article by Clara Moskowitz about the continental telescope array that could mean an astronomy revolution in Africa. And follow us on Twitter, where you’ll get a tweet whenever a new item hits the website. Our Twitter name is @SciAm. For Scientific American Science Talk I am Steve Mirsky. Thanks for clicking on us.
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For information about clinical trials related to the concepts in this article, go to http://clinicaltrials.gov/show/NCT01821729