Treating Pancreatic Tumors: Drug Delivery Systems & Pancreatic Cancer


Kazuki Sugahara MD, PhD, is an assistant professor of surgery here at Columbia Medical Center. Dr. Sugahara is a physician scientist. He studies drug delivery systems to enhance the diagnosis and therapy of various cancers, especially pancreas cancer. 

Dr. Sugahara joined Dr. Hyesoo Lowe on an episode of Columbia Surgery’s podcast Conversations and Curbsides. The two doctors discuss the difficulty of treating pancreatic cancer tumors, and how drug delivery systems can potentially improve both chemotherapy and immunotherapy. 

The following is a transcription of the discussion, and is lightly edited for context and clarity.

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THE CHALLENGES OF TREATING PANCREATIC CANCER

Dr. Hyesoo Lowe

What are the main challenges in treating cancer, pancreas or otherwise as it relates to drug delivery or how we give chemotherapy?

Dr. Kazuki Sugahara

There are many features of pancreas cancer that make it very difficult to treat. One feature includes early metastasis, wherein the disease starts spreading very early, much earlier than we think. But, another feature is the tumor itself. 

The tumor is stiff, very hard. It also has a “micro environment'', in which the body’s immune system cannot work well so the cancer cells can survive better. There are all sorts of features like that.

So while a lot of drugs have been made, they don't work really well at the moment because of those challenges, and that's where we're trying to make some improvements.

Dr. Hyesoo Lowe

Can you elaborate on the concept of a “micro environment''?

Dr. Kazuki Sugahara

“Micro environment” means that, if you look into the tumor, you can see all sorts of different components within the tumor tissue. It starts, of course, with cancer cells. It also has blood vessel cells. It has what we call “stromal cells” that fill in the gaps between the tumor cells. 

What's important is that tumors do their own job to create an environment which they like, so that the tumor cells can grow more or the blood vessels can function in their own way. So those tumor cells or the other cells can secrete different things to change the biology of the tumor. 

And one more important component is the immune cells. They all work together to create the tumors that we all see in the body.

DRUG DELIVERY: REACHING THE TUMOR

Dr. Hyesoo Lowe

That's very helpful. So it's interesting to know that there are different characteristics of different cancers and particular tumors that can make treating them a challenge, even with the same medications and the variety of medicines we have now. 

Dr. Kazuki Sugahara

Yeah, exactly. Especially pancreatic cancer. One of the features that a pancreas tumor has is that it is very stiff.

The reason why that makes it difficult is because drugs cannot really reach the tumor. The medicine can get to the blood vessels, but it cannot spread into the tumor because the tumor is so stiff, it's like a ball. 

So a lot of people have tried to come up with systems to increase the spreading of drugs into the tumor, so that the drugs can attack the tumor cells more efficiently.

Dr. Hyesoo Lowe

Are you talking about primary treatment without surgery? Or after the patient has had surgery and we're talking about what's left behind?

Dr. Kazuki Sugahara

It can be used for both.

Before surgery we want to sometimes shrink the tumor, and if we can make the drugs reach the tumor cells more effectively, then we can shrink the tumor much faster and get the patient to an operation. 

After an operation, some patients experience what we call recurrence. This means that the tumor comes back and starts forming a mass again. That is another opportunity for us to treat, using systems where we can deliver drugs more efficiently to those tumors.

Dr. Hyesoo Lowe

I'm sensing a theme to your talk about getting a drug to the tumor more effectively. Is that mainly what you're working on?

Dr. Kazuki Sugahara

That's exactly what I do. I work in the field of drug delivery. I think there is a big potential in the field because even if you make a really good drug, the drug cannot work as efficiently as it should if it cannot reach the tumor cells. 

So that's where we are trying to make progress to send effective drugs more directly into the tumor.

PANCREATIC CANCER: TREATING THE TOUGHEST TUMORS

Dr. Hyesoo Lowe

So tell us a little more specifically what you're working on there?

Dr. Kazuki Sugahara

Yes, so let me start a little bit from the history of drug delivery. 

Initially, it goes back to where people discovered the interaction between some molecules against certain other molecules. Specific types of interactions can mediate cells to attach to surfaces or cause small molecules to attach to cells. 

So using that mechanism, people started to coat drugs with the molecule that can bind to tumor cells. This way if we deliver the drug, the drug can attach to the tumor cell—but not to other tissue—and kill the tumor cells right there. 

But one issue that came up with that system was that, even though the drug can bind to tumor cells, it cannot actually reach the tumor cells, to begin with, because, if the tumor is so stiff like pancreas cancer, it just cannot penetrate into the tumor tissue. 

So we developed a new system which can really enhance the spreading of drugs within stiff tissue. And that's the main theme that I'm working on right now.

Dr. Hyesoo Lowe

Very interesting. So it sounds like something about pancreas cancer makes it very challenging to get the drug to the tumor.

Dr. Kazuki Sugahara

Exactly.

Dr. Hyesoo Lowe

I see. And so you not only need great drugs, but you need to get those drugs to the actual tumor, and that presents its own set of challenges.

A PROGRESS TIMELINE

Dr. Hyesoo Lowe

Got it. So where in the timeline of progress are we, would you say? I'm thinking about the way normal pharmaceuticals get approved. So from the original animal studies and then human studies, and then phase one, phase two. Where in there would you say we are in terms of drug delivery?

Dr. Kazuki Sugahara

Yes. So we have several different versions, but there is one particular drug that we have been working on.

It is a peptide, which is a small piece of protein that attaches to the blood vessels in the tumor. And what it does there is that it opens up the gate of the blood vessels so that other things can also spread into the tumor.

We have tested that drug with all sorts of different drugs, all sorts of different tumors, and one of the most effective tumors was pancreas cancer. And we have sorted out the mechanism as to how the drug works and why it works so well in pancreas cancer.

For a drug to get approved, it has to pass three different phases of clinical studies. And we have finished the first phase with very promising results.

So now there are multiple “Phase Two” studies being performed in different countries: Australia, United States, China, and we're trying to expand the studies to Japan and other parts of the world. Hopefully we will get a really convincing result in the next two years from one of the phase two studies, and then we will be pretty close to getting approved.

Dr. Hyesoo Lowe

Fantastic. That sounds very optimistic. And again, I think a theme on our pancreas cancer series has been, there is reason to be hopeful and reason to be optimistic, even with a diagnosis of pancreas cancer that in the past has been so very serious. So we're delighted to hear this news. 

IMMUNOTHERAPY vs. CHEMOTHERAPY

Dr. Hyesoo Lowe

Now, immunotherapy, can you tell us the difference between immunotherapy and regular conventional chemotherapy?

Dr. Kazuki Sugahara

Right. So the traditional chemotherapy is a toxic drug, in short terms. The drug can kill all sorts of different cells. (It can also kill normal cells, and that's why it can cause side effects.) But it works better in tumor cells because we use a little bit of the feature of the tumor cells. They grow faster so they tend to be more sensitive to those toxic drugs. 

Immunotherapy is a totally different type of therapy, which activates immune cells that can attack tumor cells.

The drug itself doesn't really kill the tumor cells. It facilitates the work of the immune cells that can then start attacking tumor cells. And that has become a big wave after the recent Nobel prize.

IMMUNOTHERAPY & PANCREATIC CANCER

Dr. Hyesoo Lowe

Immunotherapy for other cancers has certainly broken through in the effectiveness and the sort change in the approach to treating cancer. And if it could be helpful in pancreas cancer, wouldn't that be wonderful?

Dr. Kazuki Sugahara

Yes. Maybe I can tell you a little bit about our more recent work related to the same system that we use for drug delivery.

Pancreas cancer has an environment that makes immune cells not work. 

That has been a huge issue in pancreas cancer treatment. A lot of immunotherapies have been tested for pancreas cancer, but none of them have worked really well. And we all think that it is the environment that pancreas cancer makes, which suppresses the immune cells to work.

We found that our drug delivery system can change the environment to make the immune cells work better. 

So we have now a couple of clinical trials coming up where we combine our drug delivery system with immunotherapy—instead of the usual chemotherapy—to test how well the immunotherapy works.

Dr. Hyesoo Lowe

That sounds like a game changer.

Dr. Kazuki Sugahara

Hopefully it will.

Dr. Hyesoo Lowe

So the drug delivery system, is it like a coating around the drug? How does it get incorporated with the actual drug?

Dr. Kazuki Sugahara

That's a very good question. The traditional way of doing drug delivery is that you attach a drug to a molecule coating that can bind to tumor cells or other targets in the tumor. 

But that makes it very difficult, in some cases, because you need to change the design of the drug and the molecule that you're using. You need to manufacture them together. 

In our system, our molecule touches a switch in the blood vessel of tumors—only in tumors—and opens the gate right there. Now, the cancer drug can sort of leak into or penetrate into the tumor. 

In other words, we don't even have to attach the drug to our molecule coating. We can just mix whatever drug you're interested in with our molecule and inject them together. By doing that, the drug and our molecule will go into the tumor together.

Dr. Hyesoo Lowe

Interesting. So the form of this drug delivery is actually soluble, it's like a liquid?

Dr. Kazuki Sugahara

It can be in a liquid, it's a small piece of protein, but it mixes really well with liquid.

Dr. Hyesoo Lowe

I see. Fascinating. Are you allowed to tell us the name of the drug or this is so early, there is no name?

Dr. Kazuki Sugahara

The scientific name is called I-R-G-D. That's what it shows up as in academic papers. Now in the drug company name, it is called L-S-T-A1, LSTA1. It comes from a company called LSTA Therapeutics.

Dr. Hyesoo Lowe

Fascinating. Anything we've left out in our talk?

Dr. Kazuki Sugahara

I think that was a good summary!

Dr. Hyesoo Lowe

It certainly was a good summary. Innovations and pancreas cancer brought to us by Dr. Sugahara. Thank you so much for being here.

Dr. Kazuki Sugahara

Thank you. It was a pleasure.

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