Professor Erkki Ruoslahti, University of California, Santa Barbara
Chris - Also in the news this week, researchers in California have shown how a new drug, which they call iRGD, can help to fight tumours. And that's done by boosting levels of chemotherapy agents that can get inside the cancer. And to explain more how they've done this, we're joined now by Professor Erkki Ruoslahti who is from the Stanford-Burnham Insitute at the University of California, Santa Barbara. He is with us now. Hello, Erkki.
Erkki - Hello.
Chris - Welcome to the Naked Scientists.
Erkki - Thank you.
Chris - Wonderful paper. I enjoyed reading it very much. Tell us if you could. First of all, what is the problem with getting chemotherapy drugs inside cancers in the first place?
Erkki - Tumours are blood vessels and anything that is introduced into the circulation, of course, will then get into the tumor. That thing includes anti-cancer drugs. The problem is that tumors have a high internal pressure and the tissue fluid is actually from the tumor to the surrounding tissue, which means that it is difficult for drugs to penetrate into tumours. And they only get a couple of cell diameters from the blood vessels, which leave some of the tumour cells with a supple optimal amount of drug that contributes to recurrence and also the resistance that tumours usually develop.
Chris - And so, of course, physicians try to compensate by increasing the concentration of the drug in the blood stream. But then that, of course, has a knock-on effect for healthy tissue because it begins to generate side effects?
Erkki - That is correct. So one can only go that far using that approach.
Chris - So if you've got a way of carrying chemicals selectively into tumors far further and far more easily, in other words at lower concentrations in the blood than previously, you could potentially hit the tumor much harder where it hurts, leaving healthy tissues spared and, therefore, minimize the side effects.
Erkki - That is right. And that is what we are able to do with iRGD.
Chris - How does iRGD work? What is it and what does it do?
Erkki - iRGD is a peptide. We originally found it using screening of huge peptide libraries in live mice. It is possible to make libraries of billions of peptides. And we started screening them in vivo for their ability to go to tumors. And one of the peptides we found turned out to be quite special. It has the RGD sequence, that's arginine-glycine-aspartic acid, which my laboratory found 25 years ago as a key sequence for cell attachment. Now, the receptors for this sequence are up regulated, present at high concentrations in the blood vessels of tumors, but not in normal tissues. So the RGD sequence makes the peptide concentrate in tumor blood vessels. It then gets cleaved there by an enzyme which takes away most of the RGD activity, but exposes another receptor-binding sequence that now transfers the peptide to another receptor called Neuropilin-1. And when a peptide binds to Neuropilin-1, it activates the transport system. And that transport system can take the anti-cancer drugs deep into the tumor.
Chris - And so, doing some simple experiments to work out, how much better it is if you give this agent to the tumour alongside some kind of anticancer agent, how much higher concentrations of anticancer drugs can you get in the tumors when you do that?
Erkki - Well, it depends on the time when we look at the drug concentration. If we look at it fairly soon after the single injection, we can get seven to 40 times more of the drug into the tumour. Then, if the treatment is long-term, let's say, several weeks, then the difference becomes somewhat smaller. But it persists even after weeks of treatment.
Chris - And is this with the iRGD protein linked chemically to the drug or with the drug just given separately and at the same time into the blood streams so the two molecules are washing around together, and the iRGD drills a hole in the tumor and the drug then goes in?
Erkki - We originally would couple our homing peptides to the drug and that makes them more effective. But we then discovered, and that's the message of this newest paper, that we didn't have to couple the two together. We could just give them at the same time. And as you say, what happens is that the peptide activates this transport pathway, and it's a bulk transport pathway such that it takes in and through the tumor anything that is around when the peptide is there and has activated the system.
Chris - And, lastly, you’ve obviously showed, this as you said in mice, will this work in men so we've got something that works in mice and men?
Erkki - Yeah. Well, so far we know that we can grow human tumors in mice and the system works. We have not tested anything in humans yet, that requires a lot more preliminary work. We’re just tooling up to start those studies.
Chris - Well, we wish you luck and thank you very much for joining us. A wonderful study. If you'd like to read it, it's actually published in the Journal Science this week.