New ways of hitting cancer: peptide rockets and nanobombs

ResearchBlogging.org

You can make a cancer drug that only targets cancer cells while leaving healthy cells alone. You can even tailor a cancer drug so that it specifically targets genetic mistakes that are unique to the particular subtype of cancer that a patient has. But if you can’t get that drug into the cancer—I mean, get it all the way into and around the depths of a solid tumor mass—then you’ve got nothing. Well, not nothing. But drugs that barely shave a few millimeters off a solid tumor or those that prolong survival by 3-6 months are not the standard that we should be shooting for.

An intricate blood vessel network within a solid tumor

That’s pretty much where the world of cancer research and drug development is at right now. At the gigantic American Society of Clinical Oncology meeting that just wrapped up in Chicago this week, about 30,000 people (researchers, clinicians, pharma company folks, journalists, patients and patient advocacy groups, venture capitalists and business analysts) listened to hundreds of presentations on how dozens and dozens of drugs against various cancers are performing in clinical trials right now. But all of the drugs aimed at cancers that give rise to solid tumors—pretty much everything with the exception of drugs for blood cancers like leukemia and lymphoma—face the same, crippling roadblock: they penetrate only a few cells deep into the mass of a solid tumor tissue. Such a feeble attack on the tumor basically gives the bad guys within a chance to regroup and come back stronger, with greater resistance to the drug.

The reason that most solid tumors are impervious to drugs has to do with the blood vessels that these tumors are tangled up in. Although there’s a pretty extensive blood vessel network within tumors (which is why chemotherapy is given intravenously), the actual flow of blood within this network is pretty weak. Another problem is that of push-back: the tumor side of a blood vessel exerts pressure against the vessel, preventing stuff inside the vessel from oozing into the tumor. Currently, doctors deal with these drawbacks by upping the dose of the drug, which, of course, usually triggers pretty horrendous side-effects.

But two studies that came out recently indicate that this situation seems to be about to change. The studies are about delivering drugs into the very heart of a solid tumor using two very different approaches, which, nonetheless share the same principle. The two delivery systems are like intelligence-guided missile systems that can home to the tumor and penetrate it, thereby allowing the payload (cancer drugs) to infiltrate the tumor and finish it off.

One system, described in a paper published in Science a couple of weeks ago, is actually a peptide — a short bit of protein —  called iRGD that homes in to a tumor like a rocket by first seeking out and binding to molecules called av integrins that are found only on the walls of blood vessels within the tumor. The iRGD-av binding in turn flips a molecular switch and activates a transport system, which allows whatever particles are floating around in the tumor blood vessels to flow into the tumor.

In one proof-of-concept experiment, researchers grafted solid tumors from human breast cancer into mice and coinjected these test animals with iRGD and trastuzumab, a current treatment for women with breast cancers that are positive for the HER2 receptor protein. The results seem pretty incredible to me.

  • Compared to controls — cancer-grafted mice that got trastuzumab alone — injection of both drug and iRGD peptide resulted in a 40-fold higher penetration of trastuzumab into the tumors.
  • The coinjection of iRGD peptide “improved therapeutic index” of the drug — meaning that the drug could shrink the tumor at a much lower dose than when it was injected alone without the peptide.
  • Tumors decreased in size — well they seem to have disappeared within 4 weeks of treatment — and there weren’t any cases where tumors got bigger or metastasized.

The other neat thing about this iRGD peptide as a delivery system is that its payload — the drugs — don’t have to be chemically hooked up with the peptide for the treatment to work. Which means that pharma scientists don’t have to spend ages trying to reengineer current drugs so that they still work when modified to stick to the peptide.

So theoretically, doctors could start coinjecting the peptide with all the drugs they already have in hand in phase I trials of cancer patients immediately. In a commentary on the paper and in a press release, the researchers say that they’ve already joined up with various hospitals to start doing that. Let’s hope the usual regulatory red tape proves easier to penetrate than a solid tumor.

The other system, which is described in a paper in Nature, is being tested in a phase I clinical trial. It’s a nanoparticle — a submicroscopic spherical ball — that encloses short RNA molecules that shut off a cancer-causing gene in patients with melanoma, a particularly nasty and malignant form of skin cancer. Folks in the cancer therapy field are pretty excited about this development because it’s the first time that this trick of using RNA bits to shut down genes (which are made of DNA), a phenomenon known as RNA interference (RNAi), has been shown to work clinically in humans.

Nano"bomb" - made of two polymers and studded with a protein that attaches to the surface of a cancer cell

RNAi is a powerful way of “silencing” trouble-making genes and thereby reducing the amount of dangerous proteins that they code for. Here’s how researchers use it to target any, not just cancer-causing genes.

They design a short piece of RNA called small-interfering RNA whose sequence matches the RNA made by the target gene (reminder to non-biologists: a gene’s DNA is first copied into RNA, which then serves as a blueprint for making protein). Once the siRNA piece gets into a cell, it finds it’s matching RNA sequence and sticks to it. This attracts the attention of cellular enzymes that act like a pair of molecular scissors – they slice up the RNA sequence flagged by the siRNA. No more RNA, no more protein. And when the protein happens to be one that fuels cancer cell growth, then there’s no more cancer either.

In the words of the paper’s lead author,

“What’s so exciting is that virtually any gene can be targeted now. Every protein now is druggable. My hope is to make tumours melt away while maintaining a high quality of life for the patients. We’re moving another step closer to being able to do that now.”

But we’re getting ahead of ourselves. In the Nature paper, the scientists got as far as proving that the nanobombs accumulate in the tumors of melanoma patients, deliver the siRNA against the target cancer gene, and the siRNA in turn does what it’s supposed to do – reduce the amount of the cancer-causing protein. What the scientists don’t know yet, or didn’t include in the paper, are the answers to two important questions – did the nano-bombed cancer cells die? What happened to the patients’ tumors?

We’ll have to stay tuned and read the next paper that will discuss the phase I trial’s results, which are due out in about four months. But the nanobomb approach looks like it’s here to stay. The particles, which are guided specifically to cancer cells, fall apart easily once they deliver their payload and don’t trigger messy immune reactions — all the traits doctors could hope for in a delivery vehicle.

Sugahara, K., Teesalu, T., Karmali, P., Kotamraju, V., Agemy, L., Greenwald, D., & Ruoslahti, E. (2010). Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs Science, 328 (5981), 1031-1035 DOI: 10.1126/science.1183057

Davis, M., Zuckerman, J., Choi, C., Seligson, D., Tolcher, A., Alabi, C., Yen, Y., Heidel, J., & Ribas, A. (2010). Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles Nature, 464 (7291), 1067-1070 DOI: 10.1038/nature08956

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