Reducing Chemo Side Effects by Exploiting Tumor Cell "Doors"

Results from the DoD's Era of Hope Conference

Yesterday we looked at the challenges of delivering next generation peptide drugs to breast tumors. Today we'll continue to talk about the importance of drug delivery, but in the context of chemotherapeutics, by looking at more research coming out of this week's Era of Hope conference in Orlando.

Drs. Andras Lacko and Nirupama Sabnis from the University of North Texas Health Science Center in Fort Worth showed a technology that could potentially improve the efficacy and decrease the side effects of any chemotherapy drug.

Chemotherapy drugs are by definition poisons. So ideally you want them to enter tumor cells and not healthy cells where they can do things like cause hair loss and worse. But how to accomplish this?

Here's how: find a molecular "door" that only exists on tumor cells -- or that exists in much greater abundance on tumor cells compared to healthy calls.

This is what our featured research team did.

They found that a certain cell surface receptor called "scavenger receptor type B1" (SR=B1) is much more prevalent on tumor cells. This receptor's function on healthy cells is to extract a portion of circulating HDL cholesterol molecules needed for normal cell processes. But since tumor cells grow and proliferate much more rapidly than normal cells, they need much more of this HDL cholesterol element. So tumor cells put many more of these HDL-grabbing SR=B1 receptors on their surface.

So there it is! Our door!

The researchers exploit this door by creating so-called "rHDL nanoparticles" containing drugs of interest. A nanoparticle is an aggregate (a grouping) of defined molecules. In this case, the main component of the nanoparticle is rHDL. The "r" stands for "reconstituted." The other component is the drug of interest. The goal is to trick the cell's SR-B1 receptors into pulling the drug-containing nanoparticles into the cell.

And that's what happens. In Drs. Lacko and Sabnis' research they tricked tumor cells in mice to pull in a drug that isn't a standard chemotherapeutic. But as they said at the conference, "This novel drug delivery system has the potential to be compatible with most of the commonly used chemotherapy agents."

You might recognize that this drug delivery model has similarities with Abraxane, the "nanoparticle albumin-bound" version of the chemotherapeutic Taxol (paclitaxel) that is FDA-approved for the treatment of breast cancer. In the case of Abraxane, the protein used in the nanoparticle is albumin, which tends to attach to albumin receptors in blood vessels around tumors.

So this concept of creating protein-chemo nanoparticles seems to be gaining momentum.

Next the University of North Texas researchers are going to look at replacing the rHDL with a smaller protein, or peptide, that is known to mimmick HDL and which is currently used and approved for the treatment of arteriosclerosis. This would make any future drug easier to get through regulatory approval and likely less expensive.

My thanks to Dr. Sabnis for speaking with me yesterday about her research.

Opening Up the Potential of Peptide Drugs -- A New Delivery Method

Results from the DoD's Era of Hope Conference

Scientists are teasing apart the molecular causes of breast cancer so that they can develop more targeted drugs. But applying this new model of personalized, targeted treatment depends as much on developing new technologies to deliver drugs as developing the active components of the drugs.

Why is drug delivery is so critical? To explain, today we'll look at research results presented yesterday at the Era of Hope conference in Orlando, which featured research funded by the Department of Defense's Breast Cancer Research Program (BCRP). Today I spoke to Dr. Gene Bidwell of the University of Mississippi Medical Center who presented findings on a new "thermally-targeted" approach to delivering peptide drugs. (Press releases from the conference can be found here.)

Dr. Bidwell's research was performed in an animal model and is years away from the bedside. But it is an exciting approach. It also underscores several larger trends in cancer research and future treatment. So let me explain the context and relevance before describing his new system.

First, peptides. What are they? The term "peptide" simply refers to a small protein. While a typical protein is a chain of hundreds of amino acids, peptides are tens or teens. Dr. Bidwell's H1 peptide, the focus of this research, is 16 amino acids long.

Peptides have the potential to be fabulous drugs. Most of the molecular activity in cells is about proteins interacting with other proteins. So peptides (being proteins themselves) are a natural in terms of interacting with, changing or inhibiting proteins gone awry.

In addition, today we have machines that make peptides to order. You just type in any series of amino acids you want, and out pops the peptide. So researchers can make a peptide, try it out, adjust it a bit (maybe switch one of the 16 amino acids), make that one, try that out and iterate little by little to create the perfect drug. This process is called "rational drug design."

Today, some drugs are large proteins called monoclonal antibodies (for example, Herceptin), which work well if the target lies on the surface of the tumor cell. But most drugs are "small molecules" -- chemicals.

Pharmaceutical companies make enormous collections (libraries) of millions of random chemicals that they then robotically test. The process of finding a good small molecule drug is literally like throwing the entire library against a wall (actually against the molecule they're targeting) and seeing which "stick," or attach to that molecule. If one or more do stick, they still have to figure out if it sticks such that it interrupts the molecule's function. If not, they move on. This process doesn't allow the research team to iterate small changes to perfect the drug nearly as easily as with peptides. So there are big advantages to peptides in terms of a rational drug design approach.

But today there are no peptide cancer drugs. Why? First, small peptides degrade in the bloodstream. So they need to be attached to another molecule (sometimes just larger peptides) for protection until they arrive at the tumor. Second, peptides need to get inside tumor cells to do their thing. That doesn't happen naturally.

Many research teams are trying to solve this problem and Dr. Bidwell's research provides a great and an exciting example. He created a three part peptide drug. All three parts are peptides. Together create a larger and more stable molecule. It's really tricky. Here's how it works.

- The first part is the peptide drug itself, called H1. It targets a growth signaling protein in cancer cells called c-Myc.

- The second part is called elastin-like peptide (ELP). The ELP enables the drug to remain soluble and stable in the bloodstream. But right at the tumor site a mild heat is applied (according to Dr. Bidwell, "about 5-10 degrees hotter than body temperature... like a high fever") using ultrasound. The focused heat changes the shape of the ELP, and causes the drug to aggregate and accumulate where it's needed.

- The third part is called cell-penetrating peptide (CPP). When the drug aggregates at the tumor cell, the CPP provides entry into the cells.

This is a powerful approach. All three parts of the drug have distinct functions. Mild heat is used to aggregate the drug to where it's needed at the tumor and to avoid exposure of other tissues.

According to Dr. Bidwell, there are other approaches being developed to deliver peptides to breast tumors, including synthetic polymers and liposomes. But those aren't thermally-targeted, which provides not only stability, but also (potentially) increased effectiveness and fewer side effects.

So cross your fingers. Let's hope that Dr. Bidwell's thermally-targeted delivery mechanism, or a variant of it, will open up the full potential of next-generation peptide drugs against cancer. And thanks again to Dr. Bidwell for taking the time to speak with me today.