“Molecular Legos” and more
Cancer Therapeutics Program finding new agents, delivery systems to treat cancer
Drug discovery once occurred largely by chance, and a bit of luck. Penicillin was discovered because Alexander Fleming left a window open. A spore wafted in on the breeze and landed, fortuitously, on a petri dish where bacteria were growing. The spore produced a substance that killed those bacteria and Fleming noticed.
Similarly, the first chemotherapy agent for cancer came from mustard gas used in World War I. Somebody noticed that the victims were low on white blood cells, presumably killed by the mustard gas, and they decided to try it out as a treatment for lymphoma, a cancer of the white blood cells.
But serendipity plays a diminished role these days. Now researchers engage in a process they refer to as rational drug design. Nowhere is that more evident than at the UC Davis Comprehensive Cancer Center, where members of the Cancer Therapeutics Program attempt to discover new drugs with this process. The aim is to find promising treatments for cancer, take them through the necessary trials and proof, and then get them to the clinic.
Professor Kit Lam, chair of Biochemistry and Molecular Medicine and chief of the Division of Oncology and Hematology, is something of a collector. He has a catalogue of more than one million peptides, which he can put together, with infinite variety, and make new molecules – molecules that might kill cancer cells.
“We’re doing molecular Legos,” he likes to say.
Lam is known as the inventor of the “one-bead one-compound” combinatorial library method. He can test hundreds, even thousands, of molecules at one time, and do so methodically so that the discovery of new drugs is not a craps shoot.
Lam starts with a few peptides and, just by mixing properly so that the peptides combine, creates a number of different, novel molecules. Each of these is attached to a microscopic bead, which is then dropped into an extremely tiny well on a sheet with as many as 10,000 such wells, called a microarray. Because much of the process is automated, it can be done very fast.
A wash of cancer cells is spread across the top of the sheet, and those cells are left to multiply and grow – or not to multiply or grow. If the cells don’t grow or multiply around one of the wells, Lam and his researchers are interested. If the cells die around one of the wells, they assume they have a bona-fide candidate drug.
When that occurs, the bead is removed, and the molecule is separated from the bead and identified.
There are other projects, as well.
Because certain molecules have one end attracted to water and another end repelled by water, they will naturally form into a sphere in the presence of water, with one end of the molecule on the outside and one end on the inside, forming a membrane. It works a little like soap bubbles that form around dirt. Lam’s group has developed one of these spheres, called a micelle, using polyethylene glycol. Inside of the micelle they have placed a cancer drug, paclitaxol, used to treat ovarian cancer.
The problem with paclitaxol is that its toxicity is not limited to cancer cells. Cancer cells are just a little more sensitive and susceptible to the drug than healthy cells, either because they divide more rapidly, or because they are perpetually immature and therefore weaker, or for other reasons.
With paclitaxol inside the micelles, Lam’s invention can prevent the drug from interacting much with normal tissues. Lam’s group injects the micelles into the bloodstream, which preferentially accumulate in a tumor because tumors have leakier blood vessels than other tissues. Then, after some time, the micelles break down and the drug is released.
In a recent experiment using mice, Lam’s group found they could increase by 2.5 times the amount of drug that reached the tumor. That could be the difference between a cancer that is cured, and one that shrinks but returns when treatment is stopped. At present, doctors cure only about 35 percent of patients with ovarian cancer.
Another project of the Cancer Therapeutics Program is the effort of Carlito Lebrilla, a professor of chemistry. Lebrilla studies glycoproteins, that is, molecules that are part sugar and part protein, joined together. He estimates that perhaps half of all protein molecules in the body are glycoproteins.
Lebrilla realized that glycoproteins made by cancer cells might be different from those made by normal cells, and if detected in blood, cancer cells could be found early, when disease is most treatable.
Lebrilla has set about developing a way to quickly identify particular glycoproteins, and is looking at some cancers, including ovarian cancer, which is rarely detected early and therefore not often treated successfully. In a recent investigation, Lebrilla found that ovarian cancer cells produced at least four unique glycoproteins that might be used as a cancer marker.
Another project is led by Wenwu Xiao, a post-doctoral researcher in Lam’s laboratory. He employed the same microarray approach to sort the potential drugs to search for a molecule that would bind to the outside of glioblastoma cells. Glioblastoma is the most common type of brain cancer, one that is almost always fatal.
Xiao found one such molecule, called LXY1. Xiao hopes that if LXY1 is combined with a cancer drug it can be used to ferry the drug right to the cancer cells, increasing the treatment’s potency.
Xiao also has begun to search for a binding molecule for breast cancer.
Those are just three of the projects within the Cancer Therapeutics Program. But with Lam’s library of molecules, the possibilities are practically endless.