Photo by Clay Eals
When a throbbing headache strikes, the last thing on a sufferer's mind is the biological basis for how aspirin melts away the pain. It's also typically been the last thing on the minds of drug discoverers.
Scientists took more than 100 years to discover that aspirin's ability to relieve aches and pains was due to its inhibition of synthesis of the hormone prostaglandin - and aspirin has not been unique in its elusive mode of action.
In fact, many successful drugs used today - including a host of anti-cancer agents - work in ways mysterious to scientists, largely because of insufficient biochemical knowledge of the ailments whose symptoms they relieve.
Often, scientists know how a drug works, its mechanism of action, and yet the reasons some cancer cells are sensitive to that drug are not clear.
But armed with a better understanding of the molecular profiles of diseases, including some cancers, scientists like the Hutch's Dr. Julian Simon, head of Molecular Pharmacology, are approaching drug discovery with a more rational eye.
Simon, an investigator in the Clinical Research and Human Biology Divisions, mines for potential anti-cancer drugs using a battery of strategies that rely on an understanding of the genes and molecules that may be disrupted in cancer cells.
The approach is already paying off. With Hutch staff scientist Dr. John Lamb, Simon recently identified a compound that may improve on drugs that treat ovarian and other cancers.
To do this, they developed an efficient, high-throughput method for evaluating drug toxicity in mammalian cells.
The key to successful drug discovery, Simon said, is to know as much as possible about both the drug and the cells on which drug acts.
"There are three components to cancer chemotherapy: drugs, drug targets and the context of the cancer cell," he said. "To develop a truly successful drug, the relationship among all three aspects must be evaluated and understood."
Simon's favorite approach is to examine the context of the cell - properties that make distinct cell types unique in their normal and cancerous states.
"For example, the chemotherapeutic drug cisplatin damages DNA in a certain way. The drug works really well in testicular and ovarian cancer, but not as well in other tumors," he said. "The question is, why? By understanding the context of a cell, we may identify compounds that work selectively on different cancers.
"Each cancer context defines the specific drug targets. It's up to us to find the drugs that will act upon those targets."
Sorting out the biochemical differences between cells relies on more than just an understanding of the genes that cause cancer.
Humans have many cell types - nerve cells, blood cells, skin cells, to name a few - and while each cell contains the same genetic instructions, different parts of the genetic information are used to produce proteins in each type of cell. A drug that acts on a protein produced only in liver cells might have little effect on a blood cell.
Cancer also provides a unique context. For a tumor to develop, cells must undergo a series of genetic changes, or mutations, that cause them to proliferate uncontrollably. While some mutations are common to many types of cancers, other genetic changes may be unique to certain tumors.
The ideal situation for context-based drug screening,Simon said, is to test compounds on "matched sets," meaning that a normal cell's response to a drug is compared side-by-side with a cell with one or a few mutations.
Simon's organism of choice for this strategy is the Saccharomyces cerevisiae, the simple yeast used to make beer and bread. In addition to having its genome completely sequenced, scientists have access to strains of yeast with mutations in virtually every gene.
Although lacking specialized cell types found in higher organisms and unsusceptible to cancer, Simon said that yeast is often a suitable model for preliminary drug screening before the drug's potential is evaluated in mammalian cells.
"Obviously aspects of cancer are missing in yeast, but many cell processes are shared with human cells," he said. "Where yeast has worked as a good system is when there is a direct similarity not only in DNA sequence of a gene, but also in the function of those genes and the proteins that they code for."
The drugs Simon's lab evaluates are obtained from a chemical bank at the National Cancer Institute that consists of more than 900,000 compounds donated by chemists who have synthesized or isolated novel chemicals.
Simon's strategy is to compare the effects of a drug on a normal strain of yeast and a strain with a mutation in one of the many genes that affect normal cell division - a property that is disrupted in cancerous cells.
"What we're looking for is differential toxicity," he said. "Can we identify compounds that selectively kill or inhibit the growth of the mutant cells?"
An example of this comparative approach is used by Lamb, who has identified a drug that selectively inhibits strains of yeast with a defect in a pathway that repairs DNA double-strand breaks.
The new compound targets topoisomease I, an enzyme that is already exploited for cancer chemotherapy by topotecan and irinotecan.
While these drugs are effective in the treatment of some tumors, dose-limiting toxicities limit their widespread use.
The compound that Lamb is analyzing appears to circumvent some of these limitations.
In another method, called target-based screening, potential anticancer drugs are identified by looking for compounds that mimic specific mutations that halt proliferation of cancer cells.
Once a compound from the NCI bank shows promise, larger quantities of the drug are synthesized in the laboratory - a task that is relatively easy for Simon, who is trained as an organic chemist and has amassed a lab full of elaborate glassware and vials filled with mysterious powders.
How did an expert in organic synthesis end up at a cancer research center? Simon's own interest paralleled the evolution of synthetic organic chemistry as a discipline.
"The golden age of synthetic organic chemistry occurred between 1973 and 1987, when chemists began to have the ability to synthesize incredibly complex molecules," he said. "Once chemists got over the excitement of being able to make anything, their attention turned to making functional molecules, and for me, the most interesting molecules are those with pharmaceutical or chemotherapeutic potential, particularly those that act on cancers.
"Cancer is the most difficult disease to develop drugs for. There are hundreds of potential targets, but very few have been verified."
An exciting development in rational anticancer drug design is Gleevac, a drug that acts on a protein unique to the defective white blood cells in chronic myelogenous leukemia and on a related protein in a rare form of gastrointestinal cancer.
While such well-defined drug targets have been harder to identify in other cancers, Simon is optimistic that the rational approach to drug discovery will continue to show promise and invites collaborations with Hutch investigators studying potential anticancer drug targets.
"We'd like to be a general resource for others at the Center," he said. "The most exciting thing would be to have a drug developed here be used to treat Hutch patients."