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It's said that a bureaucrat's blunder can change the course of an empire. In the molecular machinery of cells, the consequences of imperfection can be similarly dramatic.
Although cancer is thought to begin with a mistake in a single gene – a derangement of its DNA, an upsurge in its activity, a mis-synchronization of its signals – no gene acts in isolation.
Each operates within a "pathway" (multiple pathways, actually), a bucket brigade-like unit in which gene A acts on gene B, which acts on gene C, and so on. This continues until the cell performs some action, such as absorbing a nutrient, secreting a protein, or proceeding with division.
If a particular gene malfunctions, the repercussions will be felt by genes far "downstream" in the cascade. And if the broken gene happens to be involved in a cell's division, death, or mobility, the breakdown in gene teamwork can be a step toward cancer.
The existence of genetic pathways underscores both the complexity of cancer and the surprising variety of ways by which it may be attacked. As researchers have begun constructing maps of these pathways over the past decade, the picture of how cancer occurs – a portrait traditionally limited to individual genes and their misbehavior – has become denser with detail.
As the information gaps get filled in, new avenues for cancer therapy are exposed.
Dana-Farber's Kwok-Kin Wong, MD, PhD, who tests potential cancer agents in animals before they're studied in human patients, explains:
"Many of the genes that are known to play key roles in cancer cannot be targeted with current drugs. They may operate in inaccessible parts of the cell or be impossible to block without damaging other, necessary genes. In such cases, blocking one of their upstream or downstream genes may have the same effect as blocking the disease genes themselves."
Wong's own research provides an example.
"One of the most commonly mutated, or abnormal genes in cancer is KRAS [which helps transmit growth signals in cells], but no drug is known to target it," he says. "Our lab is focusing on downstream genes in the KRAS pathway that can be targeted instead."
Wong and his colleagues are focusing on two such genes, PI3K and MEK, for which inhibitor drugs already exist. In a study published last year in the journal Nature Medicine, the Dana-Farber researchers showed that when mice with lung tumors harboring KRAS mutations were treated with these drugs, the tumors shrank significantly.
"The more we know about the biology of cells … the more vulnerabilities we can exploit with drugs," Wong says.
"The more we know about the biology of cells – the more pathways we can trace – the more vulnerabilities we can exploit with drugs," Wong remarks. "It's like an electrical circuit: it doesn't matter whether you cut the beginning or the end of the wire, the current stops flowing."
Although the term "genetic pathway" is an accepted part of the scientific lexicon, it's actually something of a misnomer. Since genes work by issuing instructions for the production of specific proteins, the circuits that switch genes on or off in sequence might more accurately be called protein pathways.
By either name, pathways were only sketchily understood prior to the late 1990s. Given their critical role in cell life and their ability to reveal potential drug targets, pathways might have seemed worthy of more thorough investigation.
The obstacle, researchers say, was a lack not of scientific curiosity but of technology. Without the ability to track how activity among genes is orchestrated, scientists could make only slow progress in tracking one gene's response to another.
"It's hard to talk about pathways when you don't have a lot of dots to connect," says Dana-Farber's Anthony Letai, MD, PhD.
It was only with the development of sophisticated equipment capable of reading the activity levels of thousands of genes simultaneously that researchers could see which genes seemed to operate in unison, and might therefore belong to the same pathway.
"Gene-profiling machinery was essential," Letai says, "but so was the investigators' persistence in following up on the leads provided by the technology, and the belief of their financial supporters in the value of this research."
Letai and his colleagues are advancing the work of his Dana-Farber mentor, the late Stanley Korsmeyer, MD, who pioneered the study of apoptosis, a natural process by which cells direct their own death when sufficient abnormalities are detected.
Korsmeyer showed that a gene called BCL2, whose function hadn't been clear, is part of a pathway that controls cell death. Cancer cells often have a breach in the pathway – an error in BCL2 or one of the genes related to it – that enables them to break the rules of normal cell behavior without committing suicide.
Pharmaceutical companies have developed an array of compounds capable of blocking mutated BCL2. Such agents can selectively kill cancer cells that rely on excessive BCL2 protein for survival.
"The aim is to trick cancer cells into committing suicide," Letai remarks. "One of the qualities that makes BCL2 so intriguing is that it stands very close to the end of the pathway for apoptosis, the point at which a cell commits to dying." BCL2 blockers have shown promise in clinical trials involving patients with a variety of cancer types.
Even as researchers learn more about the major players in genetic pathways, the frame of reference for the field is changing. Each gene participates not in one pathway, but in many – possibly dozens. Pathways interweave and overlap in a pattern that resembles a tangle of ivy more than a set of neat, separate strands.
"It might be more useful to talk about genetic webs or networks than pathways," Letai says. "We're only beginning to appreciate how complex the system is."
At Dana-Farber, pathways research ems virtually every tumor type and stage of disease. Scientists are combining data from gene-scanning experiments with the results of gene-function and mechanics studies to identify new pathways and the genes within them. The outcome of this work is both a better understanding of the molecular circuits by which cancer cells survive and new strategies for blocking them.
Among the Dana-Farber research projects where a focus on pathways is resulting in significant gains:
• Thomas Roberts, PhD, and Jean Zhao, PhD, are working to develop a backup therapy for women with "HER2-positive" breast cancer that has become resistant to the drug Herceptin. They've shown that altering a gene in a critical growth pathway can spur the proliferation of breast cancer cells whose growth had been halted by Herceptin. This suggests that drugs targeting the gene may be effective for some patients.
• Lynda Chin, MD, and Matthew Meyerson, MD, PhD, led a panoramic genetic survey of glioblastoma, the most common and deadly form of adult brain cancer. They found that three signal-carrying pathways were disrupted in more than three-quarters of glioblastoma tumors. The pathways may harbor genes susceptible to treatment.
• Alan D'Andrea, MD, and colleagues are developing a series of lab tests to determine which of six pathways involved in DNA repair are active in breast and ovarian tumor samples [Targeted therapy, POP SS 2009]. Such information will help doctors determine which patients are the best candidates for novel drugs known as PARP inhibitors, or other treatment.
Fall/Winter 2009 Table of Contents