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October 26, 2009
Volume 87, Number 43
p. 20


Missing The Target

Some researchers call for moving beyond targeted therapies when tackling cancer

Lisa M. Jarvis

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When scientists sequenced the human genome in 2003, a shot rang out in drug discovery labs around the world. It signaled the start of a race to uncover the cellular pathways of disease and find small and large molecules to interrupt those pathways. Cancer has been a ripe area for research, and the pipeline is now packed with “molecularly targeted” drugs. Many targeted therapies, such as Genentech’s Herceptin and Avastin, have come to market and significantly improved the lives of cancer patients.

But some researchers are starting to question whether targeted molecules represent the best way forward for cancer treatment. They argue that these drugs have limitations, and they suggest the time is right to devote resources to approaches that might change cancer into a manageable disease.

The National Cancer Institute defines targeted cancer therapies as ones that work “by interfering with specific molecules involved in tumor growth and progression.” They include Herceptin, which targets a specific genetic mutation in breast cancer, and Avastin, which targets a receptor that enables blood vessels to grow. They can bring billions of dollars in sales over their lifetimes.

For patients, however, the usefulness of such drugs can be limited; that’s because cancer cells do a pretty good job of evading the pathways those drugs block.

“The problem with cancer is it is not like diabetes, where all of the cells in diabetes have wild-type DNA, and so much as we know, we’re treating one disease,” says Steven F. Dowdy, Howard Hughes Medical Institute investigator and professor of cellular and molecular medicine at the University of California, San Diego Medical Center. Instead, cancer operates by hyperactive mutation, and when one cell turns into two, the two resulting cells are not identical, Dowdy explains. As those two cells turn into four, then eight, and eventually a billion, “you end up with an entire colony of tumor cells that are closely related but also genetically distinct.”

If those cancer cells are blasted with a traditional chemotherapeutic, enough can be killed to send a patient into remission. The problem, however, is that the drug doesn’t always kill 100% of them. Any cancer cells lying dormant can be particularly dangerous, for they are resistant to the chemotherapy used. They already display a variety of mutations, and once they begin to run amok they can be hard, if not impossible, to stop with follow-up drugs—if those drugs even exist.

The time is right to devote resources to approaches that might change cancer into a manageable disease.

Dowdy argues that targeted drugs can also succumb to resistance. Although a handful of treatments are good at suppressing cancer for several years, many extend life for only a few months, and all of them have the potential to induce a more resistant disease. So far, only a few follow-up drugs have been developed to treat that recurrent disease.

It now costs nearly $1 billion to bring the typical new drug to market. Given the cost, Dowdy wonders: “Is the juice worth the squeeze?” Although the incremental steps targeted therapies offer patients are important, given the resistance problem, Dowdy believes the answer to the question “is probably ‘no.’ ”

Yet companies big and small continue to devote billions of dollars of research money to finding newer and better targeted cancer treatments. Most are hotly pursuing the latest kinase or other molecular target that might be implicated in a particular form of the disease.

Some prominent scientists contend that other horizons need to be explored as well. James D. Watson, who won the Nobel Prize in Medicine for determining the structure of DNA, wrote an editorial in the Aug. 6 New York Times advocating bolder strategies from scientists.

“While targeted combination chemotherapies would be a big step forward, I fear we still do not yet have in hand the ‘miracle drugs’ that acting alone or in combination would stop most metastatic cancer cells in their tracks,” Watson wrote. “To develop them, we may have to turn our main research focus away from decoding the genetic instructions behind cancer and toward understanding the chemical reactions within cancer cells.”

Watson advocates revisiting the notion that all cancer cells have commonalities—the mechanism for metabolizing glucose, for example—that can be hit with drugs.

Indeed, there appears to be renewed interest in trying to find an Achilles’ heel for cancer. Dowdy points to the work of Harvard University’s Lewis Cantley and the University of Pennsylvania’s Craig Thompson, which has helped elucidate the links between glucose metabolism and cell growth. The logic in pursuing the avenue was affirmed in a recent epidemiological study comparing diabetes patients taking insulin to those taking metformin, which suppresses glucose production in the liver. It showed that pancreatic and colon cancer risk was halved in the metformin patients.

“If you could restrict cancer cells’ glucose uptake and thereby starve tumors from growing, that would be great,” Dowdy says, acknowledging at the same time that “it hasn’t been done.”

Dowdy thinks RNA interference, the mechanism by which cells silence gene expression, could hold the key to permanently suppressing cancer. He envisions a scenario in which a patient takes a cocktail of short interfering RNA to quell the disease. Once a mutation crops up, the tumor is biopsied and a new cocktail is mixed. In a sense, it is a targeted, but easily adaptable drug.

However, scientists still need to come up with an effective method for delivering RNA-based medicines—no small feat (C&EN, Sept. 7, page 18). Like the suppression of glucose metabolism, such strategies to change cancer from a killer disease into a chronic disease are, unfortunately, still a pipe dream.

Views expressed on this page are those of the author and not necessarily those of ACS.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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