Drug Firms Hope to Showcase More Effective Anticancer Drug
By GAUTAM NAIK
Staff Reporter of THE WALL STREET JOURNAL
Scientists have taken small but promising steps toward developing a new class of drugs that may be more effective in treating various cancers and reducing some of the nasty side effects of chemotherapy.
Cytokinetics Inc., a closely held South San Francisco, California, company, and its partner, British drug company GlaxoSmithKline PLC, plan to announce Monday that they have identified a compound that has worked well against stubborn human cancers -- of the colon, breast, ovary, lung and pancreas -- when tested in animal models. In many cases, the compound caused fewer side effects than standard treatments, the companies say.
Common chemotherapy drugs like Taxol, made by Bristol-Myers Squibb & Co., work by disrupting cell division, the process by which normal cells, and tumors, multiply. But Taxol and related drugs don't treat all cancers and do cause side effects. Cytokinetics has identified a new group of cancer targets, known as mitotic kinesins, that are also involved in cell division.
Cytokinetics and Glaxo plan to present the data from animal studies at Monday's meeting of the American Association for Cancer Research in San Francisco. Later this year, they hope to begin phase-1 human trials for one especially promising compound.
Despite the favorable results in animals, the compound could fail in human trials. Kinesins "are the most novel opportunity that we've come across in the last five years," says Allen Oliff, head of drug discovery in Glaxo's oncology business. "But there have been lots of things that worked well with animals and didn't do anything for people."
Many common chemotherapy drugs such as Taxol are limited in their appeal because they poison the entire body. Newer treatments like Novartis AG's Gleevec and AstraZeneca PLC's Iressa have been shown to be effective only for certain cancers. Two other promising types of anticancer agents -- certain proteins that attack tumors, and medicines that block the formation of blood vessels feeding new tumors -- also have limitations.
So scientists are keenly awaiting word of the new kinesin approach taken by Cytokinetics. A typical chemotherapy drug like Taxol disrupts cell division by attacking tiny tracks called microtubules, which run within a cell and act as its transport network. But the tracks are involved in more activities than just division, so disrupting them also harms healthy cells, causing side effects.
Cytokinetics's technique of attacking a specific kinesin is more precise. Kinesins, akin to microscopic motors, travel along the microtubules, hauling bits of protein around the cell. Many transport DNA, which makes them vital for cell division -- the key issue in cancer's spread. Cytokinetics figures that if it can disrupt kinesins that occur only in tumor cells, it can effectively target tumors alone.
"You can attack cancer by either blowing up the cars or the highways," says James Sabry, president and chief executive of Cytokinetics. "The old way is to blow up the highways. We decided to blow up just the cars."
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New Weapons
Some new anti-cancer agents researchers are working on and how they attack the disease:
Type of Agent Action
Angiogenesis inhibitors Drugs that block blood vessels feeding tumors
Monocolonal antibodies Proteins that attack specific molecular targets
Kinase inhibitors Compounds that disrupt cellular signals
Kinesin inhibitors Compounds that disrupt DNA movement in cell
Source: WSJ reporting
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In its search for kinesin inhibitors, Cytokinetics screened more than 200,000 compounds. One, which the company declined to identify, is especially promising. When tested against a mouse model of human pancreatic cancer -- a hard-to-treat disease -- it reduced tumor growth by more than 75%. Some of the tumors also shrank, according to the company. By comparison, an existing pancreatic cancer drug called gemcitabine reduced tumor growth in a control group by 73% but resulted in no shrinkage.
A similar animal study of the compound against colon cancer reduced tumor growth by 69%, compared with a 73% reduction by irinotecan, an existing colon-cancer drug. But in two other colon-cancer models using the compound, the tumors disappeared completely, Cytokinetics says. (It is unclear whether the tumors would eventually regrow.)
The compound was well tolerated by mice in many of the tests, and there was no evidence of side effects of the nervous system commonly associated with drugs like Taxol. In one animal trial, the tumors shrank when the compound was administered at one-third the dose at which serious side effects would emerge.
Scientists have long known that tiny motors exist in the human body, but kinesins were discovered only in 1984, when researchers at the Marine Biological Laboratory in Woods Hole, Mass., noticed them in the nerve cell of a squid. "We saw that it was a completely new kind of motor powering motion within a cell," says Ron Vale, one of the scientists who discovered kinesins, helped found Cytokinetics and is on the company's scientific advisory board. It is known that these microscopic motors exist in every cell of every organism, though exactly how they create motion remains mysterious.
Cytokinetics's research attracted several venture-capital investors. Between 1998 and July 2001 the company raised more than $90 million (€102 million) in equity funding, including a $14 million purchase of its preferred stock by GlaxoSmithKline. Separately, the British drug maker has made an upfront cash payment of $14 million and committed more than $20 million to Cytokinetics for research. In exchange, GlaxoSmithKline gets certain rights to commercialize any promising drugs that result.
Write to Gautam Naik at gautam.naik@wsj.com
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