The surge of optimism for new cancer drugs that target cell signaling pathways has been tempered by a dose of reality. Some patients taking Gleevec (imatinib mesylate) have developed resistance to the drug as a result of mutations in the bcr-abl fusion protein or gene amplification. The U.S. Food and Drug Administrations Oncologic Drugs Advisory Committee recently recommended AstraZenecas Iressa (gefitinib) for accelerated approval for third-line therapy for non-small cell lung cancer, but with strong reservations; a large phase III trial of the drugwhich targets the epidermal growth factor receptorresulted in no improvement in survival (see News, Nov. 6, p. 1596). And Pharmacias SU5416, which targets the vascular endothelial growth factor receptor, was abandoned in February after extensive phase II and phase III testing.
Thus far, signaling inhibitors have not proven to be a panacea, and researchers are wondering whether the problem is in the target or in the drug. "Its probably a combination of both those things," said Bill Kaelin, M.D., an associate professor of medicine at Harvard Medical School in Boston.
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Cancer cells typically accumulate a half dozen or more growth-promoting mutations, and their ability to mutate rapidly has foiled every treatment strategy. But that very genetic instability may render them vulnerable to the right targeted drug. "Can we use an agent to force a cancer cell to kill itself?" asked Louise Grochow, M.D., chief of the National Cancer Institutes Investigational Drug Branch.
Lethal Combination
Cancer researchers borrowed the term "synthetic lethality" from classical genetics to describe situations where a cancer mutation and a drug together cause the tumor cells death. ("Synthetic" is used in the sense of "synthesis," or coming together.) Either the mutation or the drug alone cannot kill. Put them together, and the cancer cell dies.
There is growing evidence for synthetically lethal drug activity. In the summer of 2001, three laboratories showed that mutations in the PTEN tumor suppressor gene make mouse tumors dramatically more responsive to treatment with Wyeths rapamycin derivative CCI-779 than tumors with normal PTEN. PTEN is mutated (and presumably inactivated) in more than half of human brain cancers and endometrial cancers and in 20% of metastatic prostate cancers. Based on the mouse results, patients with PTEN mutations should respond better to the drug than those without.
"Theres no doubt theres synthetic lethality," said Stuart Schreiber, Ph.D., professor of chemistry and chemical biology at Harvard University. "Im dying to know why theres synthetic lethality." Schreiber said he thinks that the drug tricks the cancer cell into thinking it is in a hostile environment and drives the cell into apoptosis, or programmed cell death. For whatever reason, a cancer mutation proves to be the tumors downfall.
If this principle could be applied to other tumors, it would open a whole new realm of possibilities for targeted therapies. "We want to find a [drug] that has an untoward effect on cells only if the cell harbors a cancer-causing gene or lacks a tumor suppressor gene," explained Schreiber. In other words, use drugs to force cancer cells to die from cancer.
"The concept, I think, is a very valid one," said Paul Workman, Ph.D., director of Cancer Research U.K.s Centre for Cancer Therapeutics. "What do cancer cells have that normal cells dont? Well, they have mutations, [and] you can take advantage of those."
Cancer Unmasked
Synthetic lethality may also explain how another promising drug, the geldanamycin derivative 17-AAG, works. Geldanamycin interferes with heat shock protein 90 (Hsp90), a chaperone protein that is vital for the proper folding of many signaling proteins. Susan Lindquist, Ph.D., director of the Massachusetts Institute of Technologys Whitehead Institute, has shown that Hsp90 impairment accelerates the appearance of genetic abnormalities in fruit flies, and she speculates that Hsp90 normally serves to "buffer" mutations by binding to abnormal proteins and blocking their expression. Expose cells to stress and divert the available Hsp90 to other damaged proteins, Lindquists theory goes, and these mutations are suddenly released and expressed.
Similarly, in cancer cells, it is possible that geldanamycin, by blocking Hsp90 activity, releases a variety of mutations that together prove synthetically lethal to the tumor. Normal cells, which lack the tumor cells genetic instability, are relatively unaffected.
So far, such synthetically lethal interactions are pure speculation, but the theory is plausible, said Len Neckers, Ph.D., of the NCIs Cell and Cancer Biology Branch. Cancer cells "are prone to mutations," he said. "Treating with Hsp90 inhibitors, you might release these mutations that have accumulated in cancer cells that dont exist in normal cells." The result: cell death.
Another possibility is that genetically altered cancer-driving oncogene products might need Hsp90 to fold properly while nonmutated proto-oncogenes do not. "Maybe certain tumors have a load of such mutations, and thats why theyre sensitive [to the drug]," speculated Neal Rosen, M.D., head of molecular oncogenesis at the Memorial Sloan-Kettering Cancer Center, New York.
The cancer cell cycle is also vulnerable to synthetic lethality. Paul Nghiem, M.D., Ph.D., who works in Schreibers laboratory at Harvard, has used caffeine to block ATR (a checkpoint kinase) in cells harboring certain oncogene and tumor suppressor gene mutations and killed the cancer cells. They die because, with the checkpoint removed, no DNA repair takes place. Normal cells, lacking the lethal mutations, do not die when they jump ahead to cell division. That, anyway, is the theory. "Now, will this relate to an actual tumor in a patient?" asked Schreiber. "We dont know." Caffeine at high concentrations is too toxic and nonspecific to be a drug, but Merck is now working on specific ATR inhibitors.
Whereas caffeine tells the cancer cell to "go" when it should stop, another approach instructs the runaway cell to stop, but with similarly lethal results. Harvards Kaelin has demonstrated that cells with high levels of the transcription factor E2F (a hallmark of many cancers) can be killed with peptides that indirectly generate more free E2F. This E2F, presumably, remains attached to the DNA and halts the cell cycle. "The cell seems to get stuck in S phase and then ultimately undergoes programmed cell death," Kaelin explained. His laboratory is now working on small molecule versions of these peptides, as are Bristol-Myers Squibb, Pharmacia, and Astra-Zeneca, among others.
House of Cards
Generating more oncogene products to treat cancer is an obvious paradox. But "its turning out to be a general theme," said Kaelin. "There are a variety of oncogenes that induce apoptosis if you have too much." Kaelin speculates that tumor cells are delicately balanced between proliferation and programmed cell death and are vulnerable to a drug that tips the balance and triggers a fail-safe mechanism. "If the engine gets too hot, then the cell undergoes apoptosis," he explained. The genetically unstable tumor cell should, according to this view, be poised on the brink of death even as it wildly proliferates. If so, the right synthetically lethal drug, like Kaelins indirect E2F agonist, could push the tumor cells over the edge while sparing normal cells.
Another reason to be hopeful: there is growing evidence that cancer cells become "addicted" to a given growth pathway, perhaps because mutations cause the loss of redundant pathways that are present in normal cells. "The tumor cell is a house of cards where you have many mutations involved," speculated Workman. "But if you take any one of those away from the ... lower level of the deck of cards, then the house of cards collapses." For example, Kaelin pointed out that Gleevec works not only against chronic myelogenous leukemia, which has a single transforming genetic defect, but also against gastrointestinal stromal tumor, which has many such abnormalities but still responds to a single targeted drug.
Academic laboratories and biotechnology companies are now systematically looking for new synthetically lethal cancer drugs. Kaelins laboratory at Harvard is genetically screening C. elegans for genes that, when knocked out, kill worms harboring cancerous mutations while sparing normal worms. Schreibers research group has also been doing synthetic lethality screens. "Although its still fairly early ... we have not yet undertaken a screening study using synthetic lethality that has failed to yield an intriguing hit," he said.
Mechanistic studies must now be done before selecting drug candidatesa time-consuming step that has, so far, discouraged large drug companies from screening. But Schreiber thinks such unbiased screens are the future of cancer drug discovery. The traditional reductionist approach of dissecting signaling pathways and then selecting targets has limitations, because tumors have many ways of overcoming such drugs. "Everyones going in and targeting raf or ras or MAP kinase, but everything talks to everything," Schreiber said. "Real biology is systems biology. ...Were not as smart as we think we are."
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