"In its own microscopic way, becoming cancerous is about the most glamorous and successful thing a cell can do. An ordinary, non-cancerous cell is a plodding drone of a thing ... it beavers away for its genetically allotted span, reproduces itself by splitting into mother and daughter cells, dies. [By contrast], the cancerous cell wants to go places, do things that its parents never had the chance to do. A cancer cell is the one that never grows up, [that] bears all the nastier traits of reckless youth. It defies order, goes where it likes and above all believes itself to be immortal ... the cancer cell would live for ever [sic] were it not that doing so does away with the host upon which it needs to live."
It is fully two decades since the first oncogenic mutation was characterized in humans. Since then, a remarkably detailed picture of signaling pathways and cancer-related aberrations has emerged, brilliantly distilled by Douglas Hanahan and Robert Weinberg in a classic review in Cell a couple of years ago as the six hallmarks of cancer. Mutations in oncogenes and tumor suppressor genes render cells self-sufficient in growth signals and resistant to growth-inhibitory signals. Cancer cells escape programmed cell death (apoptosis) and acquire the ability to replicate incessantly. They commandeer the blood supply (angiogenesis) and ultimately metastasize to invade other tissues. In each category, a host of molecular miscreants is known, many of which offer enticing targets for therapeutic strategies to curtail, and perhaps conquer, the disease.
The Gleevec Generation
The Novartis AG drug STI-571, popularly known as Gleevec, is the poster-child of rational drug design and a testament to the importance of targeting a specific (genetically selected) population. Gleevec is a small-molecule drug that specifically inhibits the aberrant fusion protein BCR-ABL, the product of the telltale genetic rearrangement in chronic myelogenous leukemia (CML) known as the Philadelphia chromosome. This chimeric protein has what is termed "enhanced kinase activity" — kinases are enzymes that add key regulatory phosphate groups to other proteins. STI-571 was originally synthesized as part of the kinase inhibitor program at Novartis, and about six years ago, was shown to specifically inhibit BCR-ABL and another kinase, c-KIT. Following impressive clinical trials led by Brian Druker, last year the FDA granted approval of the drug in record time for treatment of CML, as well as a rare form of stomach cancer. (Herceptin, used in some forms of breast cancer, also targets tyrosine kinases.)
Gleevec has been widely proclaimed as the first of a new wave of rationally designed drugs to combat those forms of CML resulting from the Philadelphia chromosome. The drug has "validated nearly four decades of cancer research into the molecular etiology of cancer," says Druker, "and has substantiated the concept that a precise understanding of the pathogenesis of a cancer can lead to effective therapies." But Gleevec is not the last word. Excitement surrounding the dramatic remissions in CML patients was quickly tempered by reports of drug resistance in later-stage cases of the disease. This resistance results from spontaneously arising mutations affecting the BCR-ABL gene that impair Gleevec's binding efficiency. Nevertheless, the power of rational drug design was evident for all to see.
Two new reports in the June 18 issue of Cancer Cell by D. Gary Gilliland, a Howard Hughes Medical Institute investigator at the Brigham and Women's Hospital and Dana Farber Cancer Institute, and his co-workers provide exciting evidence that the Gleevec story is not a flash in the pan. The studies focus on acute myelogenous leukemia (AML), the most common form of adult leukemia, with more than 10,000 new cases and about 7,500 associated deaths in the United States each year. About one-third of AML cases are caused by a mutation in the gene for the FLT3 receptor, which is also a member of the tyrosine kinase family.
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The FLT3 receptor has been a promising target for some years and recently received independent validation from a study by another team of Harvard Medical School researchers, led by Todd Golub and Stanley Korsmeyer. In a masterful example of microarray analysis that appeared in January's Nature Genetics, the Harvard team documented gene expression profiles that clearly distinguished AML, acute lymphoblastic leukemia (ALL), and mixed lineage leukemia (MLL) as three diseases of discrete molecular origins. The most highly correlated expression difference that distinguished MLL from the other two was that of FLT3, prompting the authors to conclude that, "FLT3 represents an attractive target for rational drug development."
In his two latest studies, one with researchers at Novartis (E. Weisberg, et al.), the other with collaborators at Millennium Pharmaceuticals Inc. (L.M. Kelly, et al.), Gilliland and his team investigated two drug candidates that specifically target and switch off the constitutively active mutant FLT3 receptor. The Novartis study shows that PKC412, a previously characterized compound that had been studied in clinical trials, is an extremely effective inhibitor of the FLT3 receptor. Animal studies using mice with a form of AML could not be more encouraging: All such mice given oral doses of the drug recovered, whereas all those given a placebo died. Similar results were observed with the Millennium drug CMT53518, although some mice appeared resistant for causes that are under investigation.
These two drugs are currently in clinical trials, as are two other anti-AML drugs from Cephalon Inc. and Pharmacia Corp. (The Novartis and Cephalon drugs are already in Phase II trials.) From a chemical perspective, the drugs complement each other, so as Gilliland says, "If we encounter cases of [AML] that are resistant to one drug, we have alternatives that give us the very best chance for circumventing that resistance." And even if, as seems likely, a tumor should develop resistance to one FLT3 inhibitor, it will have a difficult time thwarting the combined effect of four different drugs, each targeting the protein in a different way.
Gone in 60 Seconds
In the heady atmosphere that marked the initial human genome celebration, former President Clinton proclaimed, "Our children's children will know the term 'cancer' only as a constellation of stars." As the latest national cancer statistics make clear, to realize that utopian vision will require enormous advances in epidemiology, prevention, and public awareness, to complement the rapid progress in molecular biology. As recorded by the American Cancer Society, cancer causes 23 percent of deaths in the United States, ranking second only to heart disease. The disease will claim more than 550,000 lives this year — that's one fatality every 60 seconds. Almost 1.3 million new cases of (invasive) cancer will be diagnosed this year, up slightly from 2001. It is a sobering fact that two out of five people in developed countries will be diagnosed with cancer during their lifetime — although it could be argued that given the profusion of environmental risk factors and the aging population, what is even more remarkable is that three out of five people will not.
The encouraging new drug findings suggest we are on the cusp of an exciting new era in cancer treatment, at least for tumors that are genetically well-defined. The root cause of many forms of cancer should be ferreted out in the next few years. At the Wellcome Trust Sanger Institute in Cambridge, England, for example, researchers involved in the cancer genome project recently identified the most frequently mutated gene in melanoma, BRAF. New gene targets coupled with well-documented signaling pathways will pave the way for a new round of drugs. "One day," write Hanahan and Weinberg, "we imagine that cancer biology and treatment — at present, a patchwork quilt of cell biology, genetics, histopathology, biochemistry, immunology, and pharmacology — will become a science with a conceptual structure and logical coherence that rivals that of chemistry or physics."
But as Brian Druker observed in the inaugural issue of Cancer Cell last February, the astonishing success of Gleevec was largely attributed to the fact that "it targeted the most validated target in all of oncology ... As easy as [Gleevec] made it look, there is still much work to be done."
ART BY CELL PRESS