Monoclonals move up
The 1990s heralded the approval of several monoclonal antibodies for the targeted treatment of cancer and other diseases. Of the dozen or so now used in the clinic, trastuzumab (Herceptin) was the first monoclonal antibody sanctioned for the treatment of a solid tumor.
Trastuzumab targets the growth factor receptor Her2, which is amplified in 25–30% of breast cancers; these are some of the most aggressive tumors. Work in the 1980's and 1990's showed that antibodies against Her2 inhibited the growth of HER2-overexpressing cancer cells, prompting clinical trials.
In 1996, Baselga et al. (J. Clin. Oncol. 14, 737–744) published the first report of clinical efficacy of an anti-Her2 antibody, trastuzumab. They found an encouraging response rate, measured as decreased tumor size in some breast cancer patients. These and similar results ultimately led to the antibody's approval by the US Food and Drug Administration in 1998 for the treatment of Her2-overexpressing metastatic breast cancers. Slamon et al. (N Engl J Med. 344, 783–92; 2001) went on to combine trastuzumab treatment with chemotherapy and found in phase 3 trials that disease progression was delayed by several months and survival improved. Some patients, however, experienced cardiotoxicity, tempering enthusiasm.
Thus far, Her2 expression is the second marker (besides the estrogen receptor) available for stratifying the breast cancer patient population for therapeutic intervention. Current work focuses on developing small molecules that inhibit Her2 activity and antibodies that can target tumors that express even low levels of Her2. —AF
Aiming for angiogenesis
In the late 1960s, Judah Folkman and colleagues began the work that would capture the imagination of cancer biologists years later. They established that the formation of new blood vessels—angiogenesis—drives tumor expansion. By the mid-1990s, the potential therapeutic relevance of these insights became clear, notably through the work of Kim et al. (Nature 362, 841; 1993) and Warren et al. (J. Clin. Invest. 95, 1789; 1995), who showed that inhibition of vascular endothelial growth factor (VEFGF) inhibited blood vessel formation and tumor growth in mice.
The tumor angiogenesis field burgeoned throughout the 1990s with the hope that anti-angiogenesis therapy would be widely applicable to many tumor types, have few side effects and not be prone to drug resistance. Results from initial clinical trials, however, were mixed. More recently, Hurwitz et al. reinvigorated the field by finding that a VEGF monoclonal antibody, bevacizumab, prolongs lifespan in patients with metastatic colorectal cancer when given as an adjuvant to standard chemotherapy (N. Engl. J. Med. 350, 2335; 2004). Whether bevacizumab acts by a direct anti-angiogenesis mechanism is as yet unclear, but this clinical validation is now spurring the development of new anti-angiogenic agents, as well as tailored dosing regimens and combinatorial treatment strategies with other types of anticancer agents. —MB
Vanquishing a virus
Despite screening programs implemented over the past 50 years, cervical cancer continues to threaten women's health, accounting for 250,000 deaths worldwide each year. Cervical cancer is invariably associated with infection by human papillomavirus (HPV)—a prime target for therapeutic and prevention efforts.
In work culminating years of animal and pilot studies, Koutsky et al. (N. Engl. J. Med. 347, 1645–1651; 2002) tested a vaccine based on the major viral L1 protein, which forms immunogenic virus-like particles. The authors focused on HPV type 16 (HPV-16), found in more than 50% of cervical cancers. They found that young, uninfected women given three doses of the vaccine were completely protected from persistent HPV-16 infection and early-stage HPV-16-associated disease.
Follow-up studies will include more patients and evaluate whether the vaccine offers long-term protection against tumors, which generally arise 20–30 years after viral exposure. Improved vaccines under development target other HPV strains or are designed to treat existing HPV infections. Widespread rollout of the prophylactic HPV vaccine, thought to be just a few years away, holds the promise of greatly reducing cervical cancer worldwide. —CW
Prognosticators and array makers
Upon its introduction in the mid-1990s, the microarray miniaturized, mechanized and revolutionized nucleic acid hybridization techniques—and that was just in the first incarnation. Microarrays enabled the mass production of unprecedented amounts of biological information, and almost immediately were put to use to determine the molecular differences between cancer cells. In February 2000, Alizadeh et al. applied the technique to diffuse large B-cell lymphoma (Nature 403, 503), the most common subtype of non-Hodgkin lymphoma. Among patients with this condition, 40% respond well and live long lives; the remainder succumb to the disease. The researchers distinguished, at the level of gene expression, tumors likely to respond to treatment from those likely to kill the patient. Two years later, van't Veer et al. identified a molecular signature associated with metastasis in breast cancers that outperformed all other clinical parameters in predicting disease outcome (Nature 415, 530; 2002). Standardization between labs remains an issue. Nonetheless, in early 2003 Van't veer and colleagues were the first to begin using the technique routinely in the clinic, at the Netherlands Cancer Institute in Amsterdam. —CS
In 1990, Mary-Claire King and colleagues mapped the position of the breast cancer susceptibility gene BRCA1 to a small region of chromosome 17. The discovery touched off a race to clone BRCA1, won in 1994 by researchers at Myriad Genetics in collaboration with scientists at the University of Utah and the US National Institutes of Health (Swensen et al., Science 266, 66). BRCA1—and BRCA2, cloned 15 months later—led the way in confronting new issues for hereditary mutations, ranging from patenting to genetic testing. Myriad obtained patents for many disease-associated BRCA1 mutations, giving it a legal lock on genetic testing—a position recently eroded by a decision this May by the European Patent Office. The sequence of the human genome dramatically accelerated the identification of cancer susceptibility polymorphisms, such as those in BRAF (melanoma) and RNASEL (prostate cancer). —CS
Written by Michael Basson, Alison Farrell, Charlotte Schubert and Charlotte Wang; in consultation with experts in the field.
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Historical Research Highlights. Nat Med 10, 788 (2004). https://doi.org/10.1038/nm0804-788
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