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© Oxford University Press 2008.
IN THIS ISSUE
Imatinib-Resistant Leukemia and LYN KinaseThe tyrosine kinase inhibitor imatinib is used to treat chronic myelogenous leukemia (CML). Failure of imatinib treatment is associated with mutations in the BCR-ABL kinase in some, but not all, CML patients. The LYN kinase regulates survival and responsiveness of CML cells to inhibition of the BCR-ABL kinase, and differences in LYN regulation have been found between imatinib-sensitive and imatinib-resistant CML cell lines. Wu et al. (p. 926) investigated whether LYN kinase was involved in imatinib-resistant CML by evaluating mononuclear cells from 12 imatinib-resistant CML patients with BCR-ABL mutation–negative leukemia and from six imatinib-sensitive patients. Imatinib treatment suppressed LYN activation in cells from imatinib-sensitive patients but not cells from imatinib-resistant patients. Reducing LYN activation or expression in cells from imatinib-resistant patients reduced cell survival. The authors conclude that the failure of some CML patients to respond to imatinib may be associated with a BCR-ABL–independent mechanism of LYN activation.
In an editorial, O'Hare et al. (p. 908) note that the finding that LYN kinase appears to be important in imatinib-resistant cells with mutation-negative BCR-ABL takes us outside the realm of previously studied kinase domain mutation–based resistance and toward an improved understand of BCR-ABL–independent disease. They point out new areas of research, including investigating the effects of other drugs, such as the ABL and LYN dual tyrosine kinase inhibitor INNO-406, on LYN signaling and expressing a "gatekeeper-mutated" variant of LYN in imatinib-resistant cells to determine whether LYN activation on its own will confer resistance to drugs like dasatinib. They conclude that therapies targeting both BCR-ABL and LYN may prove beneficial in the treatment of patients with certain types of imatinib-resistant CML.
CHD5 is a Tumor Suppressor Gene for Neuroblastoma
Neuroblastoma is a childhood cancer of the sympathetic nervous system that is characterized by deletion of a region of the short arm of chromosome 1 (1p). Because the deletion occurs in only one copy of the gene, it is thought that a tumor suppressor gene resides there. Previous findings suggest that CHD5 is a candidate. To identify the potential tumor suppressor gene, Fujita et al. (p. 940) determined whether CHD5 expression was associated with the outcomes of 99 neuroblastoma patients. CHD5 expression was inversely associated with disease-free and overall survival of the neuroblastoma patients. The authors also re-expressed CHD5 in neuroblastoma cells that normally have no or very low expression and compared cell growth as colonies in soft agar and growth of tumors in athymic mice. Compared with neuroblastoma cells with low or no CHD5 expression, those that were engineered to re-express CHD5 formed fewer colonies and smaller tumors in the mouse model. The authors conclude that CHD5 is a tumor suppressor gene in the chromosome 1p region that is often deleted in neuroblastoma.
Immunization with GCC to Prevent Colon Cancer Metastasis
Guanylyl cyclase C (GCC) is a protein that is expressed in all metastatic colorectal cancer cells but only in intestinal mucosa in the normal colon. To determine whether GCC may be a good therapeutic target for metastatic colon cancer, Snook et al. (p. 950) immunized mice carrying colon cancers with GCC-expressing or control viral vectors and compared numbers of liver and lung metastases and survival over time. Mice immunized with GCC-expressing vectors had fewer metastases and longer median survival time than mice immunized with control vectors. Also, the treatment was effective without causing autoimmunity. The authors conclude that proteins that are specifically expressed in the mucosa of the normal intestine have potential as therapeutic targets for metastatic tumors of the intestine.
Fine Mapping of a Cancer Susceptibity Locus
Recent studies have identified and confirmed associations between breast, prostate, and colorectal cancer and sequence variants within a large region on chromosome 8 that does not code for any known genes. Ghoussaini et al. (p. 962) assessed the frequency of single-nucleotide polymorphisms within this region in case subjects with breast, colorectal, prostate, or ovarian cancer and matched control subjects. Their analysis suggests that at least five independent loci defined by recombination frequency within the previously identified region on chromosome 8 are specifically associated with the risk of one or more of these cancers. The authors suggest that further study will be needed to determine how the polymorphisms they examined or other sequence variants in these loci influence cancer risk.
NSAID Use and Melanoma Incidence in a Cohort Study
Laboratory studies indicated that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. Asgari et al. (p. 967) examined the association between NSAID use and melanoma risk among 63,809 men and women in the Vitamins and Lifestyle (VITAL) cohort. Data on melanoma risk factors and NSAID consumption for the previous 10 years was reported on a baseline questionnaire between 2000 and 2002. The authors identified 349 patients with melanoma in this cohort through 2005. No association between NSAID use and melanoma risk was found. The authors conclude that NSAIDs do not appear to be good candidates for the chemoprevention of melanoma.
Evaluating Large Epidemiological Studies
Cohort studies in cancer epidemiology, which require large numbers of study participants and long time frames, have been criticized for their relatively high costs. Colditz and Winn (p. 918) propose a set of criteria that fit within the discovery, development, and delivery paradigm introduced by the National Institutes of Health that can be used to evaluate epidemiological cohort studies. The criteria are not only based on publications in peer-reviewed journals but also seek to capture the extent to which cohort studies lead to changes in health research and practice, such as initiation of clinical trials and development of prevention guidelines and risk models. The authors apply the criteria to the Nurse's Health Study, comment on the success of this initiative, and suggest a need for improved data sources for evaluations.
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