AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.

Progress and problems with the use of viral vectors for gene therapy

Gold nanoparticles in delivery applications

Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).

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Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report.

Factors contributing to retroviral integration have been intractable because past studies have not precisely located genomic sites of proviruses in sufficient numbers for significant analysis In this study, 903 murine leukemia virus (MLV) and 379 human immunodeficiency virus-1 (HIV-1) integrations in the human genome were mapped The data showed that MLV preferred integration near the start of transcriptional units (either upstream or downstream) whereas HIV-1 preferred integration anywhere in the transcriptional unit but not upstream of the transcriptional start Defining different integration site preferences for retroviruses will have important ramifications for gene therapy and may aid in our understanding of the factors directing the integration process

https://science.sciencemag.org/content/sci/300/5626/1749.full.pdf

Transcription Start Regions in the Human Genome Are Favored Targets for MLV Integration

With one French gene-therapy patient having developed a form of cancer, a frantic detective effort is under way to determine what went wrong — and to assess the risks faced by others. Erika Check reports.

A tragic setback.

Trials of a new immunotherapy drug for Alzheimer’s disease have hit a roadblock, with four of the participants developing potentially serious problems in the nervous system. Some researchers say the side-effect could have been anticipated before the trial began. The drug’s manufacturer, Elan of Dublin in Ireland, and its collaborating company, Wyeth-Ayerst of Madison, New Jersey, announced on 18 January that they were temporarily suspending a 360-patient trial of the drug, AN-1792, being carried out in the United States and Europe, while they investigate the problem. The four patients, all based in France, show “clinical signs consistent with inflammation in the central nervous system”, the statement says. Max Gershenoff, a spokesman for Elan, declined to elaborate on what led the investigators to diagnose the inflammation. He says the company hopes that the safety-monitoring committee that has been asked to establish the source of the inflammation will do so before the patients receive their next scheduled dose of the drug. A Wyeth-Ayerst spokesman says that one of the patients has already recovered. Three years ago, Elan reported that AN1792 attacks tangles of human amyloid-b protein, called plaques, in the brains of transgenic mice (see D. Schenk et al. Nature 400, 173–177; 1999). These plaques are diagnostic of Alzheimer’s disease. Elan began phase I trials (for human safety) in December 1999 and reported no ill effects in 80 recipients of the drug. Last October, the company began its phase IIA trial to evaluate the drug’s effectiveness against the symptoms of Alzheimer’s. But some scientists warn that AN-1792 could cause a dangerous autoimmune response in humans. The drug contains a synthetic version of amyloid-b, and causes the body’s immune system to attack amyloidb plaques. But scientist say the autoimmune response might also target amyloid precursor protein, which gives rise to amyloid-b. If it does, the side-effects could be devastating, because the precursor protein is found in many normal cells, including neurons. “Some people have predicted that inflammation would be a side-effect,” says Stephen Robinson, a neuroscientist at Monash University in Victoria, Australia. Robinson says he is concerned that Elan has not reported a crucial safety test of its vaccine. The company tested the vaccine in transgenic mice that had brain plaques made of human amyloid-b proteins. But mice have their own form of amyloid-b and amyloid precursor protein. Elan has not published information on whether innoculating mice with mouse amyloid-bcauses them to mount an immune response against their own amyloid precursor protein, says Robinson. “What you’re doing in the transgenic mice is simply clearing human amyloid from their brains and leaving the mouse amyloid intact,” Robinson says. “The key experiment would be to take wild-type mice and innoculate them against their own mouse amyloidb and amyloid precursor protein.” Gershenoff would not comment on whether those tests had been carried out. “We haven’t made any announcement about that,” he says. Researchers say that, as Elan has already tested AN-1792 in 360 patients in clinical trials in the United States and Europe, it may be reluctant to blame the drug for the inflammation in the French patients. “It’s premature to be overly concerned about this, given the small number of patients involved,” says Karen Duff, an associate professor of psychiatry at New York University. ■ David Adam Data sharing in human-genetics research is being hampered by concerns over intellectual property rights, says one of the first studies to try to quantify the problem. Of the 1,240 human geneticists surveyed by a team led by Eric Campbell of the Institute for Health Policy at Massachusetts General Hospital, Boston, almost half complained that a co-worker had refused them access to data, information or materials in the past three years. According to 28% of the survey respondents, such refusals meant that they could not replicate published work, and 58% felt that their own research had suffered as a result. The survey’s findings were published on 23 January in the Journal of the American Medical Association (287, 473–480; 2002). Requests for materials, such as cell lines or the ‘knockout’ mice used to help to identify gene function, were refused more often (35%) than requests for extra data (25%) or methods (16%). “It may be that material-transfer agreements have become so complex and demanding that they inhibit sharing,” says Campbell. Universities often require researchers to complete copious paperwork to ensure that the institution retains the intellectual property rights to any work deriving from the materials before they are handed over. Joann Boughman, executive vicepresident of the American Society of Human Genetics, agrees. “Transfer agreements are now horrendously complicated,” she says. “They used to be simple exchanges between scientists, but they have now evolved into complex business arrangements.” Four-fifths of those who admitted to not honouring a request cited the time and effort needed to locate or produce materials as a reason. “The difficulty is time,” agrees Kay Davies, a human-genetics researcher at the University of Oxford. “In the early days of our work we were getting three or four requests a day for probes and producing them is almost a full-time job.” Despite the scale of the problem, researchers contacted by Nature denied that there is a culture of secrecy in human genetics. “If anything is delaying progress in the field, it is changing attitudes towards intellectual property, rather than a reluctance to share,” says Robert Ferrell, chair of human genetics at the University of Pittsburgh in Pennsylvania. ■ news

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Nerve inflammation halts trial for Alzheimer's drug.

Two years ago, a new proteomic test was heralded as the future of cancer diagnostics. But since then, doubts about its effectiveness have begun to grow. Erika Check reports.

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Proteomics and cancer: running before we can walk?

/pdf/gene-therapy-put-on-hold-as-third-child-develops-cancer-2w8qu1umhr.pdf

Gene therapy put on hold as third child develops cancer.

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Erika Check

Papers

A tragic setback.

Nerve inflammation halts trial for Alzheimer's drug.

Proteomics and cancer: running before we can walk?

Gene therapy put on hold as third child develops cancer.

Harmful potential of viral vectors fuels doubts over gene therapy.