Metastasis Promoter: Paclitaxel?

Researchers at the Sanford-Burnham Medical Research Institute have developed a new assay that can test chemical compounds for their ability to influence the development of so-called invadopodia on cells. The term invadopodia loosely translates into "invasive feet," which more or less says it all: Such structures help cells move and as such are important for cancer cells during the process of metastasis. Using their authors to test a library of chemically active compounds, the team found compounds that were able to inhibit invadopodia formation. But the biggest surprise was that paclitaxel promoted invadopodia formation, which could mean it promotes metastasis. The clinical relevance of cell culture findings, of course, remains to be established. But the authors pointed out that invadopodia are dependent on a stable cytoskeleton for their formation, which is consistent with paclitaxel's mechanism of action, and that paclitaxel treatment has been shown to increase the number of circulating tumor cells in patients. The findings were published in the July 26, 2011, online edition of Science Signaling.

Chromatin Comes to Non-Hodgkin's

A sequencing study of non-Hodgkin's lymphomas identified more than 100 genes that appear to be frequently mutated in that group of cancers, and found that many of them were in genes that code for histone-modifying enzymes. Researchers from the Canadian Michael Smith Genome Sciences Centre of the BC Cancer Agency compared sequencing data from the genomes, transcriptomes and exomes of tumor and normal cells in about 125 cases of non-Hodgkin's lymphoma to identify frequently mutated genes. Histone-modifying genes were mutated in a large number of those patients – in one type of non-Hodgkin's lymphoma, nearly 90 percent of patients had a mutation in a particular type of methyltransferase. More typical mutation rates ranged from 10 percent to 30 percent, which was still high enough for the authors to conclude that "our analysis suggests a previously unappreciated disruption of chromatin biology" in the development of lymphomas. Their work, which will be published in Nature, appeared online ahead of print July 27.

3, 2, 1, Universal Vaccine!

Researchers have been working to identify broadly neutralizing antibodies to influenza viruses that could make the annual flu vaccine a thing of the past. Now, a team from the Swiss Institute for Research in Biomedicine and the British Medical Research Council have identified the broadest antibody yet, which can neutralize viruses from both group 1 and group 2 influenza A. Recently, scientists have identified antibodies that can neutralize viruses broadly within group 1 or group 2. (See BioWorld Today, July 20, 2011.) But the new antibody is the first to be able to fight viruses from both groups. The authors said the antibody "may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency." Their work appeared in the July 28, 2011, advance online issue of Science.

Notch's About-face in Head and Neck Cancers

Two independent studies by two teams of researchers – both of which include scientists from a large number of institutions, with corresponding authors coming from Johns Hopkins University, MD Anderson Cancer Center, Harvard University and the University of Pittsburgh – have conducted large-scale sequencing studies of head and neck cancers to find genes that are implicated in their development. Both studies identified a number of genes that are important in controlling the differentiation and development of squamous cells, the cell type whose growth goes awry in head and neck cancers. Surprisingly, one of those genes was Notch1, which appears to be a tumor suppressor in head and neck cancers. In other types of cancers, Notch is better known for the opposite role: It is thought to be an oncogene in several other cancers – including cervical cancer, which, like head and neck cancer, can be caused by papillomavirus infections. The papers were published back to back in the July 28, 2011, early online edition of Science.

Toxin Transport

Researchers from the Singaporean Institute of Molecular and Cell Biology have discovered both similarities and differences in the cellular pathways co-opted by two quite different toxins: potential bioterror agent ricin and pseudomonas endotoxin, which can be picked up by immunocompromised patients in hospitals to cause infections of the lungs, the urinary tract and burns. The authors tested which human genes need to be expressed for the toxins, both of which are transported into the cell by the host's transportation machinery, to actually poison cells. Though the overlap between the genes was low overall – only 13 percent – the authors identified genes jointly used by both toxins at each stop along the transportation path. They concluded that their data are "consistent with two intertwined pathways converging and diverging at multiple points." They hope their work can be used to identify therapeutic targets for one or both toxins. The experiments were published in the July 21, 2011, issue of Developmental Cell.

Sorting Out T Cells in Multiple Sclerosis

Multiple sclerosis patients can benefit from treatment with beta-interferon – or have their symptoms worsened by it, depending on which type of T cell is the main attacker in their specific case. The patients with symptoms caused by type 1 helper T cells (TH1) are the ones who are likely to benefit from beta-interferon therapy. Now, researchers from Stanford University and Pfizer Inc. have reported that cytokine interleukin-7 spurs development of TH1 cells. High blood levels of interleukin-7 predicted patients' responsiveness to interferon-beta, and blocking the interleukin-7 receptor improved the symptoms of mice with the animal equivalent of multiple sclerosis. The authors suggested that interkleukin-7 could be both a diagnostic biomarker to determine whether a patient is likely to benefit from interleukin-beta, and a possible therapeutic target for patients whose disease is driven by Th1 cells. The results appeared in the July 28, 2011, issue of Science Translational Medicine.

Take Two Bacteria, Make One Cancer Drug

Researchers from the National Cancer Institute have combined two bacterial proteins into one cancer toxin that could provide an alternative therapy to Herceptin for HER2 positive cancers. The new compound does not interfere with HER2 signaling. Instead, one bacterial protein, the Staph aureus-derived affibody, binds to HER2 and delivers a modified pseudomonas aeruginosa toxin to cells. In culture and xenograft animal models, the compound was able to kill HER2-overexpressing cells and reduce tumor size. The authors said, "HER2-Affitoxin is an effective anticancer agent and a potential candidate for clinical studies." A sizable fraction of HER2-overexpressing cancers do not respond to the HER2-targeting Herceptin (trastuzumab), and some HER2-positive tumors develop resistance to Herceptin, but continue to overexpress HER2, and HER2-affitoxin might provide an additional option in those cases. The paper appeared in the July 26, 2011, issue of Clinical Cancer Research.

Testosterone's Protective Instincts

Scientists from the German University of Jena identified one reason why fewer men than women suffer from inflammatory diseases. Female monocytes – immune system cells – react differently to inflammatory stimuli than men's, and produce almost twice as much of an enzyme – 5-lipoxygenase – important for producing proinflammatory leukotrienes. When female monocytes were suspended in male plasma, their leukotriene production decreased. Testosterone suppressed the production of leukotrienes, apparently by activating the Map kinase pathway. The authors said the findings could explain both sex differences in susceptibility to inflammatory disease and the finding that high levels of testosterone appear to protect against atherosclerosis. They also noted that their work implied it is important to test investigational anti-inflammatory drugs in both men and women. The work appeared in the July 2011 print edition of the FASEB Journal .

New findings in Cancer Metabolism

Researchers from SUNY Stony Brook described a compound that disrupts cancer cell metabolism by targeting cancer cell mitochondria. The compound, CPI-613, is an analogue of lipoic acid and targets the pyruvate dehydrogenase complex, part of one of the major metabolic pathways. Because of their changed metabolism, which includes extensive changes in how that complex works, cancer cells should be especially vulnerable to such mitochondrial disruption. The authors wrote that in cell culture, treatment of cancer cells with the compound was "followed by efficient commitment to cell death by multiple, apparently redundant pathways, including apoptosis, in all tested cancer cell lines." CPI-613, in development by Cranbury, N.J.-based Cornerstone Pharmaceuticals, also showed "strong anti-tumor activity in vivo against human non-small-cell lung and pancreatic cancers in xenograft models with low side effect toxicity." The findings were published online in the Journal of Molecular Medicine's July 25, 2011, edition.

. . . And Regular Metabolism

The brain regulates food intake and weight by keeping tabs on both circulating hormones, such as leptin, and by sensing nutrients such as glucose directly, but more is known about the former process than the latter one. Researchers from the Albert Einstein College of Medicine have described a pathway that regulates how the brain senses glucose. In their studies, they found that the transcription factor HIF, which has been implicated in metabolic changes in tumor cells, is also important in the response of normal brain cells to blood sugar levels. Overexpressing HIF made mice resistant to obesity, even in the presence of what the authors termed "nutritional excess" in the form of high blood sugar levels, while knocking out the gene led to an inability to sense blood sugar levels and weight gain. HIF appeared to work by inducing the expression of POMC, a key gene for weight control. The studies appeared in the July 26, 2011, issue of PLoS Biology.

– Anette Breindl, Science Editor