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Archive - Nov 7, 2013

Hope Builds for Drug That Might Shut Down Variety of Cancers

The most frequently mutated gene across all types of cancers is a gene called p53 (image shows 3-D structure of p53 protein). Unfortunately, it has been difficult to directly target this gene with drugs. Now a multi-institutional research team, led by Dr. Lewis Cantley and investigators at Weill Cornell Medical College, has identified a family of enzymes they say is crucial for the growth of cancers that have genetic aberrations in p53. Targeting these enzymes with novel agents might prevent the growth of p53 mutant cancers, thereby benefiting a broad spectrum of cancer patients, including those with breast, ovarian, lung, colorectal, and brain tumors. In the November 7, 2013 issue of Cell, investigators pinpoint two cellular enzymes -- Type 2 phosphatidylinositol-5-phosphate 4-kinases α and β (Type 2 PIP kinases) -- as essential for cancer growth when cells have lost p53, the powerful tumor-suppressor gene long dubbed the "guardian of the genome." More than half of all cancers lose this gene, allowing these cancers to grow at will. The researchers discovered that the Type 2 PIP kinases are not critical for the growth of normal cells but become essential for cell growth when p53 is lost due to mutations or deletions. The scientists showed, in animal and lab studies of human cancer cells, that targeting these molecules effectively shuts down the growth of p53 mutant cancers. Although the studies were conducted in human breast cancer cells, the researchers believe Type 2 PIP kinase inhibitors could block the growth of various cancers with a mutated or missing p53 gene. "The fact that one can delete the Type 2 PIP kinases in normal human cells or in mice with essentially no effect on cell survival suggests that inhibitors of these enzymes should have little toxicity," says Dr.

Scientists Discover New Driver of Estrogen-Receptor-Positive Breast Cancer

A team of researchers at the Univeristy of Texas (UT) Southwestern has found that, as cholesterol is metabolized, a potent stimulant of breast cancer is created – one that fuels estrogen-receptor-positive breast cancers, and that may also defeat a common treatment strategy for those cancers. The multidisciplinary team discovered that a cholesterol metabolite called 27-hydroxycholesterol, or 27HC, promotes tumor growth in estrogen-receptor-positive breast cancers, which are the most common type of breast cancer. Estrogen-receptor-positive breast cancer was previously believed to be stimulated primarily by the female sex hormone estrogen and it is commonly treated using endocrine-based medications that starve tumors of estrogen. The discovery of 27HC as another driver of breast cancer may explain why endocrine-based therapy is often unsuccessful, providing a new target for therapy, the researchers say. “This information can be used to develop new therapies that inhibit 27HC action or production, or increase its metabolism, in effect cutting the cancer off from a key growth stimulator,” said senior author Dr. Philip Shaul, Professor and Vice Chair for Research in Pediatrics and a member of the Harold C. Simmons Comprehensive Cancer Center. Implications of the research that appears online in Cell Reports on November 7, 2013, are significant. One million new cases of breast cancer are diagnosed each year, and about two-thirds of those are hormone-receptor-positive, meaning they contain receptors for the hormones estrogen and/or progesterone, according to the American Cancer Society. Estrogen-receptor-positive breast cancer is particularly prevalent following menopause.

Drug Breakthrough for African Sleeping Sickness, Other Tropical Parasitic Infections

Scientists at the University of Oulu, Finland, and at the Helmholtz Center Berlin (HZB) have shown the way to new directions in drug development against African sleeping sickness and other tropical parasitic infections. This was based on the structural analysis of the enzyme thiolase, which plays a central role in lipid metabolism in the parasite that causes sleeping sickness. The researchers examined the biomolecule’s structure at the MX beamline of the electron storage ring, BESSY II, at the HZB. The results were published online on August 2, 2013 in the Biochemical Journal. Sleeping sicknesses – african trypanosomiasis, kala-azar, indian leishmaniasis – are infections caused by tropical parasites. Millions get sick from them each year and thousands end up dying. Anti-parasitic drugs are expensive and often have a host of unwanted side effects. In decades, there have been no new effective therapies. This is reason enough for the World Health Organization (WHO) to consider research, which can lead to the development of new anti-parasitic drugs, a top priority. Now, Professor Rik Wierenga and his team at Oulu University have paved the way for this type of research by shedding light on the structure of the enzyme thiolase. Thiolase figures prominently in parasitic lipid metabolism. According to Dr. Wierenga, “key is knowing the geometry of the enzyme’s active site. This is the place where lipids that play a central role in parasitic metabolism attach and where chemical reactions that convert lipids into other substances take place.” This is why it’s important to investigate the active site’s structure and function: “It enables us to develop lipid-like substances that firmly attach to the active site and block it.” The molecules that are involved represent the ideal starting points for new drug development.

Harvard Study Associates Nut Consumption with Reduced Pancreatic Cancer Risk in Women

In a large prospective study published online on October 22, 2013 in the British Journal of Cancer, researchers looked at the association between nut consumption and risk of pancreatic cancer among 75,680 women in the Nurses' Health Study, with no previous history of cancer. Consumption of nuts, including tree nuts (such as almonds, Brazil nuts, cashews, hazelnuts, macadamias, pecans, pine nuts, pistachios, and walnuts), was inversely associated with risk of pancreatic cancer, independent of other potential risk factors for pancreatic cancer. Women who consumed a one-ounce serving of nuts two or more times per week had a significantly reduced risk of pancreatic cancer (RR, 0.65; 95% CI, 0.47-0.92; P=0.007) compared to those who largely abstained from nuts. "This reduction in risk was independent of established or suspected risk factors for pancreatic cancer including age, height, obesity, physical activity, smoking, diabetes, and dietary factors," stated lead author, Ying Bao, M.D., Sc.D., from the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School. Pancreatic cancer is the fourth most common cause for cancer-related mortality in the U.S., yet very few modifiable risk factors have been identified. According to the 2009 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) report, aside from cigarette smoking, body fatness was the only convincing modifiable risk factor for pancreatic cancer. While there may be concern that frequent nut consumption may result in weight gain and thereby increase the risk of developing pancreatic cancer, the opposite seems to be true. "In our cohort, women who consumed the most nuts tended to weigh less," reported Dr. Bao. Moreover, in a recent analysis of this same cohort, higher nut consumption was associated with a slightly lower risk of weight gain and obesity.

Drug-Filled Nanoparticles Can Overcome Drug Resistance in Breast Cancer Cells

Nanoparticles filled with chemotherapeutic drugs can kill drug-resistant breast cancer cells, according to an open-access study published online on November 6, 2013 in Biomaterials. Nanoparticles are just as small, or even smaller, than many blood proteins. They can therefore pass through the walls of healthy and sick cells, which make them interesting carriers of drugs against cancer and other diseases. In the present study, researchers from the Karolinska Institutet in Sweden have shown that nanoparticles made from biodegradable plastics can overcome drug resistance in breast cancer cells. Such resistance is especially common in relapsing cancer patients and depresses, even neutralizes, the effect of the therapy against the tumour in many instances. In their experiments, the researchers used breast cancer cells that responded poorly to drugs owing to their high concentrations of the enzyme microsomal glutathione S-transferase-1 (MGST-1). Abnormally high levels of MGST-1 have been associated with poor responses to several cancer drugs. The team treated the resistant breast cancer cells with nanoparticles filled with doxorubicin, a chemotherapeutic used clinically to treat bladder, lung, ovarian, and breast cancers, amongst others. "Our experiments on cultivated cells showed that the particles themselves are harmless," says research team member Dr. Andreas Nyström, Associate Professor at the Institute of Environmental Medicine, Karolinska Institutet. "We made it possible for the nanoparticles carrying the drug to kill resistant cancer cells by controlling where in the cancer cell they delivered their payload.