Archive for the ‘Human osteosarcoma research’ Category

A twist on epigenetic therapy vs cancer

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Posted 01 Dec 2011 — by James Street
Category BAI1, Brain, Epigenetics, genetic research, Methylation

November 30, 2011

Epigenetic therapies against cancer have attracted considerable attention in recent years. But many of the drugs currently being studied as epigenetic anticancer therapies may have indiscriminate effects. A recent paper in Cancer Research from brain cancer researcher Erwin Van Meir’s laboratory highlights a different type of target within cancer cells that may be more selective. Postdoctoral fellow Dan Zhu is the first author of the paper.

Erwin Van Meir, PhD

The basic idea for epigenetic therapy is to focus on how cancer cells’ DNA is wrapped instead of the mutations in the DNA. Cancer cells often have aberrant patterns of methylation or chromatin modifications. Methylation is a punctuation-like modification of DNA that usually shuts genes off, and chromatin is the term describing DNA when it is clothed by proteins such as histones, a form of packaging that determines whether a gene is on or off.

In contrast to mutations that are hard-wired in the DNA, changes in cancer cells’ methylation or chromatin may be reversible with certain drug treatments. But a puzzle remains: if a drug wipes away methylation indiscriminately, that might turn on an oncogene just as much as it might restore a tumor suppressor gene.

The ability of an inhibitor of methylation to treat cancer may depend on cell type and context, explains chromatin/methylation expert and co-author Paula Vertino. She points out that one well-known methylation inhibitor, azacytidine (Vidaza), is a standard treatment for myelodysplastic syndrome, but the strategy of blanket-inhibition of methylation can’t be expected to work for all cancers. A similar challenge exists for agents that target histone acetylation in a global fashion.

Epigenetic therapies seek to modify how DNA is packaged in the cell.

Van Meir’s laboratory has been studying a tumor suppressor protein called BAI1 (brain angiogenesis inhibitor 1), which prevents tumor and blood vessel growth. BAI1 is produced by brain cells naturally, but is often silenced epigenetically in glioblastoma cells. His team found that azacytidine de-represses the BAI1 gene.

Methylation won’t turn a gene off without the help of a set of proteins that bind preferentially to methylated DNA. These proteins are what recognize the methylation state of a given gene and recruit repressive chromatin. Zhu and colleagues in Van Meir’s group found that one particular methyl-binding protein, MBD2, is overproduced in glioblastoma and is enriched on the BAI1 gene.

“Taken together, our results suggest that MBD2 overexpression during gliomagenesis may drive tumor growth by suppressing the anti-angiogenic activity of a key tumor suppressor. These findings have therapeutic implications since inhibiting MBD2 could offer a strategy to reactivate BAI1 and suppress glioma pathobiology,” the authors write.

By itself, MBD2 appears to be dispensable, since mice seem to be able to develop and survive without it. Not having it even seems to push back against tumor formation in the intestine, for example. Targeting MBD2 may represent an alternative way to steer away from cancer cells’ altered state.

Van Meir cautions: “We need to have a better understanding of all the genes that are turned on or off by silencing MBD2 in a given cancer before we can envision to use this approach for therapy.”

Vertino, Shaoman Yin and Steven Hunter, all at Emory, are co-authors on the paper. The work was supported by grants from the NIH and the Southeastern Brain Tumor Foundation and the Emory University Research Council.

Research Finds Cancer Drug Cisplatin Binds Like Glue in Cellular RNA

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Posted 25 Nov 2011 — by James Street
Category Cisplatin, RNA, RNAi

University of Oregon researchers have revealed that an anti-cancer drug used extensively in chemotherapy binds pervasively to RNA up to 20-fold more than it does to DNA. This is a surprise finding that suggests new targeting approaches might be useful.

Medical researchers have long known that cisplatin, a platinum compound used to fight tumors in nearly 70 percent of all human cancers, attaches to DNA. Its attachment to RNA had been assumed to be a fleeting thing, says UO chemist Victoria J. DeRose, who decided to take a closer look due to recent discoveries of critical RNA-based cell processes.

“We’re looking at RNA as a new drug target,” she said. “We think this is an important discovery because we know that RNA is very different in tumors than it is in regular healthy cells. We thought that the platinum would bind to RNA, but that the RNA would just degrade and the platinum would be shunted out of the cell. In fact, we found that the platinum was retained on the RNA and also bound quickly, being found on the RNA as fast as one hour after treatment.”

The National Institutes of Health-supported research is detailed in a paper placed online ahead of regular publication in ACS Chemical Biology, a journal of the American Chemical Society. Co-authors with DeRose, a member of the UO chemistry department and Institute of Molecular Biology, were UO doctoral students Alethia A. Hostetter and Maire F. Osborn.

The researchers applied cisplatin to rapidly dividing and RNA-rich yeast cells (Saccharomyces cerevisiae, a much-used eukaryotic model organism in biology). They then extracted the DNA and RNA from the treated cells and studied the density of platinum per nucleotide with mass spectrometry. Specific locations of the metal ions were further hunted down with detailed sequencing methods. They found that the platinum was two to three times denser on DNA but that there was a much higher whole-cell concentration on RNA. Moreover, the drug bound like glue to specific sections of RNA.

DeRose is now pursuing the ramifications of the findings. “Can this drug be made to be more or less reactive to specific RNAs?” she said. “Might we be able to go after these new targets and thereby reduce the drug’s toxicity?”

While cisplatin is effective in reducing tumor size, its use often is halted because of toxicity issues, including renal insufficiency, tinnitus, anemia, gastrointestinal problems and nerve damage.

The extensive roles of RNA have come under intense scrutiny since completion of the human genome opened new windows on DNA, life’s building blocks. It had been assumed that RNA was simply a messenger that coded for protein activity. New technologies, DeRose said, have shown that a vast amount of RNA performs an amazing level of different functions in gene expression, controlling it in specific ways during development or disease, particularly in cancer cells.

In this project, DeRose’s team only explored cisplatin’s binding on two forms of RNA: ribosomes, where the highest concentration of the drug was found; and messenger RNA. There are more areas to be looked at, said DeRose, whose group initially developed experience using and mapping platinum’s activity as a mimic for other metals in her research on RNA enzymes.

DeRose is now planning work with UO colleague Hui Zong, a biologist studying how cancer emerges, to extend the research into mouse cells to see if the findings in yeast RNA hold up. An additional collaboration with UO chemist Michael Haley involves the creation of new platinum-based drugs with “reaction handles” that will allow researchers to easily pull the experimental drugs out of cells, while still attached to their biological targets. New developments in ‘deep’ RNA sequencing, available through the UO’s Genomic Core Facilities, could then provide a much broader view of platinum’s preferred resting sites in the cell.

Science and the Democratic Process

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Posted 22 Nov 2011 — by James Street
Category Carcinogens, Ethics of Science, Etiology and cause of osteosarcoma, Finance and Politics of cancer research and treatment, flouride, Osteosarcoma

NEW YORK, Nov. 21, 2011 /PRNewswire via COMTEX/ — Current science indicates that water fluoridation is not only ineffective at reducing tooth decay, but is also harmful to health. Despite this knowledge, The Pew Charitable Trusts continues to promote fluoridation by using inaccurate information, and by lobbying legislators to conceal vital information on fluoride’s adverse effects, reports The Fluoride Action Network (FAN).

Pew Using Propaganda Instead of Science

Pew has alleged that those opposing water fluoridation are misrepresenting the research (1). FAN Executive Director Paul Connett, Ph.D., strongly disagrees with this claim. Connett points out that current scientific research reveals certain groups are at an elevated risk for adverse effects from fluoridated water–including babies, kidney patients, and above average water consumers (2). According to the National Research Council’s landmark review, Fluoride in Drinking Water, “Fluoride is an endocrine disruptor” (2), with altered thyroid function observed at fluoride levels commonly consumed by many Americans on a daily basis. Additionally, African Americans and Mexican Americans are more likely to suffer more often, and from the more severe forms of dental fluorosis–a discoloration of the teeth indicating fluoride overexposure during childhood–than are Caucasians (3), making fluoridation an Environmental Justice issue.

Pew Children’s Dental Campaign Director Shelly Gehshan recently accused fluoridation opponents of trying to “raise fears about fluoridation’s safety by citing foreign studies of fluoride levels that were at least two or three times higher than the level used to fluoridate U.S. public water systems” (1). According to Dr. Connett, “The foreign studies Gehshan alludes to are likely the 25 studies linking fluoride to reduced IQ. Several of these studies were not high dose studies. For example, Ding et al. (4) found a lowering of IQ in children drinking water with 0.3 to 3 ppm fluoride. This covers the range of that used in the U.S. fluoridation program (0.7-1.2 ppm). The threshold level in the Xiang et al. study (5a,5b) was 1.9 ppm. Clearly there is no margin of safety for this very serious end point.”

Dr. Connett continues, “Furthermore, by claiming that there is no problem with fluoridation simply because the concentrations of fluoride found to cause harm in some published studies were higher than used in artificial fluoridation, indicates that Ms. Gehshan has no understanding of toxicology. There is an important difference between concentration and dose. For example, someone drinking two liters of water at 1 ppm would get more fluoride than someone drinking one liter of water at 1.9 ppm. Moreover, when extrapolating from a study that finds harm in a small group, a margin of safety (usually a safety factor of 10) must be applied to account for the large range in sensitivity expected for any toxic substance, and thus to more adequately protect everyone in a larger population.”

Another issue of concern is that, immediately following publication of a study by Kim et al. (6) that found no association between bone fluoride levels and osteosarcoma (a frequently fatal form of bone cancer), Pew issued talking points (7,8) aimed at promoting this study while discrediting an earlier Harvard study by Bassin et al. (9). Pew’s misleading talking points inaccurately stated that the Kim et al. study had successfully refuted the study by Bassin and colleagues, which had found that boys exposed to fluoridated water in their 6th-8th years had a 5-7 fold increased incidence of osteosarcoma.

Dr. Connett says, “The study by Kim et al. had been promised for five years by Chester Douglass, Bassin’s thesis adviser at Harvard (10). When it finally appeared, it proved to be a very poorly designed study, and failed miserably to refute Bassin’s findings. Bone fluoride levels measured at diagnosis or autopsy give no indication of the fluoride exposure during the critical period, as found by Bassin. It’s incredible that Pew should stoop to what amounts to outright propaganda. It is also revealing that the Kim et al. study was not published in the journal where Bassin published her article (Cancer Causes and Control)–or in any other cancer or medical journal–but rather in a dental journal (Journal of Dental Research).

Pew Undermining the Democratic Process

At the top of their homepage, Pew states that the organization “applies a rigorous, analytical approach to improve public policy, inform the public and stimulate civic life” (11). However, instead of stimulating civic life, Pew has dampened it by paying for lobbyists (12) to convince Arkansas legislators–behind closed doors and without citizen input–to quickly pass a statewide mandatory fluoridation law, over-riding citizen referenda in many Arkansas cities that had rejected fluoridation on several occasions.

Mixing infant formula with fluoridated water puts babies at unnecessary risk of developing discolored or pitted teeth (dental fluorosis), without any proven benefit. This is acknowledged by federal government agencies, health departments and organized dentistry (e.g. 13-15). Despite this, Pew recently urged the Austin City Council to conceal this information from water customers, and to ignore science-based requests from Austin residents to put such warnings on water bills (16). “Pew has decided that protecting fluoridation is more important that protecting babies,” says Dr. Connett.

A Positive Path Forward

Pew claims that the foundation uses expertise “valued for its nonpartisan balance and grounding in sound science.” FAN therefore challenges Pew to hire a team of independent experts in toxicology and epidemiology to carefully review the book “The Case Against Fluoride” (17), and respond in kind to all of the carefully documented and referenced arguments therein. If Pew is indeed grounded in “sound science,” we believe the results of this honest inquiry will lead Pew to abandon its relentless promotion of artificial fluoridation.

References:

1. The Pew Charitable Trusts. 2011. Pew applauds California vote to fluoridate, urges policy makers to be guided by sound science. News Release. November 15. http://www.prnewswire.com/news-releases/pew-applauds-california-vote-to-fluoridate-urges-policy-makers-to-be-guided-by-sound-science-133911828.html

2. National Research Council. 2006. Fluoride in Drinking Water: A Scientific Review of EPA’s Standards. National Academies Press, Washington D.C. http://www.nap.edu/openbook.php?record_id=11571

3. Beltran-Aguilar ED, Barker LK, Canto MT, et al. 2005. Surveillance for dental caries, dental sealants, tooth retention, endentulism, and enamel fluorosis–United States, 1988- 1994 and 1999-2002. CDC, MMWR, Surveillance Summaries, August 26, 2005, vol. 54, No SS-3, pp. 1-44. See Table 23 online at http://www.fluoridealert.org/table23.html

4. Ding Y, Gao Y, Sun H, Han H, Wang W, Ji X, Liu X, Sun D. 2010. The relationships between low levels of urine fluoride on children’s intelligence, dental fluorosis in endemic fluorosis areas in Hulunbuir, Inner Mongolia, China. Journal of Hazardous Materials doi:10.1016/j.jhazmat.2010.12.097.

5a. Xiang Q, Liang Y, Chen L, Wang C, Chen B, Chen X, Zhou M. 2003a. Effect of fluoride in drinking water on children’s intelligence. Fluoride 36(2):84-94. Full study at http://fluoridealert.org/scher/xiang-2003a.pdf

5b. Xiang Q, Zhou M, Zang H. 2003b. Blood lead of children in Wamiao-Xinhuai intelligence study. Fluoride 36(3):198-199. Full study at http://fluoridealert.org/scher/xiang-2003b.pdf

6. Kim FM, Hayes C, Williams PL, Whitford GM, Joshipura KJ, Hoover RN, Douglass CW. 2011. An assessment of bone fluoride and osteosarcoma. J Dent Res 90(10):1171-6.

7. Kincade K. 2011. Study finds no link between fluoride and osteosarcoma. DrBicuspid.com. July 28. Shelly Gehshan, Director of Pew Children’s Dental Campaign: “I would say that this [Kim et al., 2011] study can put peoples’ fears to rest because it shows no correlation between fluoride and osteosarcoma. In 2006, the National Research Council said that if fluoride might be linked to cancer, osteosarcoma would be the most plausible form of cancer. But now that’s been ruled out. We can now say that fluoride does not cause any kind of cancer.” http://www.drbicuspid.com/index.aspx?sec=sup&sub=orc&pag=dis&ItemID=308238

8. American Water Works Association. 2011. Suggested Talking Points for the Harvard-Douglass Study from the Pew Center on the States. August 1. http://www.awwa.org/files/GovtPublicAffairs/AdvisoriesAlerts/080111FluorideBoneCancer.pdf

9. Bassin EB, Wypij D, Davis RB, Mittleman MA. 2006. Age-specific fluoride exposure in drinking water and osteosarcoma (United States). Cancer Causes Control 17(4):421-8.

10. Douglass CW, Joshipura K. 2006. Caution needed in fluoride and osteosarcoma study (Comment). Cancer Causes Control 17(4):481-2.

11. The Pew Charitable Trusts. http://www.pewtrusts.org/

12. Nathe C. 2011. Water fluoridation in Arkansas. RDH 31 (7). http://www.rdhmag.com/index/display/article-display/3187095135/articles/rdh/volume-31/issue-7/columns/water-fluoridation-in-arkansas.html

13. CDC (U.S. Centers for Disease Control and Prevention). 2011. Overview: Infant formula and fluorosis. http://www.cdc.gov/FLUORIDATION/safety/infant_formula.htm – 1

14. Mayo Clinic. 2010. Infant formula: 7 steps to prepare it safely. http://www.mayoclinic.com/health/infant-formula/MY00193/NSECTIONGROUP=2

15. Delta Dental. 2010. Fluoride in infant formulas. http://oralhealth.deltadental.com/Children/Infant/22 ,DD63

16. Doggett, Libby. 2011. Email to PHHSC Committee Chair Martinez. 12 October. Available at http://fluoridefreeaustin.com/handouts.html

17. Connett P, Beck J, Micklem HS. 2010. The Case Against Fluoride: How Hazardous Waste Ended Up in Our Drinking Water and the Bad Science and Powerful Politics That Keep It There. Chelsea Green: White River Junction, VT. 372 Pp.

SOURCE Fluoride Action Network

Copyright (C) 2011 PR Newswire. All rights reserved

Mirna Presents Animal Data on miRNA Mimics in Liver Cancer, Aims for Phase I in 2013

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Posted 18 Nov 2011 — by James Street
Category Liver, siRNA
November 17, 2011

By Doug Macron

Mirna Therapeutics this week released new details on its efforts to develop a microRNA-based treatment for liver cancer, reporting data showing that five mimics of miRNAs with tumor-suppressor activity could “significantly” inhibit tumor growth in a mouse model of the disease.

Based on these and other findings, Mirna is advancing its lead miRNA drug candidate for solid tumors and expects to begin phase I testing in early 2013, President and CEO Paul Lammers told Gene Silencing News.

Mirna presented the data at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics and the 2011 CPRIT Innovations in Cancer Prevention and Research conference.

According to the company, its researchers transfected liver cancer cells with the miRNA mimics and analyzed them four to eight days later for proliferation.

Cells were also transfected with an siRNA targeting kinesin family member 11, which lowers proliferation by 60 to 80 percent in hepatocellular carcinoma cell lines, in order to provide a comparison point for the anti-proliferative activity of the miRNAs.

Eight miRNAs demonstrated the highest “capacity to significantly inhibit the proliferation of multiple HCC cell lines,” the company said in a poster from the AACR-NCI-EORTC event. These included miR-34, which is the basis for Mirna’s lead drug candidate; miR-16; and let-7. The other miRNAs remain undisclosed.

The investigators then evaluated four undisclosed siRNA-delivery technologies in an orthotopic mouse model of human liver cancer using either a mimic of miR-34 or negative control.

Analysis by qRT-PCR revealed that the least effective delivery approach boosted levels of miR-34 in the mouse livers by around 40 copies per cell. The most effective — a lipid-based nanoparticle system — increased levels by more than 100,000 copies per cell and also delivered 10,000 copies of the miR-34 mimic per cell to spleen, lung, kidney, and pancreas one day after injection, Mirna said.

Lammers noted that Mirna expects to use this delivery system with its first drug candidate.

To assess the therapeutic effect of the miRNAs, mimics of miR-34, let-7, and two other undisclosed miRNAs were encapsulated in the nanoparticles of the best-performing delivery system and then frozen. Model mice were then given either one of the miRNA mimics, a negative control, or no treatment daily for three days and then every other day for 10 days.

“Four mice per treatment group were sacrificed on the thirteenth day after the initiation of treatment, while three animals per group were selected for five additional injections of formulated miRNA,” the company said. The mice were monitored for behavior and serum alpha fetoprotein levels, which were used to judge tumor growth.

Once AFP levels in the mice reached excessive levels or they stopped grooming themselves, the animals were sacrificed.

For the control mice, AFP levels increased exponentially during the two weeks following the start of the study. Levels in animals receiving the let-7 mimic were “significantly lower than the control groups,” but still higher than in mice receiving other miRNA mimics.

AFP levels in mice treated with miR-34 and two other unnamed miRNAs were unchanged during the treatment period, and most of them “actually had lower serum AFP levels after the treatment period than they had prior to the initiation of treatment,” Mirna noted.

“In effect, [this] meant there was a regression of the liver cancer,” an effect confirmed after the animals were sacrificed and analyzed, Lammers said.

Specifically, the team found no tumors in mice receiving one of the undisclosed miRNA mimics, and an immunohistochemical assay revealed that the “majority” of mice in the treatment groups contained no tumor cells at all.

Additional animals from the treatment groups received additional dosing for nine days. All four miRNAs “significantly increased the survival rates” of these animals, while those receiving mimics of two undisclosed miRNAs failed to develop tumors large enough to meet the moribund criteria set by the company during the study.

Despite the positive effects observed with the two undisclosed miRNAs, Mirna still intends to take its miR-34 mimic into the clinic first, Lammer said.

“We have done a lot of work on miR-34, and it is one of the most widely published microRNAs, as well,” he said. There is clearly a lot of interest” in it.

Notably, miR-34 has been linked to the tumor-suppressor protein p53. In 2007, for instance, two research groups separately reported that p53 directly targets members of the miR-34 family, suggesting the miRNA is a key component of the p53 network (GSN 6/7/2007).

At the same time, Mirna has built an intellectual property estate around the therapeutic use of miR-34. Earlier this year, the company announced that the US Patent and Trademark Office had allowed claims within an application describing methods of reducing cancer cell viability by introducing the miRNA into tumor cells (GSN 4/7/2011).

“Perhaps there is a luxury of riches we have because we have three phenomenal microRNAs that could all be very effective in liver cancer,” Lammers said. However, “we have to make choices in life,” especially as a small biotech with limited resources.

As part of its efforts to advance its miR-34 candidate, Mirna is in licensing talks with the owner of the drug-delivery technology it hopes to use with the drug, he said, although he declined to provide additional details.

The company has also identified oligo manufacturers and is preparing to conduct investigational new drug application-enabling toxicology work. Should everything remain on schedule, Mirna plans to file the IND by the end of 2012 and begin human testing early the next year.

Wirral mum has been given three months to live if she doesn’t get life saving treatment abroad

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Posted 20 Oct 2011 — by James Street
Category Etiology and cause of osteosarcoma, Immune System, Metastases, Osteosarcoma

Oct 19 2011 by Linda Foo Guest, Birkenhead News

A WIRRAL mum has been given three months to live if she doesn’t get life saving treatment abroad.

For the past four years mum-of-two Susan Saul has been battling a rare form of bone cancer which was first diagnosed after she gave birth to her second daughter Estelle.

Susan, 39, has osteosarcoma, which eats away the bone.

The cancer started in her knee and spread to her femur but it has now spread to Sue’s pelvis, spine and rib.

Medics think the Pensby mum may have contracted it while pregnant.

Susan, mum to Seren, eight, and Estelle, four, told the News: “We do not know when it came, but it might have been from a trip when I was pregnant and I put immense pressure on my leg to stop myself from falling. I was in pain after that. Who knows, it could have been lying dormant?”

Sue needs £45,000 to receive life saving treatment in Germany or China. Friends and family have organised a series of fundraisers for the coming months, but so far they have raised £10,000 from a curry night, bike ride, and hairdressing event.

Husband Marcus said: “We have been busy researching and managed to uncover some solutions – this has gone from a position of no hope to some hope.

“There are two major treatments available in China or Germany and the doctors are very optimistic which is good.

“In Germany they can give her chemotherapy emovolisation, but the main hope is in adoptive immunisation which enhances your immune system.

“In China they use the adoptive immunisation method or gene therapy which gives cancer patients a severe fever and kicks starts the system. It is very cutting edge.

“The NHS have been brilliant, they have all been amazing and have said they will speak to doctors abroad about Sue’s condition.

“It is very humbling what the community have done, we are bowled over with everyone’s support.”

SAVE Our Sue fundraising events organised for the coming months include a music night at the Casa Bar on Hope Street, Liverpool city centre on October 29 from 7pm. Tickets cost £7 and can be purchased from Ian Carroll on             07824 359201      .

La tumor registry gets $794,000 pediatric grant

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Posted 03 Oct 2011 — by James Street
Category Diagnostic, Finance and Politics of cancer research and treatment, Foundations, genetic research, genetic research, Osteosarcoma, Politics and Finance of Child Cancer research
JANET McCONNAUGHEY, Associated Press
Published 02:55 p.m., Monday, October 3, 2011

NEW ORLEANS (AP) — The Centers for Disease Control and Prevention is giving the Louisiana Tumor Registry a three-year, $794,000 grant to develop a system to quickly collect and report children’s cancers.

Hospitals often take six months or more to report cancer cases because they want to include information about treatment, said Dr. Vivien Chen, director of the registry at LSU Health Sciences Center New Orleans.

She said the grant will let the registry work with pathology laboratories, which diagnose cancers, and get that information within a couple of months. Regional registry workers will go to hospitals in their areas each month to get more information, she said.

Chen said the tumor registry will collaborate with state pediatric organizations and with doctors and hospitals treating children with cancer. Key partners include Lafayette, Baton Rouge and Shreveport clinics affiliated with St. Jude Research Hospital, large out-of-state children’s hospitals, and the LSUHSC-New Orleans pediatric oncology program at Children’s Hospital in New Orleans, where about half of the new pediatric cases in Louisiana are diagnosed or treated.

LSUHSC’s registry will also link to birth records, since a baby’s birth weight and any other abnormalities noted on the birth certificate, and even the parents’ ages may be linked to cancer, she said.

“As we move on, we might explore some other information. Medicare might be another thing we might link on,” she said.

This grant is the second awarded to the tumor registry since December and brings its federal support to about $3.5 million a year, according to LSU.

Can Forteo cause osteosarcoma?

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Posted 20 Sep 2011 — by James Street
Category Carcinogens, Carcinogens, Etiology and cause of osteosarcoma, Osteosarcoma

press release

Sept. 19, 2011, 8:15 p.m. EDT

Research Suggests FORTEO® Significantly Increases Bone Strength

SAN DIEGO, Sept. 19, 2011 /PRNewswire via COMTEX/ — Eli Lilly and Company LLY -0.77% today presented a study that assessed the effects of 18 months of treatment with FORTEO® (teriparatide [rDNA origin] injection) on vertebral and proximal femoral strength, and the relationship of these effects to changes in the underlying volumetric BMD (vBMD) of postmenopausal women with osteoporosis. Researchers concluded that FORTEO increased vertebral and femoral strength in the spine and hip bones compared to baseline.1 These findings were presented in an oral presentation at the 2011 Annual Meeting of the American Society for Bone and Mineral Research (ASBMR) in San Diego, Calif.

“Low bone strength is an important factor in the risk of fracture for patients with osteoporosis,” said Tony Keaveny, MD, director, Orthopaedic Biomechanics Laboratory, Department of Mechanical Engineering, University of California, Berkeley. “These data provide supportive evidence that treatment with FORTEO has the potential to increase bone strength in two areas prone to fracture, the hip and spine.”

The study used finite element analysis (FEA) of quantitative CT scans to measure changes in vertebral and proximal femoral strength. Although FEA is one of the most widely accepted means of non-invasive bone strength assessments, data are scarce on changes in vertebral and femoral bone strength for patients treated with FORTEO; therefore, the biomechanical effects of FORTEO treatment in postmenopausal women are not well understood.2

Researchers performed FEA of quantitative CT scans from study participants to measure bone strength and found statistically significant increases in both vertebral and femoral strength in women treated with FORTEO, compared to baseline (median:16.6 percent and 2.3 percent)(median:respectively)(median:pless-than or equal to 0.05).3 The results indicated significant increases in both trabecular and peripheral densities in the spine (median:12.8 percent and 5.8 percent)(median:respectively)(median:pless-than or equal to 0.05) and an increase in trabecular density in the hip (median:3.9 percent)(median:pless-than or equal to 0.05). 4 There was no observed change in peripheral density in the hip.4

“These study results are encouraging, as they provide additional evidence that FORTEO treatment may result in increased bone strength in appropriate patients,” said Kelly Krohn, MD, Eli Lilly and Company. “Studies that reinforce the already established efficacy of medications can help healthcare professionals determine the right medicine to treat their patients with osteoporosis.”

FORTEO is used in both men and postmenopausal women with osteoporosis who are at high risk for having broken bones (fractures). FORTEO is used in both men and women with osteoporosis due to use of glucocorticoid medicines, such as prednisone, for several months, who are at high risk for having broken bones (fractures). FORTEO can be used by people who have had a fracture related to osteoporosis, or who have several risk factors for fracture, or who cannot use other osteoporosis treatments.5

FORTEO is a prescription medicine given as a 20 mcg once daily dose available in a 2.4 mL prefilled delivery device for subcutaneous injection over 28 days.5

During the drug testing process, the medicine in FORTEO caused some rats to develop osteosarcoma, which, in humans, is a serious but rare bone cancer. Osteosarcoma has been reported rarely in people who took FORTEO, and it is unknown if people who take FORTEO have a higher chance of getting the disease. Before patients take FORTEO, patients should tell their healthcare provider if they have Paget’s disease of bone, are a child or young adult whose bones are still growing or have had radiation therapy.5 For more information about FORTEO, please see the important safety information, including Boxed Warning regarding osteosarcoma, below.

About the Study6

“Increases in both vertebral and femoral strength in postmenopausal osteoporotic women after 18 months of treatment with teriparatide” was an 18-month, open-label study using finite element analysis of quantitative CT scans to analyze the effects of treatment with FORTEO on vertebral and proximal femoral strength.

Quantitative CT scans were taken of the lumbar spine and hip at baseline and at 18 months (or at an early termination visit). All patients who had two evaluable CT scans at both time points were included in the analysis (n=30 spine; n=26 hip).

Volumetric density was measured for the trabecular, peripheral (outer 2-3 mm of bone that contains both cortical and some adjacent trabecular bone) and both (“integral”) compartments. Non-linear finite element analysis was performed for uniform compression for the spine and a sideways fall for the hip to provide measures of vertebral and femoral strength.

Important Safety Information about FORTEO

What is the most important information I should know about FORTEO?

        WARNING: POTENTIAL RISK OF OSTEOSARCOMA
        During the drug testing process, the medicine in FORTEO caused some rats to develop a bone cancer called osteosarcoma. In people, osteosarcoma is a serious but rare cancer. Osteosarcoma has been reported rarely in people who took FORTEO. It is not known if people who take FORTEO have a higher chance of getting osteosarcoma. Before you take FORTEO, you should tell your healthcare provider if you have Paget's disease of bone, are a child or young adult whose bones are still growing, or have had radiation therapy.

Who should not take FORTEO?

You should not take FORTEO for more than 2 years over your lifetime.

Do not use FORTEO if you are allergic to any of the ingredients in FORTEO. Serious allergic reactions have been reported.

What should I tell my healthcare provider before taking FORTEO?

Before you take FORTEO, you should tell your healthcare provider if you have a bone disease other than osteoporosis, have cancer in your bones, have trouble injecting yourself and do not have someone who can help you, have or have had kidney stones, have or have had too much calcium in your blood, take medications that contain digoxin (Digoxin, Lanoxicaps, Lanoxin), or have any other medical conditions.

You should also tell your healthcare provider, before you take FORTEO, if you are pregnant or thinking about becoming pregnant. It is not known if FORTEO will harm your unborn baby. If you are breastfeeding or plan to breastfeed, it is not known if FORTEO passes into your breast milk. You and your healthcare provider should decide if you will take FORTEO or breastfeed. You should not do both.

What are the possible side effects of FORTEO?

FORTEO can cause serious side effects including a decrease in blood pressure when you change positions. Some people feel dizzy, get a fast heartbeat, or feel faint right after the first few doses. This usually happens within 4 hours of taking FORTEO and goes away within a few hours. For the first few doses, take your injections of FORTEO in a place where you can sit or lie down right away if you get these symptoms. If your symptoms get worse or do not go away, stop taking FORTEO and call your healthcare provider. FORTEO may also cause increased calcium in your blood. Tell your healthcare provider if you have nausea, vomiting, constipation, low energy, or muscle weakness. These may be signs there is too much calcium in your blood.

Common side effects of FORTEO include nausea, joint aches, pain, leg cramps, and injection site reactions including injection site pain, swelling and bruising. These are not all the possible side effects of FORTEO. You are encouraged to report negative side effects of Prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Additional safety information about FORTEO

There is a voluntary patient registry for people who take FORTEO. The purpose of the registry is to collect information about the possible risk of osteosarcoma in people who take FORTEO. For information about how to sign up for this patient registry, call 1-866-382-6813 or go to www.forteoregistry.org .

The FORTEO Delivery Device has enough medicine for 28 days. It is set to give a 20-microgram dose of medicine each day. Before you try to inject FORTEO yourself, a healthcare provider should teach you how to use the FORTEO Delivery Device to give your injection the right way. Inject FORTEO one time each day in your thigh or abdomen (lower stomach area). Do not inject all the medicine in the FORTEO Delivery Device at any one time. Do not transfer the medicine from the FORTEO Delivery Device to a syringe. This can result in taking the wrong dose of FORTEO. If you take more FORTEO than prescribed, call your healthcare provider. If you take too much FORTEO, you may have nausea, vomiting, weakness, or dizziness.

How should I store FORTEO?

Keep your FORTEO Delivery Device in the refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze the FORTEO Delivery Device. Do not use FORTEO if it has been frozen. Do not use FORTEO after the expiration date printed on the delivery device and packaging. Throw away the FORTEO Delivery Device after 28 days even if it has medicine in it (see the User Manual).

For more safety information, please see Medication Guide ( http://pi.lilly.com/us/forteo-medguide.pdf ) and Prescribing Information, including Boxed Warning ( http://pi.lilly.com/us/forteo-pi.pdf ). Please see full user manual that accompanies the delivery device.

TE Con ISI 07Mar2011

About Eli Lilly and Company

Eli Lilly and Company, a leading innovation-driven company, is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers — through medicines and information — for some of the world’s most urgent medical needs. Information about Lilly is available at www.lilly.com . P-LLY

FORTEO® is a registered trademark of Eli Lilly and Company.

This press release contains forward-looking statements about FORTEO for the treatment of osteoporosis. It reflects Lilly’s current beliefs; however, as with any such undertaking, there are substantial risks and uncertainties in the process of drug development and commercialization. There is no guarantee that future study results and patient experience will be consistent with study findings to date or that FORTEO will continue to be commercially successful. For further discussion of these and other risks and uncertainties, please see Lilly’s latest Forms 10-Q and 10-K filed with the U.S. Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

1 Keaveny, T., et al. “Increases in both vertebral and femoral strength in postmenopausal osteoporotic women after 18 months of treatment with teriparatide.” Abstract presented at the ASBMR 2011 Annual Meeting, Sept. 19, 2011, 4:00 PM.

2 Keaveny, T., et al. “Increases in both vertebral and femoral strength in postmenopausal osteoporotic women after 18 months of treatment with teriparatide.” Abstract presented at the ASBMR 2011 Annual Meeting, Sept. 19, 2011, 4:00 PM.

3 Keaveny, T., et al. “Increases in both vertebral and femoral strength in postmenopausal osteoporotic women after 18 months of treatment with teriparatide.” Abstract presented at the ASBMR 2011 Annual Meeting, Sept. 19, 2011, 4:00 PM.

4 Keaveny, T., et al. “Increases in both vertebral and femoral strength in postmenopausal osteoporotic women after 18 months of treatment with teriparatide.” Abstract presented at the ASBMR 2011 Annual Meeting, Sept. 19, 2011, 4:00 PM.

5 FORTEO PI. Available at http://pi.lilly.com/us/forteo-pi.pdf .

6 Keaveny, T., et al. “Increases in both vertebral and femoral strength in postmenopausal osteoporotic women after 18 months of treatment with teriparatide.” Abstract presented at the ASBMR 2011 Annual Meeting, Sept. 19, 2011, 4:00 PM.

SOURCE Eli Lilly and Company

Copyright (C) 2011 PR Newswire. All rights reserved

 

Comtex

Fluoride Can Cause Cancer, Studies Show

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Posted 16 Sep 2011 — by James Street
Category Etiology and cause of osteosarcoma, Flouridation and osteosarcoma

NEW YORK, Sept. 15, 2011 /PRNewswire-USNewswire/ — Many published human and animal studies have reported an association between fluoride and various cancers, including valid and unrefuted scientific evidence that fluoride can increase the risk of osteosarcoma (a type of bone cancer) in boys and young men, reports the Fluoride Action Network (FAN) in its recent submission to the California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA). (1)

Fluoride is commonly added to municipal water supplies and dental products with the intention of reducing tooth decay. However, current scientific evidence shows  that swallowing fluoride does much more harm than good.

OEHHA requested public comments on its recently-released document “Evidence on the Carcinogenicity of Fluoride and Its Salts,” (2) where OEHHA states:

“multiple lines of evidence…appear to support several plausible hypotheses: that fluoride is incorporated into bones…where it can stimulate cell division of osteoblasts [bone-forming cells]…; induce genetic changes; induce other cellular changes leading to malignant transformation, and alter cellular immune response…thereby increasing the risk of development of osteosarcomas” (our emphasis).

The Carcinogen Identification Committee (CIC) of OEHHA’s Science Advisory Board is scheduled to review the carcinogenicity status of fluoride on October 12-13.

FAN Executive Director Paul Connett, Ph.D., says, “Special interest groups are already protecting fluoride rather than the people who are consuming it.” For example, the American Dental Association recently gave the California Dental Association $200,000 “to assist in our effort to prevent the placement of ‘fluoride and its salts’ on the List of Chemicals Known to the State to Cause Cancer” (3).

Organized dentistry must overcome the following inconvenient facts if it continues to assert fluoridation is safe for everyone:

According to the National Research Council’s (NRC) 2006 Fluoride in Drinking Water report, “fluoride appears to have the potential to initiate or promote cancers, particularly of the bone … osteosarcoma is of particular concern …”

Bassin et al. (2006) reported in Cancer Causes and Control that fluoride exposure is linked to an increased risk of osteosarcoma in boys and young men.

Bassin’s Harvard University doctoral advisor, Chester Douglass, signed off on Bassin’s results, but then promised his larger study would refute Bassin’s findings. However, Douglass’s study, when finally published in the Journal of Dental Research (7/28/11), was seriously flawed and incapable of refuting Bassin’s results. (4)

Connett says, “Douglass’s ‘financial ties to corporations profiting from fluoride sales make Douglass’s involvement with any study related to fluoride and health effects a serious conflict of interest.’”

But Bassin’s isn’t the only study linking fluoride with an increased risk of cancer.

In 1990 the National Toxicology Program (NTP) reported an increase in osteosarcoma in male rats exposed to fluoride, an increased risk for liver and oral cancers, and an increase in thyroid follicular cell tumors.

Among human studies, Hoover et al. (1991) found a 79% increase in osteosarcoma in males under 20 years old in fluoridated counties, compared to a 4% decrease in non-fluoridated counties over time.

Cohn (1992) similarly reported an increased risk for osteosarcoma in males under age 20 living in fluoridated versus non-fluoridated counties.

Also, the NRC recommends further research be conducted on the effects of fluoride on the risk of bladder cancer.

In addition, the most commonly used fluoridation chemicals (silicofluorides) have been linked with increased levels of lead in children’s blood, according to Kathleen Thiessen, Ph.D., a risk analysis professional who has served on two NRC subcommittees dealing with fluoride toxicology.

Thiessen’s submission to CIC states: “[U.S.] EPA considers lead to be a probable human carcinogen…there is considered to be no safe level of lead exposure, and the MCLG [maximum contaminant level goal] for lead is zero. OEHHA should be aware that silicofluoride use is associated with increased blood levels of a human carcinogen (one that is also associated with neurotoxicity and developmental toxicity), apart form the carcinogenicity of fluoride itself.” (5)

FAN’s submission concludes: “While we understand that there will be tremendous pressure put on the CIC and OEHHA by the proponents of fluoride and fluoridation, we ask that the Committee continue to rely on its high level of scientific knowledge and integrity when deliberating and reaching a final conclusion on the carcinogenicity status of fluoride and its salts.”

References:

  1. FAN (Fluoride Action Network). 2011. Comments on Evidence on the Carcinogenicity of Fluoride and Its Salts. 6 Sept 2011. Online at: http://www.fluoridealert.org/fan_oehha_9_6_11.pdf
  2. OEHHA (Office of Environmental Health Hazard Assessment). 2011. Evidence on the Carcinogenicity of Fluoride and Its Salts. California Environmental Protection Agency, Reproductive and Cancer Hazard Assessment Branch, Office of Environmental Health Hazard Assessment. July 2011. Online at: http://oehha.ca.gov/prop65/hazard_ident/070811hid.html
  3. CDA (California Dental Association). 2010. CDA Receives ADA State Public Affairs Program Grants. Executive bulletin from the desk of Executive Director Peter DuBois. January 12.
  4. FAN (Fluoride Action Network). 2011.  New Study Fails to Refute Fluoride- Osteosarcoma Link. Press release August 02, 2011. Online at: http://www.fluoridealert.org/Alert/United-States/New-Study-Fails-to-Refute-Fluoride-Osteosarcoma-Li.aspx
  5. Thiessen, K.M. 2011. Comments in Response to Evidence on the Carcinogenicity of Fluoride and Its Salts, July 2011. 6 Sept 2011. Online at: http://www.fluoridealert.org/thiessen_oehha_sept_2011.pdf

 

SOURCE Fluoride Action Network

Sequencing Kids’ Genomes To Learn How Cancer Grows

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Posted 27 Aug 2011 — by James Street
Category Foundations, Gene sequencing, genetic research, genetic research
BY Nidhi SubbaramanFri Aug 26, 2011

Complete Genomics is taking a look at the genomes of 1,000 children to get a better picture of how to understand and treat pediatric cancer.

Ever since we sequenced the first human genome, projects that involve delving into genes have exploded–scientists even recently just sequenced marijuana’s genome. Now, a new project aims to look at some slightly younger genes. One thousand children will have their genomes sequenced by Complete Genomics, a California-based whole human genome sequencing company, for a big study on pediatric cancer.

Comparing the genomes of tumor cells in cancer patients to healthy cells, sometimes at different times in the tumor’s life, is one way researchers learn more about how the cancer grows and lives, paving the way for possible treatment methods. This particular study is being carried out by SAIC-Frederick, a company associated with the National Cancer Institute. Complete Genomics will earn $8 million for its participation, paid for by the American Reinvestment and Recovery Act of 2009 (you might know that as the stimulus bill).

Whole genome sequencing is an expensive and elaborate affair that demands technology as well as the know-how and resources to collate and interpret the reams and reams of sequencing data that result from it. Complete Genomics’ goal is to serve as one-stop-shop for researchers’ sequencing needs.

Early this year, the Institute for Systems Biology tapped Complete Genomics to sequence 615 genomes for a study on neurodegenerative diseases, the latest and largest of a series of partnerships between the two organizations.

In this study, the research teams hope to speed up the development of therapies and treatments for the most common kinds of devastating childhood cancers. If studies like these are successful, their benefit goes beyond giving researchers insights into the disease they’re studying–each genome sequenced makes the process cheaper, more accessible, and open to broader application.

[Image: Flickr user andylepp]

Nidhi Subbaraman writes about technology and science. Follow Nidhi on Twitter.

Taiwan researchers discover protein that boosts cancer cell growth

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Posted 24 Aug 2011 — by James Street
Category genetic research, HIF1A, Hypoxia, KLHL 20, KLHL 20, PML

2011/08/24 14:02:11

Taipei, Aug. 24 (CNA) An Academia Sinica research team has identified a protein — called KLHL 20 — that plays a key role in tumor progression, a discovery that could provide a new focus for future research into treating aggressive tumors.

In a statement released by Taiwan’s top academic institution on Wednesday, research team leader Chen Ruey-hwa said the KLHL 20 protein was induced by a protein called HIF-1, a key target of cancer researchers.

HIF-1 regulates a large panel of genes that promote tumor cell survival in low oxygen conditions, induce cancer cell migration and contribute to resistance to chemotherapy and radiotherapy.

Understanding how tumor cells control HIF-1 synthesis has long been an attractive cancer research topic and considered to be a major target for pharmaceutical intervention in cancer therapy, said Chen, deputy director of Academia Sinica’s Institute of Biological Chemistry.

The link to HIF-1 is key, Chen said, because of KLHL 20′s ability to form a complex with proteins Cullin 3 and Roc 1 that can cause degradation of the protein PML, a well-known tumor suppressor protein.

“PML itself inhibits HIF-1. Thus, the HIF-1-induced PML degradation successfully relieves the inhibitory effect of PML on HIF-1,” Chen explained.

Tumor cells, Chen added, exploit this mechanism to amplify HiF-1 production in the early phase of hypoxia or low oxygen conditions, thereby aiding tumor progression.

The identification of KLHL 20′s role in the mechanism could offer a new target for cancer drugs to break down HIF-1′s proliferation and resistance to proteins or treatments, the Academia Sinica statement said.

The study done by Chen’s team has been published in the latest issue of leading cancer journal “Cancer Cell.”

The full article, called “A cullin3-KLHL20 ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression” can be found online at the Cancer Cell website at: http://www.sciencedirect.com/science/article/

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