Archive for the ‘genetic research’ Category

MD ANDERSON: MUTATED KRAS SPINS A MOLECULAR LOOP THAT LAUNCHES PANCREATIC CANCER

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Posted 31 Jan 2012 — by James Street
Category genetic research, Kras, Pancreatic
tct main 2010
MD ANDERSON: MUTATED KRAS SPINS A MOLECULAR LOOP THAT LAUNCHES PANCREATIC CANCER
Published 01/28/2012 – 2:17 p.m. CST
UT MD Anderson-led team identifies new potential treatment avenue to block an elusive target

HOUSTON — Scientists have connected two signature characteristics of pancreatic cancer, identifying a self-perpetuating “vicious cycle” of molecular activity and a new potential target for drugs to treat one of the most lethal forms of cancer.

The research, reported in the journal Cancer Cell and led by scientists at The University of Texas MD Anderson Cancer Center, connected the molecular dots between:

Mutated versions of Kras, a gene that acts as a molecular on-off switch but gets stuck in the “on” position when mutated.
Heightened activity of a protein complex called NF-?B that controls activation of genes.

“Kras is mutated in 80 to 95 percent of pancreatic ductal adenocarcinomas, and is the most frequent mutation among all cancers,” said senior author Paul Chiao, Ph.D., professor in MD Anderson’s Department of Molecular and Cellular Oncology.

About 42,000 new cases of pancreatic ductal adenocarcinoma are diagnosed in the United States each year. Estimates vary, but the 5-year survival rate has been 1 to 3 percent for decades and median survival after diagnosis is six months, the researchers note.

Interleukin-1a is a new potential drug target
“There have been many attempts to inhibit mutated Kras, but it’s an elusive target that so far has defied treatment,” Chiao said. “So if we can’t hit Kras, maybe we can target one of its downstream genes. This research identifies some of those genes and suggests that interleukin-1apha (IL-1a) is a potential therapeutic target.”

Chiao and colleagues identified IL-1a as a crucial player in a feed-forward loop that:

Begins with mutationally activated Kras triggering a chain reaction that induces IL-1a expression;
This in turn activates NF-?B via the protein kinase IKK2/ß, which blocks the inhibitor of NF-?B.
In the cell nucleus, NF-?B oversees gene transcription and regulates a number of inflammation-promoting genes, including IL-1a.
IL-1a and another protein called p62 activate NF-?B which in turn cycles back to perpetuate the loop by activating its activators.

“It’s a vicious cycle,” Chiao said. The overactive NF-?B fuels pancreatic cancer by activating genes that promote inflammation, the growth of new blood vessels and block programmed cell death.

Chiao has three research grants from the National Cancer Institute to study pancreatic cancer. “We study signaling transduction pathways to try to find out why it’s such a bad disease and to find a weak point for targeted therapy,” he said.

In the Cancer Cell paper, the authors conclude: “Our findings suggest that the prime mover responsible for cancer-related inflammatory response and the development of pancreatic intraepithelial neoplasia (precancerous lesions) and pancreatic ductal adenocarcinoma is the mutant Kras-initiated constitutive activation of NF-?B.”

This process, they further noted, creates a pro-tumor microenvironment by promoting inflammation, creation of new blood vessels and tissue repair that is similar to conditions found in inherited pancreatitis, inflammation of the pancreas that is linked to the development of cancer.

Kras mutation, IL-1a, NF-?B go together with poor survival
The team analyzed mouse and human tumors and mouse strains with mutated Kras expressed in their pancreases. In a series of experiments they found:

Active IKK2/ß – the activator of NF-?B – was required for the Kras-mutated mice to develop either pancreatic cancer or precancerous legions.
Deletion of IKK2/ß interrupted Kras-stimulated inflammation and cell proliferation, suggesting that chronic inflammation is a key factor in promoting pancreatic cancer development.
Microarray profiles of gene expression showed that several NF-?B-regulated inflammatory genes were present in high levels in mice with mutated Kras and active IKK2/ß but only found at lower levels in mice with IKK2/ß knocked out.
In human pancreatic tumors, high expression of the same inflammatory genes in the mutated Kras mice were associated with positive lymph node status, high-risk, late tumor stage and poor survival.
Expression of several genes regulated by NF-?B progressed from low levels in normal pancreases to higher levels in precancerous lesions and tumors, including IL-1a.
IL-1a was known to be both a target of and an inducer of NF-?B, but its expression had not previously been connected to mutated Kras. The team found that downstream targets of Kras, including IL-1a, are interrupted when IKK2/ß is inactivated.
Analysis of 14 human pancreatic cancer tumor samples showed that overexpression of IL-1a, the presence of Kras mutation and the activation of NF-?B are correlated and are associated with poor survival.
Continued activation of NF-?B and its gene transcription activity are sustained by IL-1a and p62.

Co-authors with Chiao are Jianhua Ling, Ph.D., Rulying Zhao, M.D., Ph.D., Qianghua Xia, Ph.D., Zhe Chang, Ph.D., and Mien-Chie Hung, Ph.D., of MD Anderson’s Department of Molecular and Cellular Oncology; Ya’an Kang, M.D., Ph.D., and Jason Fleming, M.D., of MD Anderson’s Department of Surgical Oncology; Huamin Wang, M.D., Ph.D., and Jinsong Liu, M.D., Ph.D., of MD Anderson’s Department of Pathology; Dung-Fang Lee, Ph.D., and Ihor Lemischka, Ph.D., of the Black Family Stem Cell Institute of Mount Sinai School of Medicine; Jin Li, Ph.D., of the Center for Applied Genomics of the Children’s Hospital of Philadelphia; and Bailu Peng, Ph.D. of the Guangdong Entomological Institute, Guangdong, China.

The team’s research was funded by grants from the National Cancer Institute, including MD Anderson’s Cancer Center Core Support Grant.

Has an achilles’ heel for cancer been found?

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Posted 03 Jan 2012 — by James Street
Category Colon Cancer, DNMT1, genetic research, MBD2

RESEARCH into a gene called MBD2 could lead to new treatments for colon cancer, after experts discovered that switching it off prevents tumours from forming.

The breakthrough has been described as a “potential Achilles’ heel” by lead research Professor Alan Clarke.

It comes from the work at the Cancer Research UK Centre in Cardiff into how genes and proteins are involved in the formation of cancer.

Prof Clarke said: “The interesting thing about cancer is that one of its primary features is to turn off a number of defensive mechanisms. As the cancer develops, these defensive mechanisms are got around, usually because the genes are switched off or deactivated.”

 The first breakthrough came with the discovery of the DNMT1 gene, which, when switched off meant that cancers couldn’t develop.

But deactivating DNMT1 also had a significant effect on other bodily functions, meaning it would not make a good target for cancer therapies.

MBD2 belongs to a family of proteins which turn off other genes and research carried out in Cardiff has found that deactivating it prevents colon tumours from developing.

“It’s fantastic and does it with virtually 100% efficiency,” Prof Clarke said. “And, taking out MBD2 isn’t that damaging to other tissues and systems – it appears to be tolerated reasonably well.

“Therefore, if we were to have a therapy targeting MBD2, any off-target effects would be limited.”

The research team has been examining the impact of MBD2 by creating mice which lack the gene. But many questions remain unanswered.

Prof Clarke said: “We have to show that if you don’t have MBD2 then the likelihood of getting a tumour is much reduced. And we don’t know if you take out MBD2 from a tumour whether it will disappear.

“We’ve been trying to develop a drug that specifically targets MBD2 but, unfortunately, attempts have not been successful because it’s a very difficult protein.

“We think that MBD2 deficiency suppresses tumorigenesis by failing to turn off a number of genes – some these will be important. We’re trying to delve down and find out which of the genes it regulates are important.

“We have a potential Achilles’ heel here to stop tumours forming and we’re also trying to find a drug target.

“We can imagine that this will be useful for patients who have had a tumour and have had therapy but who have a chance of relapsing. But we’re also testing the notion that regulating MBD2 will cause tumours to regress.”

Prof Clarke added: “The remarkable thing about the way we treat cancer is that we’re stuck with pretty much ancient technology.

“We mostly use poisons but although we have made progress with virtually all forms of cancer in terms of improving treatment, if we are going to make a huge step change it will have to come from a better understanding of the mechanisms that lead to cancer.

“That will come from a molecular understanding of cancer – if we really understand the molecular basis we can create drugs that make a big difference rather than small, incremental differences.”

Scientists have devised a new, experimental vaccine that seems to be effective at shrinking cancerous tumors in mice by up to 80 percent.

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Posted 13 Dec 2011 — by James Street
Category Breast Cancer, MUC1 protein, MUC1 protein, Vaccine

Scientists have devised a new, experimental vaccine that seems to be effective at shrinking cancerous tumors in mice by up to 80 percent.

The vaccine worked at shrinking similar mouse versions of breast and pancreatic tumors, but researchers from the University of Georgia and the Mayo Clinic said that it could be applied to other cancers, too, including colorectal and ovarian cancers and multiple myeloma.

Scientists have been working for decades to find a way to mobilize the immune system to be able to identify cancerous cells. The problem has always been that the immune system doesn’t recognize the cancerous cells as dangerous because they originated from the body in the first place, and therefore doesn’t attack them, researchers said.

But the new vaccine works by targeting the sugar coating of a protein called MUC1 located on the surfaces of the cancerous cells. The sugar coating differentiates the cancerous cells from normal, healthy cells. The mice were engineered so that their cancer cells overexpressed MUC1, just like human cancer cells do.

“This is the first time that a vaccine has been developed that trains the immune system to distinguish and kill cancer cells based on their different sugar structures on proteins such as MUC1,” study researcher Sandra Gendler, a professor at the Mayo Clinic, said in a statement. “We are especially excited about the fact that MUC1 was recently recognized by the National Cancer Institute as one of the three most important tumor proteins for vaccine development.”

The study will appear in the journal Proceedings of the National Academy of Sciences.

The vaccine has potential to be used on a wide variety of cancers because more than 70 percent of deadly cancers have the MUC1 protein, researchers said. AOL Lifestyle reported that researchers hope to try the vaccine in humans in the next couple of years.

And because MUC1 is overexpressed in 90 percent of people who were unresponsive to other therapies like Tamoxifen or Herceptin, the vaccine might in the future be a viable option for people whose cancers are difficult to treat, researchers added.

The experimental cancer vaccines in the works today are different from the preventive vaccines (like ones that ward off cervical cancer-causing HPV), which prevents cervical cancer.

The Daily Beast explains:

By “cancer vaccine,” scientists mean something that will stimulate the immune system to attack malignant cells.

Recently, researchers at the National Cancer Institute developed a promising vaccine that seems to stop the spread of metastatic breast and ovarian cancers in humans. The poxviral vaccine even seemed to be effective at completely ridding one person involved in the study of cancer, WebMD reported.

However, the vaccine wasn’t as overwhelmingly successful in the other 25 patients — for some of those people, the vaccine seemed to extend the amount of time before the cancer progressed by a few months, WebMD noted.

And earlier this year, University of Pennsylvania researchers announced a leukemia treatment that seems effective at obliterating leukemia cells, and was shown to completely rid patients of the cancer or at least significantly decrease their number of cancerous cells.

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.

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.

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.

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/

Bone Cancer – Study Identifying New Genes That Give Rise To Bone Cancer Started

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Posted 05 Jul 2011 — by James Street
Category Etiology and cause of osteosarcoma, genetic research, genetic research, Human osteosarcoma research, Osteosarcoma, Osteosarcoma Outcomes

 

Monday, July 4th, 2011 | Posted by Matthew Bennett

Dual approach will find mutations in osteosarcoma and develop tools to monitor disease in patients

A new study into osteosarcoma – cancer of the bone – will use advances in genomic research and analysis to identify new genes that give rise to the condition and to create personalised blood tests for children and young adults with the condition. The study is funded by Skeletal Action Cancer Trust, SCAT.

It is hoped that the results of this new study will help doctors improve treatment of this difficult disease through better diagnosis and monitoring of this bone cancer.

Each year approximately 80 children and young adults develop osteosarcoma in the UK. This painful cancer of the bone tends to affect children and young adults and is normally treated using chemotherapy and surgery. The causes of the disease are not well known and measuring response to treatment relies on scanning and imaging. The new study seeks to bring both greater understanding to processes of developing the condition and create improved methods of measuring disease regression.

“We hope that this research project will improve the way patients with cancer are monitored and will guide the best drug treatment for the cancer in each patient,” says Professor Adrienne Flanagan from the UCL Cancer Institute, and Medical Director of the Royal National Orthopaedic Hospital (RNOH), “It is really important that we exploit new tools that emerge from cutting-edge research to see how they can benefit patients with bone tumours in the future.”

“We need the support of patients and of the wider public to make our aim of moving towards delivery of personalised cancer treatment a reality.”

Professor Flanagan, consultant pathologist at the RNOH and scientist at UCL Cancer Institute, worked with colleagues from the Wellcome Trust Sanger Institute, in which they discovered a novel cancer-causing mutation in chondrosarcoma, the second most common cancer of bone. The results of this study were published recently online in the The Journal of Pathology.

In this new programme, scientists will use recently developed methods to hunt for changes in the genomes of cancer patients, trying to pinpoint genes underlying in the disease. At the same time, they will develop new tools to monitor the disease in patients through the course of treatment. They hope that their methods, which look for tumour-specific DNA in the bloodstream of patients, will become routine for patients in the future.

“Currently, the response of patients with osteosarcomas to treatment is monitored by scanning tumours using imaging techniques,” says Dr Peter Campbell. “In contrast, blood cancers have long been monitored using simple tests that pick up recurring mutations in tumour cells in the blood and show how a patient is responding to treatment. The new project aims to see if we could develop and apply similar methods to osteosarcomas”.

The patients are being treated at the RNOH and University College London Hospital (London Sarcoma Service), and the research project is largely funded by SCAT Bone Cancer Trust based at the RNOH, with contributions from other charities including the Bone Cancer Research Trust, Rosetrees and others. The research is being carried out in collaboration with UCL Cancer Institute and the Wellcome Trust Sanger Institute.

The team will sequence the complete genome of 50 patients with osteosarcoma and will look in their plasma in many of these patients before and after chemotherapy treatment to find rearrangements – shuffled chunks of DNA – in the small amounts of DNA that have leaked out from the osteosarcoma into the bloodstream. They will be searching for rearrangements that are specific to each patient.

By developing a picture of the unique profile of mutations of each patient’s cancer and then using these mutations to monitor the amount of cancer derived DNA circulating in the blood, the clinicians hope they can deliver treatments to patients in a personalised way

In addition to seeking improvements in treatment, the researchers are looking for novel genes giving rise to osteosarcoma. The team will sequence in full the gene-containing regions of the genome in 100 osteosarcoma samples.

“The future of cancer genetics lies ultimately in drawing a complete picture of each and every mutation for each and every cancer patient who visits a hospital,” says Professor Mike Stratton, Director of the Wellcome Trust Sanger Institute and one of the project leaders. “But there are a number of steps on the way. By concentrating in this study on the so called ‘active’ areas in the genome we can begin to pick out mutations that might be driving cancer even as we embark on the journey towards comprehensive catalogues of mutations for this, and a whole range of other human cancers.”

Ultimately, the team on the osteosarcoma study will generate complete genome sequences for the whole genomes of osteosarcomas – allowing them to look in even finer detail at the spectrum of mutations in the cancer and distinguish the cancer causing mutations from the innocent bystanders.

“The research is promising, but its success relies on continued support from the public,” says Mr Steve Cannon, bone tumour surgeon at the RNOH and Chairman of SCAT, the Bone Cancer Trust. “It is great that we have been able to get this project up and running, but donations will continue to be necessary if we are to succeed in the fight against osteosarcoma and other bone cancers. In what is without doubt an exciting and important moment in the application of genetic science in cancer research, it is only right that we should be looking to apply the cutting edge tools that are now available to bone cancer.”

“Osteosarcoma is an aggressive cancer; we need an aggressive approach to tackle its effects.”

Related Research

Amary MF et al. (2011) IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. The Journal of Pathology
First published online: 19 May 2011
DOI: http://dx.doi.org/10.1002/path.2913

Scat Bone Cancer Trust is dedicated to the advancement of bone cancer research, to providing the best possible care and support at each stage of treatment and to improving the quality and dignity for life for all patients. http://scatbonecancertrust.org/

The Royal National Orthopaedic Hospital (RNOH) is the largest specialist orthopaedic hospital in the UK and is regarded as a leader in the field of orthopaedics. The Trust provides a comprehensive and unique range of neuro-musculoskeletal healthcare, ranging from acute spinal injuries to orthopaedic medicine and specialist rehabilitation for chronic back pain sufferers. http://www.rnoh.nhs.uk/

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease. http://www.sanger.ac.uk

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests. http://www.wellcome.ac.uk

Contact Details:

Don Powell Press Officer
Wellcome Trust Sanger Institute
Hinxton, Cambridge, CB10 1SA, UK
Tel +44 (0)1223 496 928
Mobile +44 (0)7753 7753 97
Email press.office@sanger.ac.uk

Anna Fox Communications and Foundation Trust Liaison Officer
Royal National Orthopaedic Hospital NHS Trust
Tel 020 8909 5349
Email anna.fox@rnoh.nhs.uk

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