Archive for the ‘genetic research’ Category

Personalized cancer treatment: Genetic differences abound in tumors

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Posted 11 Mar 2012 — by James Street
Category Biomarkers, Diagnostic, Epigenetics, Gene sequencing, genetic research
By Eryn Brown, Los Angeles Times / for the Booster Shots blogMarch 8, 2012, 5:16 p.m.

Patients are holding out hope that someday — soon, they hope — physicians will be able to personalize medical treatment more precisely than they’ve been able to in the past.  For people with cancer, this might mean taking a quick biopsy, studying the genetic profile of a tumor and then tailoring interventions  to target the cancer effectively, with as few side effects as possible.

But a study published in the New England Journal of Medicine on Wednesday underscores why the vision remains a challenge.  Cancer researchers in England showed that individual kidney tumors and their metastases had different mutations in different locations — and that those mutations, in turn, affect the biology of those tumors in varying ways in different locations.

“A single tumor-biopsy-specimen reveals a minority of genetic aberrations … that are present in an entire tumor,” wrote Dr. Marco Gerlinger of the Cancer Research UK London Research Institute and co-authors.

For example, the scientists found that one region of a renal carcinoma could display gene expression signatures associated with a good prognosis, while signatures in another region of the same tumor could be associated with a poor prognosis.

The basic insight that a single cancer can contain a number of mutations isn’t entirely new, but the team’s genetic analysis helps demonstrate why it probably won’t be possible to devise targeted, patient-specific treatment strategies by looking at minimally invasive biopsies collected from a single site, wrote Dr. Dan Longo of the National Institute on Aging in an editorial accompanying the study.

“A new world has been anticipated in which patients will undergo a needle biopsy of a tumor in the outpatient clinic, and a little while later, an active treatment will be devised for each patient on the basis of the distinctive genetic characteristics of the tumor,” he wrote.  “But a serious flaw in the imagined future of oncology is its underestimation of tumor heterogeneity.”

The Los Angeles Times has reported on tumor genetics in the past.  In April 2011, writer Amber Dance described efforts to catalog the mutations that cause cancer.  Earlier that year, Thomas H. Maugh II explained how researchers sequenced the genomes of prostate cancers in seven different men.

MIT research: Delivering RNA with tiny sponge-like spheres

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Posted 05 Mar 2012 — by James Street
Category NanoTechnology, RNAi, siRNA
Published: Monday, February 27, 2012 – 11:35 in Biology & Nature

For the past decade, scientists have been pursuing cancer treatments based on RNA interference — a phenomenon that offers a way to shut off malfunctioning genes with short snippets of RNA. However, one huge challenge remains: finding a way to efficiently deliver the RNA. Most of the time, short interfering RNA (siRNA) — the type used for RNA interference — is quickly broken down inside the body by enzymes that defend against infection by RNA viruses.

“It’s been a real struggle to try to design a delivery system that allows us to administer siRNA, especially if you want to target it to a specific part of the body,” says Paula Hammond, the David H. Koch Professor in Engineering at MIT.

Hammond and her colleagues have now come up with a novel delivery vehicle in which RNA is packed into microspheres so dense that they withstand degradation until they reach their destinations. The new system, described Feb. 26 in the journal Nature Materials, knocks down expression of specific genes as effectively as existing delivery methods, but with a much smaller dose of particles.

Such particles could offer a new way to treat not only cancer, but also any other chronic disease caused by a “misbehaving gene,” says Hammond, who is also a member of MIT’s David H. Koch Institute for Integrative Cancer Research. “RNA interference holds a huge amount of promise for a number of disorders, one of which is cancer, but also neurological disorders and immune disorders,” she says.

Lead author of the paper is Jong Bum Lee, a former postdoc in Hammond’s lab. Postdoc Jinkee Hong, Daniel Bonner PhD ’12 and Zhiyong Poon PhD ’11 are also authors of the paper.

Genetic disruption

RNA interference is a naturally occurring process, discovered in 1998, that allows cells to fine-tune their genetic expression. Genetic information is normally carried from DNA in the nucleus to ribosomes, cellular structures where proteins are made. siRNA binds to the messenger RNA that carries this genetic information, destroying instructions before they reach the ribosome.

Scientists are working on many ways to artificially replicate this process to target specific genes, including packaging siRNA into nanoparticles made of lipids or inorganic materials such as gold. Though many of those have shown some success, one drawback is that it’s difficult to load large amounts of siRNA onto those carriers, because the short strands do not pack tightly.

To overcome this, Hammond’s team decided to package the RNA as one long strand that would fold into a tiny, compact sphere. The researchers used an RNA synthesis method known as rolling circle transcription to produce extremely long strands of RNA made up of a repeating sequence of 21 nucleotides. Those segments are separated by a shorter stretch that is recognized by the enzyme Dicer, which chops RNA wherever it encounters that sequence.

As the RNA strand is synthesized, it folds into sheets that then self-assemble into a very dense, sponge-like sphere. Up to half a million copies of the same RNA sequence can be packed into a sphere with a diameter of just two microns. Once the spheres form, the researchers wrap them in a layer of positively charged polymer, which induces the spheres to pack even more tightly (down to a 200-nanometer diameter) and also helps them to enter cells.

After the spheres enter a cell, the Dicer enzyme chops the RNA at specific locations, releasing the 21-nucleotide siRNA sequences.

Peixuan Guo, director of the NIH Nanomedicine Development Center at the University of Kentucky, says the most exciting aspect of the work is the development of a new self-assembly method for RNA particles. Guo, who was not part of the research team, adds that the particles might be more effective at entering cells if they were shrunk to an even smaller size, closer to 50 nanometers.

Targeting tumors

In the Nature Materials paper, the researchers tested their spheres by programming them to deliver RNA sequences that shut off a gene that causes tumor cells to glow in mice. They found that they could achieve the same level of gene knockdown as conventional nanoparticle delivery, but with about one-thousandth as many particles.

The microsponges accumulate at tumor sites through a phenomenon often used to deliver nanoparticles: The blood vessels surrounding tumors are “leaky,” meaning that they have tiny pores through which very small particles can squeeze.

In future studies, the researchers plan to design microspheres coated with polymers that specifically target tumor cells or other diseased cells. They are also working on spheres that carry DNA, for potential use in gene therapy.

Source: Massachusetts Institute of Technology

Single-cell sequencing leads to a new era of cancer research

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Posted 05 Mar 2012 — by James Street
Category Bioinformatics, Gene sequencing, genetic research

March 2, 2012 in Genetics

BGI, the world’s largest genomics organization, developed single-cell genome sequencing technology and published two research papers for cancer single-cell sequencing in the research journal Cell. In the papers, which were published today in the same issue of Cell, BGI researchers applied their new single-cell sequencing (SCS) method to identify the genetic characteristics of essential thrombocythemia (ET, a kind of blood neoplasm) and clear cell renal cell carcinoma (ccRCC, a typical kidney cancer), and demonstrated that single cell analyses of highly heterogeneous tissues provide much clearer intratumoral genetic pictures and developmental history than previous bulk tissue sequencing.

The availability of BGI’s SCS method opens new ways for the genetic study of tumors at single nucleotide resolution, especially for those where it is difficult to identify key mutations by previous bulk tissue sequencing. The single-nucleotide resolution of this method enables application to a variety of diseases and biological processes, such as studies on cellular heterogeneity of tissues, iPS or , pre-implantation and the of .

Cells are heterogeneous in . The current high-throughput sequencing technology has been applied in a variety of fields of biological study, however, its obvious limitations on studying complex phenomena such as tumor evolution, , neuron science, and Meta genomics make it powerless on heterogeneous samples. Recently emerging single-cell analysis approaches like single-nuclei sequencing on breast cancers by Navin et al. throw light on understanding the biology underlying cellular heterogeneity.

Until now, there has been no suitable way for scientists to explore the genetics of single at a single-nucleotide resolution. To overcome this deficiency, researchers from BGI developed a high-throughput single-cell sequencing method based on an advanced multiple displacement amplification (MDA), and tested it using two single lymphoblastoid cells derived from a healthy individual (YH) who provided DNA for the first Asian diploid genome sequence. “Through the evaluation, we found our MDA-based method could provide greater resolution and genome coverage, which will enable single-cell analyses at a single-nucleotide level with relatively high sensitivity and specificity,” said Luting Song, the leading author of this study and project manager at BGI.

BGI first applied its new SCS method to conduct single-cell exome analysis of the blood neoplasm because it is much more convenient to infer the development process underlying the abnormal proliferation of hematopoietic progenitor cells. Results revealed the JAK2-negative blood neoplasm may arise from monoclonal somatic mutant cells, and identified several known and novel mutated genes that may play roles in the blood neoplasm initiation and progression. Therefore, the identified mutated genes may be of interest for future biological research.

In addition, to better understand the intratumoral genetics underlying mutations of typical solid tumor, BGI researchers applied this new method to kidney tumor. The study demonstrates it is unlikely that this tumor resulted from two most common mutations in VHL and PBRM1. This emphasizes the importance of assessing and diagnosing cancers and patients at an individual level to determine the most effective treatment. Further analysis indicated that this tumor did not contain any significant clonal subpopulation. Quantification analysis of tumor heterogeneity showed that most of the somatic mutations occurred only in a small fraction of the cells, and that mutations with different allele frequencies showed very different mutation spectrums. Researchers also screened for mutations in a group of 98 kidney tumor patients and identified potential key genes contributing to the establishment of this kidney tumor.

“Our pilot study demonstrates kidney tumor may be more genetically complex than previously thought and provides novel information that can lead to new ways to investigate individual tumors with the aim of developing more effective cellular targeted therapies,” said Xun Xu, Vice Director of BGI. “This study also provides a good example of how single-cell exome sequencing could yield novel biological insights for an individual solid tumor.”

“Our two studies demonstrate the power of our proprietary method for identifying complex, small genetic changes in a heterogeneous tumor at a greater resolution,” said Yingrui Li, Vice Director of BGI. “I believe our study will enable researchers to develop new methods to clinically evaluate tumors and promote the research of complex diseases and biological processes.”

Jun Wang, Executive Director of BGI, said, “BGI’s single-cell sequencing technology elevates genomic studies to a new level, enabling researchers to conduct biological studies at the cellular level in life processes such as the growth, reproduction and development, heredity and aberrance of organisms.”

Provided by BGI Shenzhen

Ensysce says carbon nanotubes delivered cancer drug

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Posted 29 Feb 2012 — by James Street
Category NanoTechnology, nanotubes, RNAi
By mhollmer
Created 02/14/2012 – 12:07

Ensysce Biosciences says early in vivo experiments using single-walled carbon nanotubes to deliver siRNA drugs to cancer tumors have been so promising, the company will proceed to human clinical trials within the next year or so.

The Houston startup is touting data published recently in the open-access online journal Materials, showing the single-walled, fullerene carbon nanotube tech protects the siRNA drug while carrying it through the blood. Once the treatment reached the tumor target, the company claims that it successfully penetrated the tumor and slammed into the target protein, releasing a drug payload that properly displayed anti-tumor activity. What’s more, the delivery system also appeared to generate very little toxicity to other cells.

Based on that data, Ensysce says it will launch human trials within 12 to 18 months, tweaking its drug delivery formulation in the interim, company CEO Lynn Kirkpatrick said in a statement. To get there, Ensysce will be armed, in part, with up to $1.5 million in funding from Texas’ Emerging Technology Fund and ongoing collaborations with researchers at M.D. Anderson Cancer Center and Rice University.

We’ll see. RNAi drugs hold enormous promise in their potential to turn off bad genes that cause disease, but scientists have struggled to find a competent way to deliver the drugs so they reach their target and do their job. Human trials will be interesting to follow because many of the delivery advances so far have taken place in the preclinical stage. One exception: Alnylam ($ALNY [1]) and Tekmira ($TKMR [2]), which have jointly pursued lipid nanoparticles as a tool to deliver RNAi drugs and produced some promising results in early human trials. The two have also fought bitterly over patent and license issues, highlighting what’s at stake with finding a successful RNAi delivery mechanism.

Medtronic ($MDT [3]) also has made some progress, working again with Alnylam. But rather than use nanotech, they’ve generated encouraging results in preclinical testing using a small implantable infusion system and convection-enhanced delivery to break the blood-brain barrier, and deliver an RNAi-based Huntington’s disease treatment to the brain.

- here’s the release [4]
- access the published study [5]

SA 1000 Cancer Genome Project banking tumors of patients

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Posted 25 Feb 2012 — by James Street
Category Bioinformatics, Gene sequencing, genetic research

by Wendy Rigby / KENS 5

Bio | Email

Posted on February 24, 2012 at 2:54 PM

SAN ANTONIO — A San Antonio cancer doctor is launching an ambitious new project. It’s a unique tumor bank that will help unravel the genetic puzzle of a killer disease.

Lori Vanta of San Antonio has been fighting colorectal cancer since 2008. At age 41, she’s already undergone treatment with surgery, radiation and chemotherapy.
“I have a lot of living to do,” Vanta said. “I have two beautiful children and I’m not ready to give up. I’ll never stop fighting and I’ll never stop hoping and helping.”
Vanta is helping by donating her tumor and blood to the San Antonio 1000 Cancer Genome Project which is gathering samples of the ten most common cancers in San Antonio.
It’s the brainchild of Dr. Anthony Tolcher. He has enlisted the help of more than a hundred other San Antonio doctors as well as Rackspace to gather, process and upload data about thousands of tumors.
“It is a community effort to try to understand, fully understand, the genetic abnormalities that lead to cancer and what happens to those patients with those genetic abnormalities,” Tolcher, an oncologist, explained.
That information yields a diagram showing the mutations of chromosomes in individual patients. Analysis will help doctors target therapies and come up with better treatments. Scientists from all over the world will have access to the information.
In three years, the group hopes to have a thousand tumors mapped this way.
“Once you explain what it’s going to do and what’s involved, I think people really want to participate because most patients want to see the scientific field move forward,” Tolcher commented.
“It’s all working toward helping us specifically, for my tumors and for my cancer to specifically help me,” Vanta stated. “And it’s amazing. It’s mind-boggling.”
It will take several million dollars to map the whole genome sequences of these tumors. Tolcher is raising money through a non-profit group. In just six weeks, the San Antonio 1000 Cancer Genome Project has already raised almost $250,000.

Cancer Research Institute Names 11 Outstanding Young Scientists to Receive Prestigious Postdoctoral Fellowship Award

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Posted 22 Feb 2012 — by James Street
Category Finance and Politics of cancer research and treatment, General Cancer Research, genetic research, Research Centers
Released: 2/16/2012 12:30 PM EST
Source: Cancer Research Institute

More than $1.8 Million Committed for Research in Cancer Immunology

Newswise — NEW YORK, NY, Feb. 16, 2012 – The Cancer Research Institute, Inc. (CRI), a U.S. nonprofit organization established in 1953 to support and coordinate scientific studies in the fields of immunology and tumor immunology with the goal of harnessing the power of the immune system to treat and cure cancer, announced that the Fellowship Review Committee of the CRI Scientific Advisory Council, with the approval of the Institute’s Board of Trustees, has named 11 new postdoctoral fellows from its October 2011 application round, totaling more than $1.8 million in research funding through the Irvington Institute Fellowship Program of the Cancer Research Institute.

The 11 young scientists are conducting research under the guidance of leading immunologists and tumor immunologists at distinguished academic institutions throughout the United States, including Memorial Sloan-Kettering Cancer Center, Yale University School of Medicine, Columbia University, California Institute of Technology, and University of California, San Francisco. Each of their projects is advancing knowledge about the immune system that can be directly applied to solving the cancer problem, with projects providing insights into lymphoma, ovarian, colorectal, prostate, and HIV-related cancers, among others.

Each fellow will receive stipend support totaling $160,000 over three years, plus an annual research allowance of $1,500.

Cancer Research Institute Postdoctoral Fellows Awarded in January 2012:

• Anne Chauveau, Ph.D., with her sponsor Morgan Huse, Ph.D., at Memorial Sloan-Kettering Cancer Center, New York, NY, will investigate how a family of proteins known as the diacylglycerol kinases (DGK) are involved in the process of immune cell polarization—a process that plays an important role in ensuring that T cells can accurately direct cell-killing substances against their targets, including cancer cells. A better understanding of the mechanisms involved in directional secretion could make important contributions to the design of novel cancer immunotherapeutics.

• Juan R. Cubillos-Ruiz, Ph.D., with his sponsor Laurie H. Glimcher, M.D., at Harvard School of Public Health, Boston, MA, aims to understand how immune cells called dendritic cells promote and support the development of ovarian cancer. Through his project, he aims to identify the pathways involved in immune-related cancer progression and use a nanotechnology-based strategy to effectively block these pathways as a novel therapeutic approach to complement standard ovarian cancer treatments such as chemotherapy and radiotherapy.

• Timothy Eitas, Ph.D., with his sponsor Jenny P.-Y. Ting, Ph.D., at the University of North Carolina, Chapel Hill, NC, will study a protein called NLRX1 and its role in mediating the production of inflammatory molecules called cytokines in ulcerative colitis and colitis-associated cancer. Dr. Eitas’s in vivo and in vitro experiments should offer novel immunological and molecular targets for the treatment of colorectal cancer.

• James A. Harker, Ph.D., with his sponsor Elina I. Zuniga, Ph.D., at the University of California, San Diego, La Jolla, CA, will explore a new compartment that Dr. Harker hypothesizes plays a major role in defense during chronic infection and is essential for viral control and resolution. His project will include identifying the key components of the compartment, the factors that lead to its activation, and its therapeutic potential. This work could lead to treatment strategies that significantly reduce the incidence of chronic infectious diseases and their associated cancers.

• Chunyu Jin, Ph.D., with sponsor Michael G. Rosenfeld, M.D., at the University of California, San Diego, La Jolla, CA, aims to elucidate the role of GPS2 in macrophages, immune cells that can drive pro-cancer inflammatory reactions in hormone-resistant prostate cancer. Initial results suggest that GPS2 plays a role in preventing activation of inflammatory signaling pathways. By further elucidating the role of GPS2, Dr. Jin’s studies will help shed light on macrophage-related inflammation in hormone-resistant prostate cancer, with implications for the effectiveness of selective androgen receptor modulators (SARMs) in prostate cancer treatment and the appearance of clinical resistance in prostate cancer patients.

• Lingfeng Liu, Ph.D., with sponsor Wendell A. Lim, Ph.D., at the University of California, San Francisco, San Francisco, CA, aims to optimize T cells for adoptive therapy by using synthetic biology to reengineer transgenic T cells to respond selectively to high antigen density on tumor cells and not to low antigen density on normal tissue cells. This study can potentially provide a general strategy to improve cell-based cancer therapy.

• Boryana N. Manz, Ph.D., with sponsor Arthur A. Weiss, M.D., Ph.D., at the University of California, San Francisco, San Francisco, CA, aims to study how the Dok1 tumor suppressor regulates signaling proteins in immune cells. This project will elucidate the Dok1-dependent processes that control the aberrant activation of immune cells and provide insight into the mechanisms of cancer initiation in multiple tissues. Dok1, or genetic variants identified in this study, can then be delivered to tumors to suppress their hyper-activation, or included in cell-based cancer immunotherapies, as a safety regulator against hyper-activation.

• James B. Munro, Ph.D., with his sponsor Walther Mothes, Ph.D., at Yale University School of Medicine, New Haven, CT, will utilize state-of-the-art imaging technologies to visualize HIV envelope protein (Env) molecules—the primary target for anti-HIV antibodies generated by the immune system—to elucidate how Env is capable of escaping the activity of the vast majority of anti-HIV antibodies. These insights will assist the development of an HIV vaccine.

• Vanja Sisirak, Ph.D., with sponsor Boris V. Reizis, Ph.D., at Columbia University, New York, NY, aims to study the role of a novel DNA-digesting enzyme in recognition of microbial DNA and self-DNA by immune cells called dendritic cells. This work will allow for a better understanding of how dendritic cells sense DNA and will help identify new targets for future therapy development for the treatment of autoimmune diseases, as well as offer new perspectives on cancer immunotherapy.

• Beth M. Stadtmueller, Ph.D., with her sponsor Pamela J. Bjorkman, Ph.D., at the California Institute of Technology, Pasadena, CA, will investigate the molecular mechanisms and architecture of immunoglobulin alpha (IgA) in mucosal surfaces, where many epithelial cancers arise. Using x-ray crystallography, complimentary biochemical experiments, and electron microscopy, Dr. Stadtmuller will characterize IgA and its related complexes, providing fundamental insights into the mechanisms of IgA processes, which are necessary not only to better understand mucosal immunity and disease pathology, but also to develop existing and novel cancer immunotherapies.

• Leng-Siew Yeap, Ph.D., with sponsor Frederick W. Alt, Ph.D., at Immune Disease Institute, Inc., Boston, MA, aims to understand how the enzyme Activation Induced Deaminase (AID) is attracted to specific DNA sequences in the generation of antibody diversity, dysregulation of which can lead to B cell lymphomas. This study will shed light on the mechanisms by which DNA sequence influences AID targeting in antibody diversity, as well as on potential strategies to prevent the adverse consequences of AID and the development of cancer.

The Cancer Research Institute extends its congratulations to this latest group of postdoctoral fellows. The next deadline for applications to the Institute’s fellowship program is April 2, 2012.

About the Cancer Research Institute
The Cancer Research Institute (CRI), established in 1953, is the world’s only nonprofit organization dedicated exclusively to transforming cancer patient care by advancing scientific efforts to develop new and effective immune system-based strategies to prevent, diagnose, treat, and cure cancer. Guided by a world-renowned Scientific Advisory Council that includes three Nobel laureates and thirty members of the National Academy of Sciences, CRI has invested more than $200 million in support of research conducted by immunologists and tumor immunologists at the world’s leading medical centers and universities, and has contributed to many of the key scientific advances that demonstrate the potential for immunotherapy to change the face of cancer treatment.

To accelerate the pace of progress in the field, CRI convenes and coordinates global collaborations among academics, industry scientists and decision makers, regulatory representatives, and health research associations focused on discovery, development, and refinement of new cancer immunotherapies. A founding visionary and scientific leader in tumor immunology, CRI is helping to shape the emerging field of immuno-oncology, and is ushering in a new era of medical progress to bring more treatment options to cancer patients sooner.

For more information, visit http://www.cancerresearch.org.

Introducing ATCC Tumor Cell Panels: Powerful New Tools for Cancer Research

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Posted 18 Feb 2012 — by James Street
Category Biomarkers, Diagnostic, Drug Testing, General Cancer Research, genetic research, Online Research Tools, Open Source Drug Discovery, Tumor biomarkers

PRWeb

Tuesday, February 7, 2012

ATCC launches valuable and gentically-diverse tumor cell panels for drug discovery, pathway analysis and functional genomics

Manassas, VA (PRWEB) February 07, 2012

Searching for appropriate tumor cell models often entails a time-intensive review of the literature and genomic databases. To enable cancer researchers, ATCC (American Type Culture Collection) has introduced a collection of Tissue-Specific Tumor Cell Panels. These powerful new tools combine well-characterized adherent cell lines that were selected for their genomic mutations as found in the Sanger COSMIC database, greatly reducing the time and effort scientists devote to finding these cells. Working closely with customers, ATCC scientists have identified cell lines that that are easy to grow using standard media formulations and possess critical genetic abnormalities found in tumors.

Each Tissue-Specific Tumor Cell Panel is comprised of different cell lines that have been grouped by tissue of tumor origin. In developing the panels, ATCC scientists evaluated 20 different genes associated with tumorigenesis, including TP53, CDKN2A, BRAF, and KRAS. Descriptive information for each cell line has been annotated with details regarding known mutations in these selected oncogenes or receptors. Cell panels, as research models, are as valuable as the depth of understanding and data supporting them. There are currently 10 Tissue-Specific Tumor Cell Panels in the collection, including panels for breast cancer, triple-negative breast cancer, lung cancer, ovarian cancer, colon cancer, liver cancer and pancreatic cancer.

As part of its mission, ATCC will continue to augment the available information on the Tumor Cell Panel cell lines from other databases, and will perform further characterization on the panels. When combined with the size and scope of the ATCC tumor cell line collection, this growing knowledge base enables scientists to make smarter choices when selecting cell-based research models for cancer research, drug discovery, compound screening, biomarker selection, pathway analysis and functional genomics.

“Scientists are requiring more genomic and proteomic data on the cell lines they use in their studies to understand the roles that genetic defects have in the pathobiology of cancer,” said Dr. Richard Kolodner, Member, Ludwig Institute for Cancer Research, UC San Diego School of Medicine Branch. “ATCC is helping scientists by consulting with researchers and going through the gigabytes of data and stacks of literature to find relevant cell lines with sufficient genetic diversity to create a representative panel,” he added.

ATCC Tissue-Specific Tumor Cell panels offer economy over individual lines, are supplied with comprehensive genetic profile information, and are accompanied by expert support if needed.

For more information, please go to www.atcc.org/tcp. To speak with an expert or place an order, call toll free 1-800-638-6597 (option 2) in the U.S. and Puerto Rico, or international callers can dial +1-703-365-2700, or e-mail ATCC Customer Service at sales(at)atcc(dot)org.

ABOUT ATCC
ATCC maintains the largest and most diverse biorepository in the world. The innovative, not-for-profit organization develops and provides products for life science research, services to support biotechnology development, and standards that are consistent with its mission – to acquire, authenticate, preserve, develop, and distribute standard reference microorganisms, cell lines, and related materials for research in the life sciences. With distribution to more than 140 countries and a working relationship with 12 distribution partners, ATCC has the experience, knowledge, rigorous methodologies, standards, longevity and the global reach to serve academic institutions, government agencies, biotech, biopharma, and research organizations around the world.

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For the original version on PRWeb visit: www.prweb.com/releases/prweb2012/2/prweb9174250.htm

http://sfgate.com/cgi-bin/article.cgi?f=/g/a/2012/02/07/prweb9174250.DTL

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.

Scientists discover gene responsible for lung cancer

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Posted 07 Jan 2012 — by James Street
Category genetic research, Lung Cancer

SINGAPORE, Jan. 6 (Xinhua) — A team of Singaporean scientists have identified a gene responsible for lung cancer, the Agency for Science, Technology and Research said on Friday.

A small number of cells, known as cancer stem cells or tumor- initiating cells (TIC), are responsible for the promotion of tumor growth. The team of scientists found a marker, known as CD166, to identify these cells, it said.

The team, led by Bing Lim, associate director of cancer stem cell biology at the Genome Institute of Singapore, and Elaine Lim, medical oncologist affiliated with Tan Tock Seng Hospital and National Cancer Center Singapore, did more genomic study of the TICs, and discovered several genes that were important for the growth of cancer cells.

The scientists discovered that in abnormal instances when the level of a metabolic enzyme known as glycine decarboxylase rises significantly, it causes changes in the behavior of the cell, making it cancerous.

The glycine decarboxylase is a normal occurring enzyme in cells, present in small quantities.

The finding is reported in the online advance issue of Cell on Jan. 5 and is believed to be a huge step towards finding a cure for the disease.

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.”

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