Posts Tagged ‘division’

Study identifies gene network behind untreatable leukemia, possible treatment target

Scientists from the Cancer and Blood Diseases Institute (CBDI) at Cincinnati Children’s Hospital Medical Center report their results in a study posted online Sept. 4 by Cell Reports.

The specific forms of AML and MDS in the current study involve deletions on the arm of a specific chromosome in blood cells (del(5q). In patients with less aggressive forms of del(5q) MDS, the percentage of bone marrow blasts in their blood (the earliest, most immature cells of the myeloid cell line) is less than 5 percent. This means treatment prognosis for those patients typically is good, according to the study’s lead investigator, Daniel Starczynowski PhD, a researcher in the division of Experimental Hematology and Cancer Biology, part of the CBDI at Cincinnati Children’s.

“Unfortunately, a large portion of del(5q) AML and MDS patients have increased number of bone marrow blasts and additional chromosomal mutations,” Starczynowski said. “These patients have very poor prognosis because the disease is very resistant to available treatments such as chemotherapy and radiation. Finding new therapies is important and this study identifies new therapeutic possibilities.”

The researchers conducted their study in human AML/MDS cells and mouse models of del(5q) AML/MDS. They found that reduced expression of a certain gene in blood cells (miR-146a) led to activation of a molecular signaling network involving several components of NF-kB, one of which involved a protein called p62 — a critical regulator of cell metabolism, cellular remodeling and certain cancers.

Deletion of the miR-146a gene led to overexpression of p62, which caused sustained activation of what researchers identified as an NF-kB signaling network. This fueled the survival and aggressive growth of leukemic cells in cells and in mouse models.

Earlier attempts in previous studies to directly inhibit NF-kB (a key molecular facilitator to the leukemic process) have not proven successful, according to investigators on the current paper. So the authors performed follow-up laboratory tests to look for possible vulnerabilities to NF-kB and a potential workaround by targeting instead p62 within the NF-kB signaling network.

The researcher next tested inhibiting/knocking down p62 as an experimental treatment strategy in mouse models of leukemia and in human cells. The authors reported that targeting p62 prevented expansion of leukemic cells in mouse models and reduced the number of leukemia cell colonies by 80 percent in human AML/MDS cells.

Starczynowski stressed that significant additional research is needed to further verify the findings and learn more about the molecular processes involved. He also cautioned that laboratory results in mouse models do not necessarily translate to humans, and it isn’t known at this time how the findings might be directly applicable to clinical treatment.

source : http://www.sciencedaily.com/releases/2014/09/140904131603.htm

New tool to probe cancer’s molecular make-up

Researchers from the Cancer Research UK Manchester Institute based at The University of Manchester — part of the Manchester Cancer Research Centre — and the Institute of Cancer Research, London, looked at protein kinases, molecules that control various aspects of cellular function.

The study, funded by a Biotechnology and Biological Sciences Research Council (BBSRC)/Pfizer CASE studentship and CRUK,was published in Nature Methods this week (24 August).

Earlier work has shown that mutations or increases in a range of protein kinases are linked to tumour growth, and for several decades researchers have looked to develop drugs that target and prevent this activity in order to kill cancer cells. Ten types of drugs which reduce the activity have so far been approved for cancer treatment in patients.

Dr Claus Jørgensen, who led the study as team leader in the Division of Cancer Biology at The Institute of Cancer Research, London, before taking up a new post as head of the Systems Oncology group at the Cancer Research UK Manchester Institute, said: “Protein kinases regulate how cells communicate. When these molecules are deregulated it corresponds to cells “hearing voices” with a resulting change in their behaviour. Doctors need a way to spot changes in kinase levels in individual tumours so they can see how they respond to treatments and match patients to the treatment that works best for them.”

The team investigated the make-up of over 200 protein kinases. They used a technique known as mass spectrometry to develop a method that can both identify and measure the amount of various kinases in a biological sample — for example from a part of a tumour removed in surgery. “Our new method can correctly measure the amount of protein kinases in a sample. It means we can monitor cancer cell behaviour and also how tumours respond to different therapy in cancer patients,” added Dr Jørgensen.

source : http://www.sciencedaily.com/releases/2014/08/140826085853.htm

Finding keys to glioblastoma therapeutic resistance

“There is a growing interest to guide cancer therapy by sequencing the DNA of the cancer cell,” said Clark Chen, MD, PhD, vice-chairman of Research and Academic Development, UC San Diego Division of Neurosurgery and the principal investigator of the study. “Our study demonstrates that the sensitivity of glioblastoma to a drug is influenced not only by the content of its DNA sequences, but also by how the DNA sequences are organized and interpreted by the cell.”

The team of scientists, led by Chen, used a method called comparative gene signature analysis to study the genetic profiles of tumor specimens collected from approximately 900 glioblastoma patients. The method allows investigators to discriminate whether specific cellular processes are “turned on” or “turned off” in glioblastomas. “Our study showed that not all glioblastomas are the same. We were able to classify glioblastomas based on the type of cellular processes that the cancer cells used to drive tumor growth,” said Jie Li, PhD, senior postdoctoral researcher in the Center for Theoretical and Applied Neuro-Oncology at UC San Diego and co-first author of the paper.

One of these cellular processes involves Epidermal Growth Factor Receptor (EGFR). The study revealed that EGFR signaling is suppressed in a subset of glioblastomas. Importantly, this suppression is not the result of altered DNA sequences or mutations. Instead, EGFR is turned off as a result of how the DNA encoding the EGFR gene is organized in the cancer cell. This form of regulation is termed “epigenetic.” Because EGFR is turned off in these glioblastomas, they become insensitive to drugs designed to inhibit EGFR signaling.

“Our research suggests that the selection of appropriate therapies for our brain tumor patients will require a meaningful synthesis of genetic and epigenetic information derived from the cancer cell,” said co-first author Zachary J. Taich.

The paper’s abstract can be found at: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2350

source : http://www.sciencedaily.com/releases/2014/08/140825185321.htm