Posts Tagged ‘national’

Drug used for DNA repair defects could treat leukemia, other cancers more effectively

The new study suggests that treatment with poly (ADP-ribose) polymerase (PARP) inhibitors, together with standard chemotherapy drugs, could be more effective in combating leukemia. In the same study, researchers found that the inactivation of RUNX genes causes DNA repair defects and promotes the development of leukemia and other cancers. The study was first published online in the leading journal Cell Reports last month.

Unlike other cancers which are more commonly seen in the elderly, leukemia is notorious for its high prevalence among young people. There has been little advancement in the treatment of leukemia. Chemotherapy with or without hematopoietic stem cell transplantation remains the current standard of care, resulting in a cure rate of around 50 per cent. The RUNX family genes are among the most frequently inactivated genes in leukemia and other cancers. According to previous studies, RUNX1 is one of the most frequently mutated genes in leukemia and RUNX3 is associated with the development of the disease.

In this study, the research team also showed the link between the RUNX family genes and the pathway of a rare human congenital disease called Fanconi anemia for the first time. The disease is caused by mutations in one of the 15 genes responsible for the repair of a specific type of damaged DNA. In the early stages of this study, the researchers found that RUNX deficiency resulted in an inability to produce blood cells and a massive expansion of abnormal hematopoietic cells. They recognised that these clinical manifestations are symptoms of Fanconi anemia and started investigating RUNX functions in this DNA repair pathway.

Further research showed that RUNX proteins play a critical and central role in the Fanconi anemia pathway by facilitating the recruitment of a protein involved in the repair of DNA damage called FANCD2 to sites of DNA damage. This previously unknown relationship between RUNX and Fanconi anemia prompted the research team to test the possibility that PARP inhibitors, a drug originally designed for killing a limited type of cancer cells with DNA repair defects, could be applied in the treatment of leukemia and cancers with RUNX alterations. These types of cancer were previously not thought to have DNA repair defects. The researchers demonstrated that the drug was effective in the treatment of leukemia and other cancers in cell culture experiments.

Dr Osato said, “Common sense is often a veil that keeps us from understanding the truth. PARP inhibitors have been with us for quite some time, but nobody has realised their application for leukemia. Our study has shed light on the possibility of a more effective treatment using a combined therapy with PARP inhibitors which can potentially be extended to other types of common cancers.”

The team is currently conducting further drug efficacy testing with xenograft models, as a preclinical study.

source : http://www.sciencedaily.com/releases/2014/08/140825084450.htm

Sequence of rare kidney cancer reveals unique alterations involving telomerase

The collaboration, a project of the National Institutes of Health’s Cancer Genome Atlas initiative, completed the sequence of chromophobe renal cell carcinoma and published the results today in the journal Cancer Cell.

“The Cancer Genome Atlas is a federally funded national effort that has already completed the sequence of many major types of cancer (breast, lung, ovarian, for example), but this project is now branching out to sequence more rare types of cancer,” said Dr. Chad Creighton, associate professor of medicine and a biostatistician in the NCI-designated Dan L. Duncan Cancer Center at Baylor and the lead and corresponding author on the report. “The idea is that with a better understanding of these more rare types of cancers, we gain new insight that might be relevant to how we study other types of cancer. The findings in this study are a perfect example of that.”

Chromophobe renal cell carcinoma is a rare type of kidney cancer, with approximately 2,000 new cases diagnosed each year in the United States. A majority of patients survive the disease.

Clinical impact

“Although most patients are reassured when the pathology of their kidney tumor comes back as chromophobe, we all have cared for patients who developed and died from metastatic chromophobe kidney cancers,” said Dr. Kimryn Rathmell, associate professor of hematology and oncology in the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and a co-senior author on the study. “This report is incredibly exciting for physicians who care for these patients because all of the treatment plans we have had to this point have been based on the biology of the more common kidney cancer type, as if chromophobe must be a close relative of that disease.”

The project shows with no uncertainty that chromophobe renal cell carcinoma represents a distinct cancer entity, and reveals exciting biology inherent to the disease that we hope in the future will allow new therapies to be developed specifically for the chromophobe type of kidney cancer, Rathmell said.

The team sequenced 66 tumor samples at Baylor’s Human Genome Sequencing Center. Other types of data were collected on these samples and integrated with the sequencing, including gene expression and epigenetic data. In addition to sequencing known genes, DNA from mitochondria and from the entire genome was also sequenced.

Chromosomes

A majority (86 percent) of the samples were missing one copy or a major part of chromosomes 1, 2, 6, 10, 13 and 17. Losses of chromosomes 3, 5, 8, 9, 11, 18 and 21 also were noted with significant frequencies (12 — 58 percent).

Chromosomes are the packaging of our DNA. Normally, each person receives a copy of each of 23 chromosomes from each parent for a total of 46.

When scientists looked for genes that were altered or missing, only two genes, TP53 and PTEN, were identified with a sizable frequency.

Extra step in analysis

The most surprising and significant finding came after the team took an “extra step” with their analysis, Creighton said.

“Instead of just looking specifically at the exome, we also analyzed the entire genome, something not typically done in these genomic studies,” said Creighton. The exome, the part of the genome used to make proteins, constitutes only 1 percent of the total genome, where the other 99 percent is often ignored in studies.

With whole exome analysis, scientists are just looking within the boundaries of known genes, to see which are broken and may have caused the disease, he explained.

“However, when you look outside of the genes, there is much more going on,” said Creighton. “For example, gene regulatory features of the genome can be altered.”

TERT promoter region

From whole genome analysis, the team observed a significant amount of structural rearrangements or breakpoints involving the promoter region of a gene called TERT, which encodes for the most important unit of the telomerase complex.

Telomerase represent the “clock” of the cell, Creighton said. “This plays a critical role in cell division, and with many cancer cells, telomerase levels are really high and time never really runs out, which allows the cell to never die. “

It was the promoter region, not the actual gene, that was affected, Creighton clarified. “Since there isn’t a breakdown in the actual gene, this malfunction is not picked up in whole exome analysis.”

The study also raised intriguing questions about the roles of mitochondrial DNA alterations and of the cell of origin involved in cancer initiation, the authors noted.

This could signify new approaches for how scientists should conduct molecular studies of cancer, he said. “We need to survey the regulatory regions for other cancer types as well.”

Data from all projects of The Cancer Genome Atlas are available for scientists around the world to study. “This effort has had a huge impact on how we study cancer as a whole,” said Creighton.

source : http://www.sciencedaily.com/releases/2014/08/140821124829.htm

Deletion predicts survival in advanced non-small cell lung cancer

The BIM protein can activate the programmed cell death also known as the apoptotic pathway in cells. BIM deletion has been detected in 12.8% of the Asian population but is very rarely observed in the Caucasian population. All NSCLC patients treated with any therapy, targeted or chemotherapeutic, ultimately fail their therapy but at varying times.

Researchers at the National Taiwan University Hospital examined the impact of BIM deletion on the survival outcomes of 204 advanced NSCLC patients treated with either EGFR TKIs or chemotherapy.

Results reported in the September issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer (IASLC), showed that BIM deletion was an independent predictive factor for shorter PFS in EGFR TKI treated patients (hazard ratio=2.15, p=0.002) with median PFS of 4.6 months in BIM deletion versus 8.6 months in wild type patients. Similar results were observed in chemotherapy treated patients with a hazard ratio of 2.4 (p=0.016) and median PFS of 3.5 and 5.6 months in deletion versus wild type, respectively. Overall survival was also independently predicted by BIM deletion (hazard ratio=1.65, p=0.039)

Dr. James Chih-Hsin Yang, senior author and member of IASLC, notes “our findings suggest the BIM deletion polymorphism should be considered as a clinical trial stratification factor when systemic treatment is considered in Asian NSCLC patients.” Dr. Yang also says “since little is known about whether anti-apoptotic agents are able to overcome the resistance to EGFR TKIs resulting from BIM deletion, it may be warranted to explore anti-apoptotic agents, such as obatoclax, in future clinical trials.”

source : http://www.sciencedaily.com/releases/2014/08/140823094342.htm