Posts Tagged ‘institute’

Better classification to improve treatments for breast cancer

Cancer arises due to genetic changes which cause normal cells to develop into tumors. As we learn more about breast cancer, we are seeing that it is not one single disease — the mutations in the genes that cause different cancers are not alike, and this is why tumors respond differently to treatment and grow at different rates. Currently, there are two key markers that clinicians use to predict response to treatments.

Spotting the trends in tumor genetics and creating a system to diagnose tumor types is a primary objective of cancer scientists. To this end, researchers at Cancer Research UK and the University of Cambridge have been developing the IntClust system, which uses genomic technology to create a classification system with enough detail to more accurately pinpoint which type of breast cancer a patient has, and therefore what treatment would be most appropriate.

To test the system, the scientists looked at the 997 tumor samples they had used to develop the system, and 7,544 samples from public databases, along with the genomic and clinical data including data from The Cancer Genome Atlas. They classified these using their IntClust system, and the two main systems in use today — PAM50, which groups cancers into five types, and SCMGENE, which classifies cancer into four.

They found that IntClust was at least as good at predicting patients’ prognosis and response to treatment as the existing system. But the system identified a previously unnoticed subgroup of tumors in just 3.1% of women with very poor survival rates, which appeared to be resistant to treatment. Identifying the genomic signatures for this group could flag up these high risk cancers early, and having the genomic data for these could aid in the investigation of new avenues for treatments for this type of cancer.

At present, using this system to classify tumors would be costly for most clinicians, and interpreting the results requires training that many clinical settings don’t have access to. But the detail and accuracy of this system could be of great use to breast cancer researchers, who will be able to investigate the reasons that certain groups of cancer respond better to certain treatments, in order to find clinical markers, or to identify new targets for breast cancer treatments.

Raza Ali, lead author from Cancer Research UK Cambridge Institute, says: “We have developed an expression-based method for classification of breast tumours into the IntClust subtypes. Our findings highlight the potential of this approach in the era of targeted therapies, and lay the foundation for the generation of a clinical test to assign tumors to IntClust subtypes.”

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Thunder God Vine, with assists by nanotechnology, could shake up future cancer treatment

Now a team of scientists, led by Prof. Taeghwan Hyeon at the Institute for Basic Science (IBS)/Seoul National University and Prof. Kam Man Hui at the National Cancer Center Singapore, has screened a library containing hundreds of natural products against a panel of HCC cells to search a better drug candidate. The screen uncovered a compound named triptolide, a traditional Chinese medicine isolated from the thunder god vine (Tripterygium wilfordii (Latin) or lei gong teng (Chinese)) which was found to be far more potent than current therapies. Studies from other researchers corroborate our findings as triptolide has also found to be very effective against several other malignant cancers including; pancreatic, neuroblastoma and cholangiocarcinoma. However this excitement was tempered when the drug was administered to mice as the increased potency was coupled with increased toxicity as well.

Maximizing potency, mitigating toxicity

Prof. Hyeon et al. endeavoured to alleviate the toxic burden by increasing the specific delivery of the drug to the tumor using a nanoformulation. The designed formulation was a pH-sensitive nanogel coated with the nucleotide precursor, folate. The researchers began by esterfying the polymer pluronic F127 with folate to make the coating material. They then polymerized β-benzyl-L-aspartate N-carboxy anhydride to make the core material pH-sensitive due to repulsive forces upon protonation under acidic conditions. “The combination of the two polymers forms a core/shell structured nanoparticle in water,” explains Prof. Hyeon. “We loaded triptolide into the hydrophobic core to produce a kind of drug-nanogel.”

A tumor model of folate-overexpressing HCC was then used to examine the effect of the nanogel formulation versus the free drug. As expected, the nanogel triptolide showed increased tumor accumulation and uptake into the tumor cells where the decreasing pH efficiently triggered release of the entrapped triptolide. The result was as hypothesized: In experiments on mice with HCC, the team found that its coated triptolide accumulated in the inflamed tumour tissues. Once there, the folate-targeted ligand enhances the HCC cells to take up the anticancer drug. Since the fluid inside tumour cells is more acidic (with a pH of around 6.8) compared to normal tissue (which has a pH of about 7.4), the drop in pH causes the coating to fall apart, and release the pure form of the triptolide, which then destroys the tumor cells, showing greater efficacy against the tumor and decrease the overall toxicity.

The mechanism of action of Nf-Trip-FR+ represents an auspicious therapeutic approach

While these initial proof-of-concept studies have been promising, many drugs fail to become an IND (Investigational New Drug); fewer still effectively replicate their results in human trials. However, a felicitous discovery occurred while the researchers were examining the mechanism of triptolide’s activity. Researchers at the National Cancer Center Singapore ran a profile on the effects triptolide had on protein expression in a variety of HCC cells. From this they learned triptolide primarily reduced the levels of two proteins, AURKA and CKS2, although the mechanism is still not known. The researchers then cross-checked these proteins against a clinical database of HCC patients and found an increased expression of these proteins correlates with the aggressiveness of the cancer. Thus it is hoped the negative effect triptolide has on these proteins could prove beneficial in terms of clinical outcomes when this drug finally becomes accepted for clinical studies in cancer patients.

The present work is detailed in ACS Nano.

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Cancer leaves common fingerprint on DNA

“Regardless of the type of solid tumor, the pattern of methylation is much different on the genomes of cancerous cells than in healthy cells,” says Andrew Feinberg, M.D., M.P.H., a professor of medicine, molecular biology and genetics, oncology, and biostatistics at the Johns Hopkins University School of Medicine. Feinberg led the new study along with Rafael Irizarry, Ph.D., a professor of biostatics at Harvard University and the Dana-Farber Cancer Institute. “These changes happen very early in tumor formation, and we think they enable tumor cells to adapt to changes in their environment and thrive by quickly turning their genes on or off,” Feinberg says.

Feinberg, along with Johns Hopkins University School of Medicine oncology professor Bert Vogelstein, M.D., first identified abnormal methylation in some cancers in 1983. Since then, Feinberg’s and other research groups have found other cancer-associated changes in epigenetic marks. But only recently, says Feinberg, did researchers gain the tools needed to find out just how widespread these changes are.

For their study, the research team took DNA samples from breast, colon, lung, thyroid and pancreas tumors, and from healthy tissue, and analyzed methylation patterns on the DNA. “All of the tumors had big blocks of DNA where the methylation was randomized in cancer, leading to loss of methylation over big chunks and gain of methylation in smaller regions,” says Winston Timp, Ph.D., an assistant professor of biomedical engineering at Johns Hopkins. “The changes arise early in cancer development, suggesting that they could conspire with genetic mutations to aid cancer development,” he says.

The overall effect, Feinberg says, appears to be that cancers can easily turn genes “on” or “off” as needed. For example, they often switch off genes that cause dangerous cells to self-destruct while switching on genes that are normally only used very early in development and that enable cancers to spread and invade healthy tissue. “They have a toolbox that their healthy neighbors lack, and that gives them a competitive advantage,” Feinberg says.

“These insights into the cancer epigenome could provide a foundation for development of early screening or preventive treatment for cancer,” Timp says, suggesting that the distinctive methylation “fingerprint” could potentially be used to tell early-stage cancers apart from other, harmless growths. Even better, he says, would be to find a way to prevent the transition to a cancerous fingerprint from happening at all.

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