Media Release

Researchers from Melbourne’s Peter MacCallum Cancer Centre have revealed a potential new treatment option for some women with the most lethal form of ovarian cancer, using a class of therapies already clinically approved to treat blood cancer.

Senior author of the study, Professor David Bowtell, says the findings, published this morning in Proceedings of the National Academy of Sciences, reveal that in a subset of women with high-grade serous carcinomas, the growth of their cancer is dependent on the activity of the BRCA1 gene.

‘In women with high-grade serous ovarian cancer, ten to 20 per cent of cases are driven by amplification of the Cyclin E1 gene, and about 20 per cent of patients have mutations that inactivate BRCA1 or BRCA2 genes — recently it has been shown that BRCA1 mutations and Cyclin E1 gene amplification rarely occur in the same patient.

‘By screening tens of thousands of genes, we found that cancers with Cyclin E1 amplification were particularly dependent on an in-tact BRCA1 gene — if the tumour has amplified Cyclin E1 and also mutation of BRCA1, then the cancer cells can not survive.’

Lead author, Dr Dariush Etemadmoghadam (pictured) says researchers sought to exploit the dependency of Cyclin E1 amplified cancers on BRCA1 to develop a new therapeutic approach for these tumours.

‘Recent research has shown a class of drugs known as proteasome inhibitors — approved to treat multiple myeloma in humans — are very effective at inhibiting the pathway involving BRCA1 and our laboratory experiments confirmed these drugs are effective for treating Cyclin E1 amplified tumours.

Professor Bowtell says there is great need for new therapeutic approaches for women whose ovarian cancer has Cyclin E1 amplification.

‘Women in this subset generally have poor response to standard treatment and reduced survival rates, so we are hopeful this new approach can be tested in a clinical trial in the near future.

‘We now know ovarian cancer is a very diverse disease, analogous to a Russian babushka doll — it looks like one doll until you take it apart and find layer after layer — but we’re confident when we have finally separated this cancer into all its molecular groups, we will have a much better chance of improving survival for all women.’

Source: beaker.sanfordburnham.org

A new study has revealed a rare cell type that gives rise to a type of brain cancer called medulloblastoma.

The unusual cells, called “nestin-expressing progenitors” (NEPs), are more efficient at generating medulloblastoma than other brain cells.

The research, published in Nature Neuroscience and conducted by Sanford-Burnham researchers in collaboration with scientists at Fox Chase Cancer Center, provides critical insight into how normal cells transform into tumors and may yield new approaches for targeting brain tumors. Medulloblastoma is an aggressive tumor that is located in the cerebellum, and accounts for 18 percent of all pediatric tumors.

Medulloblastoma is thought to arise during development of the cerebellum, from cells called granule neuron precursors (GNPs) that reside in the external granule layer (EGL) on the outside of the cerebellum.

Until now, most scientists believed that GNPs were the only cells that could give rise to medulloblastoma.

The study team, co-led by Robert Wechsler-Reya, Ph.D., of Sanford-Burnham, and Zeng-jie Yang, Ph.D, of Fox Chase Cancer Center, used genetically engineered mice to identify a new cell type in the EGL—NEPs. Like GNPs, NEPs are committed to generating granule neurons—very small neurons that make up 75 percent of all brain cells.

But unlike GNPs, NEPs have high levels of a protein called nestin, which is commonly found only in stem cells. The presence of nestin suggested that NEPs might be more primitive than GNPs, and like stem cells, more capable of long-term growth and survival.

“Another major difference between NEPs and GNPs is that the DNA repair mechanisms of NEPs are less active,” said Wechsler-Reya. “Since DNA repair protects cells from becoming cancerous, we speculated that NEPs might be more likely than GNPs to give rise to brain tumors.” To directly compare the tumor-forming ability of NEPs and GNPs, the researchers performed a series of transplantation experiments, using NEPs and GNPs carrying a cancer-causing mutation.

When they transplanted large numbers of cells, both NEPs and GNPs gave rise to tumors. But when they transplanted very few cells, GNPs did not cause tumors, whereas NEPs were still capable of doing so.

These results confirmed that NEPs have an increased capacity to form tumors. “Identifying the cells that can give rise to medulloblastoma allows us to compare tumor cells to their normal counterparts, so that key differences and vulnerabilities of tumor cells can be identified.

Our study describes a novel ‘tumor-prone’ cell population that may provide new insights into the mechanisms of cancer development. By studying these cells, we may find new approaches to targeting brain cancer,” Wechsler-Reya said. About Medulloblastoma Medulloblastoma is the most common malignant brain tumor, affecting about 500 children in the United States annually. Current treatment options for medulloblastoma include aggressive surgery, radiation, and chemotherapy.

Today, over two-thirds of children are successfully treated. However, survivors generally suffer long-term side effects such as cognitive and developmental disabilities due to the aggressive treatment, and in many cases the tumor reappears within a few years after treatment. Li P, Du F, Yuelling LW, Lin T, Muradimova RE, Tricarico R, Wang J, Enikolopov G, Bellacosa A, Wechsler-Reya RJ, & Yang ZJ (2013). A population of Nestin-expressing progenitors in the cerebellum exhibits increased tumorigenicity.