Functional investigation of potential therapeutic target genes in 11q-deleted neuroblastomas

Neuroblastoma is a childhood tumor of the neural crest. One subgroup of neuroblastoma has a deletion of chromosome arm 11q; these tumors are difficult to treat with current therapies. Changes in the PI3K-pathway are seen in neuroblastoma, and many of the 11q-deleted genes are involved in PI3K-signaling.

Neuroblastoma is a childhood tumor of the neural crest. One subgroup of neuroblastoma has a deletion of chromosome arm 11q; these tumors are difficult to treat with current therapies. Changes in the PI3K-pathway are seen in neuroblastoma, and many of the 11q-deleted genes are involved in PI3K-signaling.

The first aim of this project is to functionally investigate candidate neuroblastoma tumor suppressor genes in the 11q-deletion region, to pinpoint possible specific treatment target genes. A secondary aim is to investigate the involvement of PI3K-signaling, especially p37δ, with genes important in neuroblastoma biology.

Previous research has shown that neuroblastomas have different subgroups; one subgroup is aggressive tumors without MYCN-amplification but with 11q-deletion. All genes in this region were screened for mutations and epigenetic changes in primary 11q-deleted neuroblastomas, but nothing could be detected, remaining is the possibility of haploinsufficiency, lower levels of these genes are sufficient for disease. We have seen that PI3K-signaling is important, albeit complicated, in neuroblastoma biology. The PI3K-isoform p37delta, discovered recently by us, have shown to have oncogenic properties, and is over expressed in neuroblastoma as well as in colorectal and ovarian cancer.
In this research project we repress 11q-genes in neuroblastoma cell lines with or without 11q-deletion, and in neuroblasts in the fruit fly embryo, followed by screens for cancer hallmarks. Many of the 11q candidate tumor suppressor genes affect the PI3K-pathway, and we will investigate this using both cell lines and fruit fly models. For future studies we plan to develop mouse models expressing promising neuroblastoma 11q tumor suppressor genes, possibly in combination of expression of p37δ.

Still no gene in the 11q-region has been proven to be a neuroblastoma tumor suppressor gene, and it is important to pinpoint specific target genes to be able develop new treatments. The urge for better understanding and treatment is great, and that is the main goal of this project.

Fruit flies

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Project in brief

Full name of project:
Functional investigation of potential therapeutic target genes in 11q-deleted neuroblastomas.

Durance: 2015-2020

Financed by: Barncancerfonden