Combination therapy in neuroblastoma: It's all about the mix

The combination of two cell division inhibitors causes malignant nervous system tumors to die off, as scientists from the "Hopp Children's Cancer Center at the NCT Heidelberg" (KiTZ) have shown in experimental studies.The combination strategy could be the key to new targeted therapies against this aggressive type of tumor.

The Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ) is a joint institution of Heidelberg University Hospital and the German Cancer Research Center (DKFZ).

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Neuroblastoma is a childhood neoplasm of the nervous system whose cells remain immature. Neuroblastoma is relatively common in children: About every tenth malignant tumor in childhood is a neuroblastoma. However, only half of those affected can be successfully treated, albeit often with severe sequelae resulting from aggressive therapy. Novel individual treatment concepts that specifically target the tumor and spare the surrounding tissue are therefore urgently needed.

As part of their research on neuroblastomas, scientists from the DKFZ department "Pediatric Oncology" led by KiTZ director Professor Olaf Witt are exploring an enzyme family that is often associated with the development of neuroblastomas: The so-called HDAC enzymes (HDAC stands for histone deacetylase) can knock down genes in the genetic material of the nervous tissue and thereby induce uncontrolled cell division. Previous analyses have shown that an inhibitor of an enzyme from this family, the so-called HDAC8 inhibitor, can reduce uncontrolled tumor growth.

Using RNAi technology, a molecular biology method for silencing genes, the researchers have now been able to identify a second molecule for targeted therapy: Anaplastic lymphoma kinase (ALK) also plays an important role in tumor development – germ line mutations of the underlying ALK gene are the cause of most inheritable neuroblastomas. "We have found that the effects of the HDAC8 inhibitor and the ALK inhibitor crizotinib add up, and that the two compounds together are significantly more effective than the two inhibitors alone," said Ina Oehme, head of the scientific working group at KiTZ/DKFZ. With success. "In tissue cultures, this combination strategy not only stopped growth, but even induced programmed cell death in neuroblastoma cells," said Jing Shen, lead author of the study. "We hope that we will soon be able to transfer our experimental analyses to clinical trials," adds Oehme. "It will then be seen whether our strategy of combining two inhibitors of neuroblastoma development is successful."

Together with medical chemists from Halle and Freiburg as well as the DKFZ research group Cancer Drug Development headed by Aubry Miller and Nikolas Gunkel, the team is now working intensively on the development of a chemically stable HDAC8 inhibitor that would be suitable for use in clinical trials.

Original publication:
Shen et al. "A kinome-wide RNAi screen identifies ALK as a target to sensitize neuroblastoma cells for HDAC8-inhibitor treatment Cell Death & Differentiation. March,7th 2018, doi:10.1038/s41418-018-0080-0"

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