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).
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.
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”
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.
The „Hopp Children’s Cancer Center at the NCT Heidelberg” (KiTZ)
The „Hopp Children’s Cancer Center at the NCT Heidelberg” (KiTZ) is a joint institution of the Heidelberg University Hospital and the German Cancer Research Center (DKFZ). As a therapy and research center for oncologic and hematologic diseases in children and adolescents, the KiTZ is committed to scientifically exploring the biology of childhood cancer and to closely linking promising research approaches with patient care– from diagnosis to treatment and aftercare. Children suffering from cancer, especially those with no established therapy options, are given an individual therapy plan in the KiTZ, which is created by interdisciplinary expert groups in so-called tumor boards. Many young patients can participate in clinical trials which ensures access to new therapy options. Thus, the KiTZ is a pioneering institution for transferring research knowledge from the laboratory to the clinic.