Clinical Cooperation Unit Molecular Hematology/Oncology

The Clinical Cooperation Unit Molecular Hematology/Oncology has a basic science focus on causes and consequences of chromosomal instability while its clinical/translational research centers around acute myeloid leukemia (AML) and carcinoma of unknown primary (CUP). Chromosomal instability is a nearly universal feature of human malignancies and a major contributor to genetic heterogeneity and clonal evolution, themselves being at the center of cancer development, progression, relapse and therapy resistance in both solid tumors and hematologic malignancies. One basic research topic focuses on how amplified centrosomes - the spindle pole organizers responsible for correct chromosome segregation during mitosis - lead to chromosomal instability. Also, mechanisms leading to chromothripsis, a single catastrophic event leading to chromosome fragmentation, and its impact on cancer cells is examined. Recent contributions of the Department include the finding that asymmetric centriole numbers at mitotic spindle poles cause chromosome missegregation via unequal kinetochore capture and the identification of chromothripsis as being responsible for marker chromosome formation and extremely poor prognosis in AML. Additionally, we have developed a small molecule compound that specifically inhibits mutant isocitrate dehydrogenase (mIDH1) in AML and identified molecular targets by next generation sequencing in CUP.

FUTURE OUTLOOK
After having elucidated mechanisms by which aberrant centrosomes cause chromosomal instability in vitro, we now explore whether amplified centrosomes cause tumor formation in a transgenic animal model in vivo. Also, we map the landscape of centromsome aberrations in primary tumor specimens using high resolution 3D electron microscopy and mass spectrometry approaches. Small molecule screens with subsequent mechanistic analyses are performed to identify drugs that specifically kill aneuploid tumor cells using complex karyotype AML as a model system. We have currently started an international phase I trial that explores the potential of our mIDH1 inhibitor in patients with mIDH1 AML. Regarding CUP, we will start a large international, randomized phase III trial, examining the role of mutation-based targeted treatments and immunotherapy compared to standard chemotherapy in 2018. Within this trial we will also explore whether chromosomal instability predicts for poor prognosis and lack of response to immune checkpoint inhibitor treatment and whether genomewide DNA methylation profiling is able to identify organs of origin in CUP.