Translational Oncology 

Overview

The Department of Translational Oncology coordinates all major aspects of creating and growing NCT and the translational research topics of DKFZ. The department’s research focuses on the genetic diagnosis and modification of stem cell populations in cancer and other genetic diseases. Cell biology work studies the hierarchy and genetic regulation of stem and progenitor cells in blood formation and the role and mechanism that drive self-renewal and metastases formation by their functional equivalents in solid cancer. Molecular work studies mutations in inherited and acquired genetic diseases, including cancer, and virus derived therapeutics to treat them.
As part of the translational cancer research process, physician scientists of the department contribute significantly to clinical research and patient care at NCT, and support diagnostic and therapeutic translation from DKFZ and HUMS into innovative clinical trials.
The research projects of the Department of Translational Oncology follow three major topic lines, with pronounced interactions between groups and topics in multiple international collaborations:

I. Applied Stem Cell Biology
II. Molecular Diagnosis and Therapy
III. Personalized Medicine

Research projects of the Applied Stem Cell Biology Section (Head: Hanno Glimm) characterize the function and the genetic modification of stem cells and the role of their functional equivalents for the development and progression of cancer. The group has extensive expertise in the isolation, genetic modification and functional evaluation of normal hematopoietic stem cells as well as solid tumor initiating cells. A junior group of Tumor Epigenetics (Heinz Linhart) investigates genome-wide DNA methylation in colon cancer for biomarker and target identification.
In Molecular Diagnosis, the Molecular and Gene Therapy Section (Head: Manfred Schmidt) has made fundamental contributions to innovative mutagenesis research in gene therapy and cancer. The work of this group has led the field internationally in important aspects of gene therapy, and has pioneered mechanistic investigations of vector integration using state-of-the-art high-throughput genomics and bioinformatics. Towards molecular therapy, the Max Eder group Virotherapy (Guy Ungerechts) develops novel cancer therapeutics based on measles virus (MV) vaccine. This targeted cancer therapy is being translated by preparing an early phase I clinical trial.
Personalized oncology of lymphoma is the main focus of the newly formed Section Lymphoma Research (Head: Thorsten Zenz) aiming to advance our understanding of genetic lesions in the pathogenesis of lymphoma subtypes and to exploit this knowledge therapeutically.
Driving the implementation of personalized oncology at NCT, the Department of Translational Oncology fuses the essential strategic goals of therapeutic development through clinical trials and cancer genetics based diagnostics into an overarching core strategy called the NCT Personalized Oncology Program (NCT POP). This program seeks to provide a complete analysis of molecular alterations in human cancers treated at NCT, thus allowing therapeutic stratification of all cancer patients according to specific molecular targets found in their individual tumors.

Significant accomplishments of the past 5 years

The Department of Translational Oncology has:

I. Applied Stem Cell Biology

• established a novel xenotransplantation model of human hematopoiesis, which helped to discover the functional heterogeneity of human hematopoietic stem cells as well as the role of human short-term repopulating cells (Blood 2006, 108:2121-3).
• extensively characterized the post-transplant biology of human short-term repopulating cells in vivo (Blood 2010, 115:5023-5; Blood 2005, 106:893-8).
• described an intrinsically fixed differentiation program of human short-term repopulating cells that changes during ontogeny (Stem Cells Dev 2009, 19:621-8).
• identified the role of single gene events in the pathogenesis of human myelodysplastic syndrome following MDS1/EVI1 gene activation (Nat Med 2010, 16:198-204).
• demonstrated that DNA methyltransferase 3b targets the same genes that are methylated in human colon cancer, thus suggesting a causal role of Dnmt3b in tumor associated DNA hypermethylation  (J Clin Invest 2011, 121(5):1748-52).
• showed that Dnmt3b overexpression promotes intestinal tumor formation by specific de novo methylation and transcriptional silencing of tumor suppressor genes, thus underlining the causal role of regional hypermethylation in tumor formation (Genes Dev 2007, 21:3110-22).

II. Molecular Diagnosis and Therapy

• invented and provided the mutation analysis and biosafety monitoring in multiple preclinical and clinical gene therapy studies using integrating vectors in international collaborations (Nature 2006, 1123; Cell 2006, 385-98; Nat Biotechnol 2006, 687-96; Nat Med 2006, 348-53; Nat Med 2006, 12:401-9; J Clin Invest 2007, 117:2225-32; J Clin Invest 2007, 117:2241-49; Nat Meth 2007, 4:1051-1057; N Engl J Med 2010, 363:1918-27; Nat Med 2009, 15:285-92; Hepatology 2011, 53:1696-707; Mol Ther 2011, 19:703-10; EMBO Mol Med 2011, 3:89-101).
• invented comprehensive genome wide retrieval of mutations and vector insertion sites with maximum genomic access by devising mathematical and computational models and practical approaches (Nat Med 2009, 15:1431-6; Nat Protoc 2010, 5:1379-95).
• demonstrated the safety of a lentiviral-mediated gene therapy trial that provided clinical benefit in patients with X-linked adrenoleukodystrophy (ALD) (Science 2009, 326:818-23).
• developed the first immunocompetent murine model for measles virus oncolysis studies (Mol Ther 2007, 15:1991-7) and demonstrated that microRNA targeting techniques can be exploited to regulate measles virus replication (Mol Ther 2011, 19:1097-106).
• performed the first successful approach of chemovirotherapy of chemo-resistant pancreatic cancer with armed and fully retargeted measles virus (Cancer Gene Ther 2011, 18:598-608).

III. Personalized Oncology

• showed the important clinical and biological role of p53 mutations in CLL. This can be exploited for genotype specific treatment approaches in CLL (J Clin Oncol 2010, 28:4473-9; Nature Reviews Cancer 2010, 10:37-50).
• showed how microRNA components of the p53 pathway may contribute to refractory CLL (Blood 2009, 114:2589-97; Blood 2011, 117:1622-32).
• developed an innovative approach to assess the performance of zinc finger nucleases (ZFN) in combination with integrase deficient lentiviral vectors (IDLV; D64V mutant) that will aid in the further development of genome editing applications in translational research (Nat Biotech 2011, accepted).
• became active partner in the International Cancer Genome Consortium (ICGC) (Nature 2010, 464:993-8).
  

10 most significant publications of the past 5 years

• Montini E, Cesana D, Schmidt M, Sanvito F, Ponzoni M, Bartholomae C, Sergi LS, Benedicenti F, Ambrosi A, Di Serio C, Dogliosi C, von Kalle C, Naldini L: Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol 2006, 24:687-96
• Ott M, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kühlcke K, Schilz A, Kunkel H, Naundorf S,.., von Kalle C, Seger R, Grez M: Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1/EVI1, PRDM16 or SETBP1. Nat Med 2006, 12:401-9
• Woods NB, Bottero V, Schmidt M, von Kalle C, Verma IM: Gene therapy: Is IL2RG oncogenic in T-cell development?: X-SCID transgene leukaemogenicity (reply). Nature 2006, 443:E6-7
• Schmidt M, Schwarzwaelder K, Bartholomae C, Zaoui K, Ball C, Pilz I, Braun S, Glimm H, von Kalle C: High-resolution insertion-site analysis by linear amplification-mediated PCR (LAM-PCR). Nat Methods 2007, 4:1051-7
• Ungerechts G, Springfeld C, Frenzke ME, Lampe J, Johnston PB, Parker WB, Sorscher EJ, Cattaneo R: Lymphoma chemovirotherapy: CD20-targeted and convertase-armed measles virus can synergize with fludarabine. Cancer Res 2007, 67:10939-47
• Gabriel R, Eckenberg R, Paruzynski A, Bartholomae CC, Nowrouzi A, Arens A, Howe SJ, Recchia A, Cattoglio C, ..., Glimm H, von Kalle C, Saurin W, Schmidt M: Comprehensive genomic access to vector integration in clinical gene therapy. Nat Med 2009, 15:1431-6
• Boztug K, Schmidt M, Schwarzer A, Banerjee PP, Avedillo Díez I, Dewey R, Böhm M, Ball CR, Nowrouzi A, Naundorf S, Kühlcke K, Blasczyk R, Kondratenko I, Maródi L, Orange JS, von Kalle C, Klein C: Correction of Wiskott-Aldrich Syndrome by Hematopoietic Stem Cell Gene Therapy. New Engl J Med 2010, 363:1918-27
• Paruzynski A, Arens A, Gabriel R, Bartholomae CC, Scholz S, Wang W, Wolf S, Glimm H, Schmidt M, von Kalle C: Genome-wide high-throughput integrome analyses by nrLAM-PCR and next-generation sequencing. Nat Protoc 2010, 5:1379-95
• Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, Schmidt M, Krämer A, Glimm H, ,.., von Kalle C, Grez M: Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 2010, 16:198
• Gabriel R, Lombardo A, Arens A, Miller JC, Genovese P, Kaeppel C, Nowrouzi A, Bartholomae CC, Wang J, Friedman G, Holmes MC, Gregory PD, Glimm H, Schmidt M, Naldini L, von Kalle, C. An unbiased genome-wide analysis of zinc-finger nuclease specificity. Nat Biotechnol 2011, 29:816-23.

Contact

Prof. Dr. Christof von Kalle
National Center for Tumor Diseases (NCT) Heidelberg  and
German Cancer Research Center (DKFZ)
Department of Translational Oncology
Section Molecular and Gene Therapy

Im Neuenheimer Feld 460
69120 Heidelberg

Tel: +49 6221 426990
Fax: +49 6221 429930
Email: christof.kalle@nct-heidelberg.de

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