NCT Research

CCRP Pediatric

Summary

In November 2016, the Heidelberg University Hospital and the German Cancer Research Center (DKFZ) founded the Hopp Children’s Cancer Center at NCT-Heidelberg (short KiTZ). KiTZ is a therapy and research center for oncology and hematology in children and adolescents. It aims at translating promising research approaches into patient care - from diagnosis to treatment and follow-up care. At KiTZ, clinic and research will closely collaborate under one roof. Utilizing state of the art molecular diagnostics, clinicians and researchers strive to identify molecular targets for individualized therapies and thus improve the prognosis for children with relapsed/refractory/progressive malignancies. For this purpose novel Phase I/II clinical trials and individualized treatment concepts will be developed. KiTZ is the first center in Germany employing such an approach in pediatric oncology.

Pediatric
 

KiTZ is comprised of 3 pillars:
The KiTZ program „Clinical Pediatric Oncology” (headed by Prof. Dr. Andreas Kulozik) offers outpatient care, day-clinic and inpatient treatment to children suffering from cancer and serious hematologic diseases including stem cell transplantation. The program enrolls >95 percent of all newly diagnosed patients in national and international first-line therapy optimization trials.
 
The KiTZ program „Translational Pediatric Oncology” (headed by Prof. Dr. Olaf Witt) focuses on innovative, individualized treatments for children with malignancies. Novel research results are translated into early phase biomarker driven clinical trials, primarily for treatment of children that have exhausted standard established therapies.
 
The KiTZ program „Preclinical Pediatric Oncology” (headed by Prof. Dr. Stefan Pfister) combines several experimental research groups from the University Hospital Heidelberg and DKFZ. The program aims at developing innovative diagnostic methods for the classification of tumor diseases and uncovering mechanisms of tumorigenesis and tumor development to derive insights for novel therapeutic approaches.

Member designated as Contact Person

Prof. Dr. Kulozik
Clinical Program, KiTZ

 

Prof. Dr. Pfister
Preclinical Program, KiTZ

 
 

Members

Dr. Wolfgang Behnisch
Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), Heidelberg University Hospital

PD Dr. Johann Greil

Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), Heidelberg University Hospital          

Dr. David Jones               

Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), DKFZ


Prof. Dr. Andreas Kulozik, PhD

Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), Heidelberg University Hospital          

Dr. Joachim Kunz
Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), Heidelberg University Hospital          

PD Dr. Till Milde

Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), DKFZ/Heidelberg University Hospital

Prof. Dr. Martina Muckenthaler

Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), DKFZ/Heidelberg University Hospital

Prof. Dr. Stefan Pfister

Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), DKFZ/Heidelberg University Hospital


Dr. Cornelis van Tilburg

Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), DKFZ/Heidelberg University Hospital

PD Dr. Frank Westermann
Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), DKFZ


Prof. Dr. Olaf Witt
Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ), DKFZ/Heidelberg University Hospital



Internal Partner

PD Dr. Heidi Bächli
Pediatric Neurosurgery, Heidelberg University Hospital

PD Dr. Patrick Günther
Pediatric Surgery, Heidelberg University Hospital

Dr. Semi B. Harrabi

Radiooncology, Heidelberg University Hospital

Dr. Sabine Haufe
Nuclear Medicine, Heidelberg University Hospital

PD Dr. Burkhard Lehner
Orthopedics, Heidelberg University Hospital

Prof. Dr. Jens-Peter Schenk
Radiology/Pediatric Radiology, Heidelberg University Hospital

Prof. Dr. Peter Schirmacher
Pathology, Heidelberg University Hospital

Dr. Angelika Seitz
Pediatric Neuroradiology, Heidelberg University Hospital

Prof. Dr. Andreas von Deimling, Dr. Felix Sahm    
Neuropathology,, DKFZ/Heidelberg University Hospital

Department of Thoracic Surgery
, Heidelberg University Hospital

Scientific Goals

  • Create new diagnostic and therapeutic options for children with cancer
  • Develop new tumor classification systems on the basis of innovative diagnostics
  • Unravel mechanisms of tumorigenesis
  • Develop biomarker driven international combination early phase clinical trials
  • Phase I clinical trial center for innovative trials
  • Set up large scale pre-clinical drug screen program with pediatric tumor models    
  • Characterization of pathways and clone selection of T-ALL.


Aims Clinical Care

  • State of the art care for children suffering from cancer and serious hematologic diseases including stem cell transplantation
  • Offer first line treatment in cooperative group first line international (SIOP) and national (GPOH) clinical phase 3 trials.
  • Develop strategic partnerships with pharma industry and run industry initiated biomarker driven early phase clinical trials.
  • Develop individualized treatment concepts (molecularly informed personalized medicine)
  • Be an (inter)national reference center for molecular diagnostic and targeted therapy in pediatric cancer
  • Combination trials involving heavy ion therapy
  • Selt F, Hohloch J, Hielscher T, Sahm F, Capper D, Korshunov A, Usta D, Brabetz S, Ridinger J, Ecker J, Oehme I, Gronych J, Marquardt V, Pauck D, Bächli H, Stiles CD, von Deimling A, Remke M, Schuhmann MU, Pfister SM, Brummer T, Jones DT, Witt O, Milde T. Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing. Oncotarget. 2017 Feb 14;8(7):11460-11479.
  • Worst BC, van Tilburg CM, Balasubramanian GP, Fiesel P, Witt R, Freitag A, Boudalil M, Previti C, Wolf S, Schmidt S, Chotewutmontri S, Bewerunge-Hudler M, Schick M, Schlesner M, Hutter B, Taylor L, Borst T, Sutter C, Bartram CR, Milde T, Pfaff E, Kulozik AE, von Stackelberg A, Meisel R, Borkhardt A, Reinhardt D, Klusmann JH, Fleischhack G, Tippelt S, Dirksen U, Jürgens H, Kramm CM, von Bueren AO, Westermann F, Fischer M, Burkhardt B, Wößmann W, Nathrath M, Bielack SS, Frühwald MC, Fulda S, Klingebiel T, Koscielniak E, Schwab M, Tremmel R, Driever PH, Schulte JH, Brors B, von Deimling A, Lichter P, Eggert A, Capper D, Pfister SM, Jones DT, Witt O. Next-generation personalised medicine for high-risk paediatric cancer patients - The INFORM pilot study. Eur J Cancer. 2016 Sep;65:91-101. doi: 10.1016/j.ejca.2016.06.009. Epub 2016 Jul 29.
  • Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DT, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I, Ryzhova M, Koelsche C, Pfaff E, Allen SJ, Balasubramanian G, Worst BC, Pajtler KW, Brabetz S, Johann PD, Sahm F, Reimand J, Mackay A, Carvalho DM, Remke M, Phillips JJ, Perry A, Cowdrey C, Drissi R, Fouladi M, Giangaspero F, Łastowska M, Grajkowska W, Scheurlen W, Pietsch T, Hagel C, Gojo J, Lötsch D, Berger W, Slavc I, Haberler C, Jouvet A, Holm S, Hofer S, Prinz M, Keohane C, Fried I, Mawrin C, Scheie D, Mobley BC, Schniederjan MJ, Santi M, Buccoliero AM, Dahiya S, Kramm CM, von Bueren AO, von Hoff K, Rutkowski S, Herold-Mende C, Frühwald MC, Milde T, Hasselblatt M, Wesseling P, Rößler J, Schüller U, Ebinger M, Schittenhelm J, Frank S, Grobholz R, Vajtai I, Hans V, Schneppenheim R, Zitterbart K, Collins VP, Aronica E, Varlet P, Puget S, Dufour C, Grill J, Figarella-Branger D, Wolter M, Schuhmann MU, Shalaby T, Grotzer M, van Meter T, Monoranu CM, Felsberg J, Reifenberger G, Snuderl M, Forrester LA, Koster J, Versteeg R, Volckmann R, van Sluis P, Wolf S, Mikkelsen T, Gajjar A, Aldape K, Moore AS, Taylor MD, Jones C, Jabado N, Karajannis MA, Eils R, Schlesner M, Lichter P, von Deimling A, Pfister SM, Ellison DW, Korshunov A, Kool M. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell. 2016 Feb 25;164(5):1060-72. doi: 10.1016/j.cell.2016.01.015.
  • Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, Wani K, Tatevossian R, Punchihewa C, Johann P, Reimand J, Warnatz HJ, Ryzhova M, Mack S, Ramaswamy V, Capper D, Schweizer L, Sieber L, Wittmann A, Huang Z, van Sluis P, Volckmann R, Koster J, Versteeg R, Fults D, Toledano H, Avigad S, Hoffman LM, Donson AM, Foreman N, Hewer E, Zitterbart K, Gilbert M, Armstrong TS, Gupta N, Allen JC, Karajannis MA, Zagzag D, Hasselblatt M, Kulozik AE, Witt O, Collins VP, von Hoff K, Rutkowski S, Pietsch T, Bader G, Yaspo ML, von Deimling A, Lichter P, Taylor MD, Gilbertson R, Ellison DW, Aldape K, Korshunov A, Kool M, Pfister SM. Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell. 2015 May 11;27(5):728-43. doi: 10.1016/j.ccell.2015.04.002
  • The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis. Stockklausner C, Klotter AC, Dickemann N, Kuhlee IN, Duffert CM, Kerber C, Gehring NH, Kulozik AE. Blood. 2015 Feb 12;125(7):1159-69. doi: 10.1182/blood-2014-07-587170. Epub 2014 Dec 23.
  • Bender, S, Gronych, J, Wrnatz, HJ, et al. International Cancer Genome Consortium PedBrain Tumor Project. Recurrent MET fusion genes represent a drug target in pediatric glioblastoma. Nat Med. 2016 Nov;22(11):1314-1320.
  • Johann PD, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V, Jones DT, Sturm D, Hermann C, Segura Wang M, Korshunov A, Rhyzova M, Gröbner S, Brabetz S, Chavez L, Bens S, Gröschel S, Kratochwil F, Wittmann A, Sieber L, Geörg C, Wolf S, Beck K, Oyen F, Capper D, van Sluis P, Volckmann R, Koster J, Versteeg R, von Deimling A, Milde T, Witt O, Kulozik AE, Ebinger M, Shalaby T, Grotzer M, Sumerauer D, Zamecnik J, Mora J, Jabado N, Taylor MD, Huang A, Aronica E, Bertoni A, Radlwimmer B, Pietsch T, Schüller U, Schneppenheim R, Northcott PA, Korbel JO, Siebert R, Frühwald MC, Lichter P, Eils R, Gajjar A, Hasselblatt M, Pfister SM, Kool M. Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes. Cancer Cell. 2016 Mar 14;29(3):379-93.
  • Sturm D et al.: Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012
  • Jones DT et al: Dissecting the genomic complexity underlying medulloblastoma. Nature 2012, 488:100-5
  • Schwartzenstruber J. et al: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012, 482:226-31

Clinical Activities

Multidisciplinary patient management

  • thrice weekly interdisciplinary tumor boards including second opinion board
  • National and international INFORM Molecular Decision Tumor Board
  • Treatment embedded in GPOH/SIOP first line treatment protocols and ITCC early clinical trial structure
  • Diagnostic pipelines: INFORM registry, PTT2.0 and MNP 2.0


Specific Treatment Options

  • Whole spectrum of malignancies including pediatrics leukemias, pediatric brain tumors, pediatric embryonal and solid tumors.
  • Pediatric  personalized targeted therapy and molecular diagnostics
  • Immunotherapy and stem cell transplantation
  • Heavy Ion Therapy for children in collaboration with the Department of Radiooncology
  • Treatment in clinical phase I/II trials with targeted drugs and other therapeutic regimens (ZIPO) (off label, compassionate use)
  • Molecularly informed individual treatment concepts
  • Consultation and second opinion
  • International reference center for molecular diagnostic and targeted therapy
  • Founding of the Hopp Children’s Cancer Center at NCT Heidelberg (KiTZ) in 2016
  • Initiation of a Pediatric Personalized Oncology Program including specialized phase I/II unit (ZIPO) and compassionate use program
  • Approval by ITCC as a phase I/II trial center
  • Establishment of 3 international NGS diagnostic pipelines: INFORM registry (relapsed malignancies) (Worst et al., Eur J Cancer 2016), PTT 2.0 (pediatric malignancies) (Selt F., et al., Brain Pathol 2016) and MNP 2.0 (pediatric brain tumors at primary diagnosis). On a national level, more than 50% of all German pediatric oncology patients receive molecular diagnostics via our pipelines at some stage.
  • Preparation of an international phase 3 trial for pediatric LGG patients randomizing conventional chemotherapy against an oral MEK inhibitor. This is the first trial in pediatric neuro-oncology incorporating a targeted drug in first line treatment.
  • Preparation of 2 biomarker driven international phase I/II clinical trial with combinations of targeted drugs. Drug support for nivolumab (BMS) and crizotinib (Pfizer) secured. Drug support for a MEK inhibitor and HDAC inhibitor preliminary affirmed.
  • Initiation of several industry initiated early phase clinical trials providing access to experimental targeted drugs for pediatric oncology patients

Preclinical Activities

Established Technologies

  • Next Generation Sequencing technologies
  • Genetic and epigenetic characterization of large patient cohort samples
  • Drug target discovery and functional validation
  • Primary tissue culture and animal models
  • Establishment, characterization and in vivo preclinical testing of patient derived orthotopic xenograft models
  • Brain tumors: molecular subclassification identification impacting WHO classification of CNS tumors, medulloblastom subgroup classification system, chromotrypsis in medulloblastoma, H3F3 mutations in glioblastoma, molecular subgroups in PNETs, stem cell model and biomarkers in in ependymoma, oncogenic BRAF mutations in low grade astrocytomas, HDAC isoforms in medulloblastoma. PDX model development in pediatric brain tumors.
  • Unraveling molecular landscape and drivers of > 300 relapsed pediatric tumors (INFORM)
  • Neuroblastoma: Genetic and epigenetic drivers of tumorigenesis, CIMP phenotype, selective targeting of HDAC-isoforms, biomarkers and molecular mechanisms, development of HDAC8, 10 and HDAC11 selective inhibitors
  • T-ALL: Identification of activating NOTCH mutations, inactivation of TGF-ß signaling, activation of Pi3K/AKT
  • Osteosarcoma: Establishment of a novel orthotopic PDX tumor model, SAHA enhances heavy ion therapy efficacy