Department of Translational Medical Oncology

Understanding and targeting alterations in cancer

Unique alterations within tumor cells can be targets for novel treatment approaches. Scientists of the department for Translational Medical Oncology are working on identifying pivotal gene alterations and cellular subtypes that are responsible for initiating or fueling tumor growth and metastasis formation. Within individual patient tumors, a small fraction of all cells drives long-term tumor growth and metastases. Targeting this tumor-initiating cells (TIC) activity is essential to improve the long-term outcome in advanced solid cancers. The lab has developed and extensively characterized a bank of primary in vitro and in vivo models derived from solid patient tumors, e.g. CRC, PDAC and sarcomas. These functionally and genetically heterogeneous models are utilized to identify therapy relevant alterations and synthetic lethal interactions, e.g. by large scale shRNA knockdown or overexpression screening approaches. Following functional testing of potential therapeutic target alterations, targeted therapeutic strategies are developed and translated into the clinic.

The Glimm Lab, represented by the Department of Translational Medical Oncology in Dresden and the Translational Functional Cancer Genomics group in Heidelberg, welcomes researchers at both NCT partner sites to join their expertise in collaborating on these research questions.

NCT MASTER Registry trial for patients

In an interdisciplinary approach, new discoveries are directly transferred into treatment recommendations using the NCT/DKTK MASTER registry trial. The NCT MASTER (Molecularly Aided Stratification for Tumor Eradication) protocol consents young patients or patients with rare tumor diseases for molecular diagnostics approaches with the explicit purpose of evaluating and stratifying for the best molecular treatment strategy and enrolment in diagnostic and therapeutic clinical trials. The NCT MASTER is a joint NCT program between NCT Heidelberg and NCT/UCC Dresden. You can find more information about registering for the program here or download the brochure here.

Center for Personalized Oncology

The NCT/UCC Dresden Center for Personalized Oncology aims at translating latest research as well as innovative technologies and cancer therapies into clinical practice. A dedicated personalized oncology outpatient clinic provides consulting appointments to discuss innovative diagnostic approaches, results of genetic tumor profiling and molecularly guided treatment strategies. Clinical data and results of molecular analyses as well as potential therapeutic implications are discussed within a molecular tumor board participated by an interdisciplinary team of specialists in molecular diagnostics, targeted cancer therapy as well as involved clinical departments.

Non-coding RNAs (ncRNAs) are functional RNA molecules that are transcribed from DNA but not translated into proteins. Considering that only around 2% of the human transcriptome is translated, ncRNAs represent a huge proportion of the DNA encoded genetic information. Many ncRNA subspecies have been described, for instance microRNAs, small nucleolar RNAs or long non-coding RNAs (lncRNAs). They play pivotal roles in a plethora of cellular processes in development and diseases, including cancer, and can interact with nearly all cellular components.
By exploring various cancer entities and state-of-the art techniques, we want to demonstrate that non-coding RNAs can drive tumorigenesis and influence anti-cancer treatment response. In addition, we will explore their suitability to function as biomarkers for precision oncology based approaches.

RESEARCH AIMS

• Identification and characterization of cancer-driving ncRNAs
• Characterization of ncRNA-epigenome landscapes in various cancers
• Defining prognostic ncRNA scores for different targeted cancer therapies
• Exploring therapy resistance associated ncRNAs

The department closely collaborates with the Mildred-Scheel-Group “Biomedical Genomics”, headed by Dr. Anna Poetsch, exploring the possibilities of novel functional genomics and machine learning approaches to investigate DNA-damage response mechanisms in cancer.

2023

Wurm AA, Brilloff S, Kolovich S, et al. Signaling-induced systematic repression of miRNAs uncovers cancer vulnerabilities and targeted therapy sensitivity. Cell Rep Med. Published online September 12, 2023:101200. doi:10.1016/j.xcrm.2023.101200

Lauinger M, Christen D, Klar RFU, et al. BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability. Sci Adv. 2023;9(35):eade7486. doi:10.1126/sciadv.ade7486

Kerle I, Heining C. [Histology-agnostic tumor treatment - a farewell to tumor entities?]. Dtsch Med Wochenschr. 2023;148(18):1174-1181. doi:10.1055/a-1933-8141

Remde H, Schmidt-Pennington L, Reuter M, et al. Outcome of immunotherapy in adrenocortical carcinoma: a retrospective cohort study. Eur J Endocrinol. 2023;188(6):485-493. doi:10.1093/ejendo/lvad054

Martins LR, Glimm H, Scholl C. Single-cell RNA sequencing of mouse lower respiratory tract epithelial cells: A meta-analysis. Cells Dev. 2023;174:203847. doi:10.1016/j.cdev.2023.203847

Illert AL, Stenzinger A, Bitzer M, et al. The German Network for Personalized Medicine to enhance patient care and translational research. Nat Med. 2023;29(6):1298-1301. doi:10.1038/s41591-023-02354-z

Möhrmann L, Cuberi A, Brückmann S, et al. Response to (K)RASG12C and EGFR Inhibition in a Patient With NRASG12C-Mutated Rectal Cancer. JCO Precis Oncol. 2023;7:e2200666. doi:10.1200/PO.22.00666

Teleanu MV, Fuss CT, Paramasivam N, et al. Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling. Mol Oncol. Published online February 19, 2023. doi:10.1002/1878-0261.13398

Floerchinger A, Klein JE, Finkbeiner MSC, et al. A vector-encoded bispecific killer engager to harness virus-activated NK cells as anti-tumor effectors. Cell Death Dis. 2023;14(2):104. doi:10.1038/s41419-023-05624-3

2022
Hoffmeister-Wittmann P, Mock A, Nichetti F, et al. Bcl-xL as prognostic marker and potential therapeutic target in cholangiocarcinoma. Liver Int. 2022;42(12):2855-2870. doi:10.1111/liv.15392

Jahn A, Rump A, Widmann TJ, et al. Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers. Ann Oncol. 2022;33(11):1186-1199. doi:10.1016/j.annonc.2022.07.008

Rieke DT, de Bortoli T, Horak P, et al. Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards. BMC Med. 2022;20(1):367. doi:10.1186/s12916-022-02560-5

Heilig CE, Laßmann A, Mughal SS, et al. Gene expression-based prediction of pazopanib efficacy in sarcoma. Eur J Cancer. 2022;172:107-118. doi:10.1016/j.ejca.2022.05.025

Möhrmann L, Werner M, Oleś M, et al. Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity. Nat Commun. 2022;13(1):4485. doi:10.1038/s41467-022-31866-4

Dieter SM, Lovecchio D, Pataskar A, et al. Suppression of heparan sulfation re-sensitizes YAP1-driven melanoma to MAPK pathway inhibitors. Oncogene. 2022;41(32):3953-3968. doi:10.1038/s41388-022-02400-z

Heilig CE, Laßmann A, Mughal SS, et al. Gene expression-based prediction of pazopanib efficacy in sarcoma. Eur J Cancer. 2022;172:107-118. doi:10.1016/j.ejca.2022.05.025

Niger M, Nichetti F, Casadei-Gardini A, et al. MGMT inactivation as a new biomarker in patients with advanced biliary tract cancers. Mol Oncol. Published online May 27, 2022. doi:10.1002/1878-0261.13256

Schedel A, Friedrich UA, Morcos MNF, et al. Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma. Int J Mol Sci. 2022;23(9):5174. doi:10.3390/ijms23095174

Maurus K, Kosnopfel C, Kneitz H, et al. Cutaneous epithelioid haemangiomas show somatic mutations in the mitogen-activated protein kinase pathway. Br J Dermatol. 2022;186(3):553-563. doi:10.1111/bjd.20869

Veinalde R, Pidelaserra-Martí G, Moulin C, et al. Virotherapy combined with anti-PD-1 transiently reshapes the tumor immune environment and induces anti-tumor immunity in a preclinical PDAC model. Front Immunol. 2022;13:1096162. doi:10.3389/fimmu.2022.1096162

2021
Thomann S, Weiler SME, Wei T, et al. YAP-induced Ccl2 expression is associated with a switch in hepatic macrophage identity and vascular remodelling in liver cancer. Liver Int. 2021;41(12):3011-3023. doi:10.1111/liv.15048

Heilig CE, Horak P, Kreutzfeldt S, et al. Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial. ESMO Open. 2021;6(6):100310. doi:10.1016/j.esmoop.2021.100310

Horak P, Heining C, Kreutzfeldt S, et al. Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers. Cancer Discov. 2021;11(11):2780-2795. doi:10.1158/2159-8290.CD-21-0126

Herbst F, Lang TJL, Eckert ESP, et al. The balance between the intronic miR-342 and its host gene Evl determines hematopoietic cell fate decision. Leukemia. 2021;35(10):2948-2963. doi:10.1038/s41375-021-01267-5

Dieter SM, Siegl C, Codó PL, et al. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell Rep. 2021;36(3):109394. doi:10.1016/j.celrep.2021.109394

Vangala D, Ladigan S, Liffers ST, et al. Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models. Genome Med. 2021;13(1):116. doi:10.1186/s13073-021-00926-7

Koralli P, Tsikalakis S, Goulielmaki M, et al. Rational design of aqueous conjugated polymer nanoparticles as potential theranostic agents of breast cancer. Mater Chem Front. 2021;5(13):4950-4962. doi:10.1039/D1QM00479D

Simon M, Mughal SS, Horak P, et al. Deconvolution of sarcoma methylomes reveals varying degrees of immune cell infiltrates with association to genomic aberrations. J Transl Med. 2021;19(1):204. doi:10.1186/s12967-021-02858-7

Hanf D, Heining C, Laaber K, et al. Response to Cabozantinib Following Acquired Entrectinib Resistance in a Patient With ETV6-NTRK3 Fusion-Positive Carcinoma Harboring the NTRK3 G623R Solvent-Front Mutation. JCO Precision Oncology. 2021;(5):687-694. doi:10.1200/PO.20.00278

Wahjudi LW, Bernhardt S, Abnaof K, et al. Integrating proteomics into precision oncology. Int J Cancer. 2021;148(6):1438-1451. doi:10.1002/ijc.33301

Zowada MK, Tirier SM, Dieter SM, et al. Functional States in Tumor-Initiating Cell Differentiation in Human Colorectal Cancer. Cancers (Basel). 2021;13(5). doi:10.3390/cancers13051097

Koelsche C, Schrimpf D, Stichel D, et al. Sarcoma classification by DNA methylation profiling. Nat Commun. 2021;12(1):498. doi:10.1038/s41467-020-20603-4

Hlevnjak M, Schulze M, Elgaafary S, et al. CATCH: A Prospective Precision Oncology Trial in Metastatic Breast Cancer. JCO Precis Oncol. 2021;5:PO.20.00248. doi:10.1200/PO.20.00248

2020
Loosen SH, Gaisa NT, Schmeding M, et al. Prolonged Survival of a Patient with Advanced-Stage Combined Hepatocellular-Cholangiocarcinoma. Case Rep Gastroenterol. 2020;14(3):658-667. doi:10.1159/000511034

Thomann S, Weiler SME, Marquard S, et al. YAP orchestrates heterotypic endothelial cell communication via HGF/c-MET signaling in liver tumorigenesis. Cancer Res. Published online October 21, 2020. doi:10.1158/0008-5472.CAN-20-0242

Scherr AL, Mock A, Gdynia G, et al. Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer. Cell Death Dis. 2020;11(10):875. doi:10.1038/s41419-020-03092-7

Heilig CE, Horak P, Lipka DB, et al. Germline SDHB-inactivating mutation in gastric spindle cell sarcoma. Genes Chromosomes Cancer. 2020;59(10):601-608. doi:10.1002/gcc.22876

Laskin J, Liu SV, Tolba K, et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Annals of Oncology. Published online September 9, 2020. doi:10.1016/j.annonc.2020.08.2335

Cadranel J, Liu SV, Duruisseaux M, et al. Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series. Oncologist. Published online August 27, 2020. doi:10.1634/theoncologist.2020-0379

Westphalen BC, Bokemeyer C, Büttner R, et al. Conceptual framework for precision cancer medicine in Germany: Consensus statement of the Deutsche Krebshilfe working group “Molecular Diagnostics and Therapy.” Eur J Cancer. 2020;135:1-7. doi:10.1016/j.ejca.2020.04.019

Möhrmann L, Zowada MK, Strakerjahn H, et al. A Perivascular Niche in the Bone Marrow Hosts Quiescent and Proliferating Tumorigenic Colorectal Cancer Cells. Int J Cancer. Published online July 15, 2020. doi:10.1002/ijc.32933

Rippinger N, Fischer C, Haun MW, et al. Cancer surveillance and distress among adult pathogenic TP53 germline variant carriers in Germany: A multicenter feasibility and acceptance survey. Cancer. Published online June 18, 2020. doi:10.1002/cncr.33004

Messerschmidt C, Obermayer B, Klinghammer K, et al. Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC. Int J Cancer. Published online May 29, 2020. doi:10.1002/ijc.33123

Voronina N, Wong JKL, Hübschmann D, et al. The landscape of chromothripsis across adult cancer types. Nat Commun. 2020;11(1):2320. doi:10.1038/s41467-020-16134-7

Berger AK, Mughal SS, Allgäuer M, et al. Metastatic adult pancreatoblastoma: Multimodal treatment and molecular characterization of a very rare disease. Pancreatology. 2020;20(3):425-432. doi:10.1016/j.pan.2020.02.017

Horak P, Uhrig S, Witzel M, et al. Comprehensive genomic characterization of gene therapy-induced T-cell acute lymphoblastic leukemia. Leukemia. Published online March 3, 2020. doi:10.1038/s41375-020-0779-z

Stenzinger A, Endris V, Budczies J, et al. Harmonization and Standardization of Panel-Based Tumor Mutational Burden (TMB) Measurement: Real-World Results and Recommendations of the QuIP Study. J Thorac Oncol. Published online February 28, 2020. doi:10.1016/j.jtho.2020.01.023

Ronellenfitsch MW, Harter PN, Kirchner M, et al. Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors. J Clin Invest. Published online February 4, 2020. doi:10.1172/JCI130787

2019
Weber S, Koschade SE, Hoffmann CM, et al. The notch target gene HEYL modulates metastasis forming capacity of colorectal cancer patient-derived spheroid cells in vivo. BMC Cancer. 2019;19(1):1181. doi:10.1186/s12885-019-6396-4

Weinberg F, Griffin R, Fröhlich M, et al. Identification and characterization of a BRAF fusion oncoprotein with retained autoinhibitory domains. Oncogene. Published online September 26, 2019. doi:10.1038/s41388-019-1021-1

Tirier SM, Park J, Preußer F, et al. Pheno-seq - linking visual features and gene expression in 3D cell culture systems. Sci Rep. 2019;9(1):12367. doi:10.1038/s41598-019-48771-4

Glocker K, Ahlbrandt J, Knurr A, Horak P, Heining C, Ückert F. Finding Options Beyond Standard of Care in Oncology: A Proposal for Workflows Utilizing Knowledge Databases. Stud Health Technol Inform. 2019;264:950-953. doi:10.3233/SHTI190364

Mühlenberg T, Ketzer J, Heinrich MC, et al. KIT-dependent and -independent genomic heterogeneity of resistance in gastrointestinal stromal tumors - TORC1/2 inhibition as salvage strategy. Mol Cancer Ther. Published online July 15, 2019. doi:10.1158/1535-7163.MCT-18-1224

Haffa M, Lin T, Holowatyj AN, et al. Transcriptome profiling of adipose tissue reveals depot-specific metabolic alterations among colorectal cancer patients. J Clin Endocrinol Metab. Published online June 21, 2019. doi:10.1210/jc.2019-00461

Feuerbach L, Sieverling L, Deeg KI, et al. TelomereHunter - in silico estimation of telomere content and composition from cancer genomes. BMC Bioinformatics. 2019;20(1):272. doi:10.1186/s12859-019-2851-0

Leichsenring J, Horak P, Kreutzfeldt S, et al. Variant classification in precision oncology. Int J Cancer. Published online April 22, 2019. doi:10.1002/ijc.32358

Horak P, Weischenfeldt J, von Amsberg G, et al. Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance. Cold Spring Harb Mol Case Stud. 2019;5(2). doi:10.1101/mcs.a003657

Endris V, Buchhalter I, Allgäuer M, et al. Measurement of tumor mutational burden (TMB) in routine molecular diagnostics: in silico and real-life analysis of three larger gene panels. Int J Cancer. 2019;144(9):2303-2312. doi:10.1002/ijc.32002

Gröschel S, Hübschmann D, Raimondi F, et al. Defective homologous recombination DNA repair as therapeutic target in advanced chordoma. Nat Commun. 2019;10(1):1635. doi:10.1038/s41467-019-09633-9

Ehrenberg KR, Gao J, Oppel F, et al. Systematic Generation of Patient-Derived Tumor Models in Pancreatic Cancer. Cells. 2019;8(2). doi:10.3390/cells8020142

Wurm AA, Pina C. Long Non-coding RNAs as Functional and Structural Chromatin Modulators in Acute Myeloid Leukemia. Front Oncol. 2019;9:899. doi:10.3389/fonc.2019.00899

Mock A, Heilig CE, Kreutzfeldt S, et al. Community-driven development of a modified progression-free survival ratio for precision oncology. ESMO Open. 2019;4(6):e000583. doi:10.1136/esmoopen-2019-000583

Klose J, Trefz S, Wagner T, et al. Salinomycin: Anti-tumor activity in a pre-clinical colorectal cancer model. PLoS ONE. 2019;14(2):e0211916. doi:10.1371/journal.pone.0211916

2018
Lier A, Penzel R, Heining C, et al. Validating Comprehensive Next-Generation Sequencing Results for Precision Oncology: The NCT/DKTK Molecularly Aided Stratification for Tumor Eradication Research Experience. JCO Precis Oncol. 2018;2. doi:10.1200/PO.18.00171

Wünsche P, Eckert ESP, Holland-Letz T, et al. Mapping Active Gene-Regulatory Regions in Human Repopulating Long-Term HSCs. Cell Stem Cell. 2018;23(1):132-146.e9. doi:10.1016/j.stem.2018.06.003

Thomann S, Weiler S, Dittmer M, et al. Tumor stage-dependent transcriptomic signatures of endothelial cells reveal an intense paracrine crosstalk in liver capillarization. Cancer Res. 2018;78(13). doi:10.1158/1538-7445.AM2018-2050

Terziev D, Hutter B, Klink B, et al. Nivolumab maintenance after salvage autologous stem cell transplantation results in long-term remission in multiple relapsed primary CNS lymphoma. Eur J Haematol. 2018;101(1):115-118. doi:10.1111/ejh.13072

Bormann F, Rodriguez-Paredes M, Lasitschka F, et al. Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal adenomas and carcinomas. Cancer Res. 2018;78(13). doi:10.1158/1538-7445.AM2018-3305

Heining C, Horak P, Uhrig S, et al. NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer. Cancer Discov. 2018;8(9):1087-1095. doi:10.1158/2159-8290.CD-18-0036

Bormann F, Rodríguez-Paredes M, Lasitschka F, et al. Cell-of-Origin DNA Methylation Signatures Are Maintained during Colorectal Carcinogenesis. Cell Rep. 2018;23(11):3407-3418. doi:10.1016/j.celrep.2018.05.045

Speck T, Heidbuechel JPW, Veinalde R, et al. Targeted BiTE Expression by an Oncolytic Vector Augments Therapeutic Efficacy Against Solid Tumors. Clin Cancer Res. 2018;24(9):2128-2137. doi:10.1158/1078-0432.CCR-17-2651

Perera-Bel J, Hutter B, Heining C, et al. From somatic variants towards precision oncology: Evidence-driven reporting of treatment options in molecular tumor boards. Genome Med. 2018;10(1):18. doi:10.1186/s13073-018-0529-2

Martins LR, Bung RK, Koch S, et al. Stk33 is required for spermatid differentiation and male fertility in mice. Dev Biol. 2018;433(1):84-93. doi:10.1016/j.ydbio.2017.11.007

Chudasama P, Mughal SS, Sanders MA, et al. Integrative genomic and transcriptomic analysis of leiomyosarcoma. Nat Commun. 2018;9(1):144. doi:10.1038/s41467-017-02602-0