Clinical Cooperation Unit Molecular Hematology/Oncology – Research Projects
The Clinical Cooperation Unit Molecular Hematology/Oncology is a joined department between the German Cancer Research Center (DKFZ) and the Department of Internal Medicine V of the Heidelberg University Hospital with a translational and clinical research focus on Cancer of Unknown Primary (CUP). As a department involved in both research and treatment of CUP, we are committed to scientifically exploring the biology of the disease and linking research findings to patient care.
Our research activities therefore include basic, translational and clinical aspects of research on Cancer of Unknown Primary.
To advocate for the interests of patients and families impacted by CUP, we partner with patient advocates on a national and international level and encourage everyone interested to get in touch using the following links:
World CUP Alliance:
An international Alliance of all those patient advocates that are focused on improving diagnostics and treatments for all patients affected by CUP.
CUP Forum:
A German patient advocacy organization offering support and useful information for people affected by CUP.
CUP (Carcinoma of Unknown Primary)
Clinical Research
CUPISCO trial
To determine the efficacy and safety of molecularly targeted treatments or immunotherapy guided by genomic profiling, we conducted an international, randomized, multi-center phase II study (CUPISCO, NCT03498521; Krämer et al, Lancet, 2024). The trial was performed at 159 cancer centers in 34 countries and included 636 patients with newly diagnosed CUP syndrome, constituting the largest clinical trial ever conducted in patients with CUP. Following comprehensive genomic testing and randomization, trial participants gained access to targeted therapies and immunotherapy based on their unique tumor profiles. Molecularly guided treatments significantly improved survival, proving the efficacy of targeted therapies and immunotherapy in a tumor-agnostic setting. CUPISCO was the first Phase II trial to implement targeted treatments irrespective of the tumor tissue of origin, constituting a major milestone in precision oncology. Alongside with the recommendation for comprehensive molecular profiling in all patients with CUP, the final results of the CUPISCO trial led to refined diagnostic algorithms that were included into the ESMO Guidelines for the Diagnosis and Treatment of CUP.
Kaplan-Meier plot showing the progression-free survival of CUP patients treated with targeted and immunotherapy versus standard chemotherapy in the CUPISCO trial.
Krämer A, Bochtler T, Pauli C, Shiu KK, Cook N, Janoski de Menezes J, Pazo-Cid RA, Losa F, Robbrecht DGJ, Tomášek J, Arslan C, Özgüroğlu M, Stahl M, Bigot F, Kim SY, Naito Y, Italiano A, Chalabi N, Durán-Pacheco G, Michaud C, Scarato J, Thomas M, Ross JS, Moch H, Mileshkin L: Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study. Lancet 404: 527-539, 2024.
CheCUP trial
Our revious work has indicated the efficacy of immunotherapy in CUP: in a national, multicenter phase II trial (CheCUP trial, EudraCT 2018-004562-33), patients suffering from CUP syndrome relapsed or refractory after platinum-based chemotherapy were treated with immune checkpoint inhibitors using combined Ipilimumab and Nivolumab. High tumor mutational burden (TMB) emerged as a predictive biomarker of superior treatment response and survival, offering the option of immunotherapy to patients with tumors harboring this feature.
Kaplan-Meier plot showing the progression-free (left) and overall survival (right) of CUP patients with high versus low tumor mutational burden treated with immunotherapy in the CheCUP trial.
Pouyiourou M, Kraft BN, Wohlfromm T, Stahl M, Kubuschok B, Löffler H, Hacker UT, Hübner G, Weiss L, Bitzer M, Ernst T, Schütt P, Hielscher T, Delorme S, Kirchner M, Kazdal D, Ball M, Kluck K, Stenzinger A, Bochtler T, Krämer A: Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial. Nature Communications 14: 6761, 2023.
SACICUP trial
The SACICUP trial, a national, multicenter, randomized phase II trial, will determine the efficacy and safety of sacituzumab-govitecan – an antibody drug conjugate directed against the cell surface protein TROP2 – in patients suffering from CUP syndrome relapsed or refractory after platinum-based chemotherapy. The study is scheduled to start in early 2025 in several German centers.
Translational Research
Current translational research projects employ genome-wide DNA, RNA and methylation profiling of large cohorts of primary CUP tumor samples for the development of computational tools for tissue-of-origin identification.
Using multiplexed ion beam imaging (MIBI), a spatial omics strategy that allows for multiplexed in situ imaging of up to 40 antigens, we explore the interplay between tumor, tumor microenvironment and immune response to facilitate a detailed understanding of the mechanisms leading to early and aggressive metastasis on the one hand and absence of a primary tumor on the other hand in patients with CUP.
Using CUP patient-derived organoids, we perform in vitro drug screening and functional in-depth characterization of the role of different mutations and chromosomal instability for metastasis formation, clonal evolution and heterogeneity, with CUP syndrome serving as a paradigm disorder for metastatic malignancies.
Basic Research
Our basic research is focused on the causes and consequences of chromosomal instability (CIN), a hallmark of cancer cells that has been suggested to be a driving force of metastasis formation. Regarding the mechanisms leading to CIN, we are especially interested in the regulation of mitosis and its disturbance in the context of tumorigenesis. Since centrosomal aberrations have been shown to lead to mitotic aberrations and chromosomal instability, a long-standing focus of our group is centrosome biology and its interconnection to malignant transformation and metastasis. We have recently generated and in-depth characterized transgenic mice that overexpress the centriole replication protein STIL, in order to gain insights into the role of supernumerary centrosomes in CIN induction and subsequent tumor formation in vivo.
Extra centrosomes induced by STIL overexpression in transgenic mice cause chromosome missegregation and aneuploidy. Shown here is a multiplex fluorescence in situ hybridization (M-FISH) metaphase of a mouse embryonic fibroblast derived from CMV-STIL+/+ mice.
Moussa AT, Cosenza MR, Wohlfromm T, Brobeil K, Hill A, Patrizi A, Müller-Decker K, Holland-Letz T, Jauch A, Kraft B, Krämer A: STIL overexpression shortens lifespan and reduces tumor formation in mice. PLOS Genetics (in press), 2024.
To map the landscape of centrosome aberrations in primary tumor tissues at high resolution, we employ correlative light and electron microscopy (CLEM), focused ion beam scanning electron microscopy (FIB/SEM) and EM tomography with subsequent 3D reconstruction and quantitative analysis. Using these approaches we were able to demonstrate for the first time at nanoscale resolution that centriole over-elongation and the subsequent formation of gross structural centrosome aberrations frequently occur in primary human cells and seem to be associated with cell aging.
Segmented electron tomography image showing an over-elongated centriole (orange) with additional structural abnormalities in a plasma cell from human bone marrow.
Köhrer S, Dittrich T, Schorb M, Weinhold N, Haberbosch I, Börmel M, Pajor G, Goldschmidt H, Müller-Tidow C, Raab MS, John L, Seckinger A, Brobeil A, Dreger P, Tornóczky T, Pajor L, Hegenbart U, Schönland SO, Schwab Y, Krämer A: High-throughput electron tomography identifies centriole over-elongation as an early event in plasma cell disorders. Leukemia 37: 2468-2478, 2023. / Dittrich T, Köhrer S, Schorb M, Haberbosch I, Börmel M, Goldschmidt H, Müller-Tidow C, Raab MS, Hegenbart U, Schönland SO, Schwab Y, Krämer A: A high-throughput electron tomography workflow reveals over-elongated centrioles in relapsed-refractory multiple myeloma. Cell Reports Methods 2: 100322, 2022.
Translational Myeloma Research Group
© dkfz.de
Current treatment strategies against multiple myeloma are based on a combination of proteasome inhibitors, immune modulatory drugs, and monoclonal antibodies, as well as chemotherapy with autologous stem cell transplantation. Despite improved survival rates, long term remission or even cure is still rarely achieved. Personalizing tumor specific therapy is currently explored to improve the outcome of specific patient groups by correlating genomic, proteomic and clinical data of refractory myeloma patients. In order to understand mechanisms underlying drug resistance in multiple myeloma, we compare the evolution of the clonal structure of tumor cells along treatment in clinical trials and routine care with the aim to discover novel therapeutic targets in refractory disease. By combining NGS-based readouts (WGS, RNAseq, scRNAseq, scATACseq, CiteSeq) with proteome-based technologies we comprehensively map cellular signaling profiles in order to identify biomarkers as well as novel therapeutic targets. We further focus on tumor heterogeneity within individual multiple myeloma patients to understand the full spectrum of disease biology and specifically the role of residual tumor cells in clinical remission. Overall, our goal is to understand the complex processes underlying the heterogeneity of this disease. We aim to discover molecular mechanisms that lead to drug resistance, impairment of the immune microenvironment, and result in novel therapeutic targets. Due to our strong clinical affiliation with the University Hospital, we successfully translate our discoveries in clinical application.