Local recurrences and distant metastases represent a major clinical challenge in the treatment of colorectal and pancreatic carcinoma (CRC; PDAC). The aim of this DKTK-wide research project was to introduce personalised strategies into the surgical treatment of GI-tumours by identifying pre-operative biomarkers for recurrence patterns. A comprehensive biobank of liquid and solid biopsies of patients with primary CRC (n=684) and PDAC (n=569) was established from April 2018 to August 2020 with joint efforts from all DKTK-sites by using matched standard operating protocols. Comprehensive clinical annotations and longitudinal sampling of these patients confer great value to the biobank for future translational and clinical research approaches aiming at identifying molecular biomarkers that predict the recurrence behaviour of GI tumours at an early stage.
PD Dr. Christoph Kahlert
Prof. Dr. Jürgen Weitz
Prof. Dr. med. Thilo Welsch
Evaluation of New Therapeutic Concepts in Relapsed AML
Many cancers respond well to the first therapy but weeks, months or even years later the tumor comes back and, in many cases, the patients die of it. These so-called relapses are caused by tumor cells that were resistant to the initial treatment.
The focus of this research project lies on a clinical study, the so-called RELAZA 2 study (headed by U. Platzbecker, partner site Dresden) focused on the treatment of one type of blood cancer, the acute myeloid leukemia (AML). As part of the study, physicians of the DKTK sites and their colleagues at collaborating hospitals treat patients who have been diagnosed with an early stage relapse with a novel chemotherapy. They hope to slow down the relapsed disease or even stop or prevent it with the new therapy. The study is accompanied by intense research through DKTK scientists to improve the early and precise detection and treatment of relapses in AML patients.
The working group headed by Christian Thiede and Karsten Spiekermann from Dresden and Munich sequences the patients’ cancer genomes. The technology can detect cancer genes that might be used for early diagnosis or for a prognosis if a patient will profit from a certain therapy or not. At the same time, Christian Brandts and his colleagues in Frankfurt analyze the proteins of these cancer cells to test if changes in the abundance or structure of individual or several proteins allow for an accurate and early diagnosis or prognosis. Under certain circumstances the identified proteins might also be used as target structures for novel therapies.
In Munich, Irmela Jeremias works with the patients’ AML biopsies to simulate the patients’ disease in animal models as precisely as possible. These advanced models are particularly well suited to test new therapies. In collaboration with Simone Fulda from Frankfurt they also test substances that cause cell death.
Furthermore, Justus Duyster and Cornelius Miething in Freiburg and Magdalena Götze in Munich conduct functional studies with AML cells as well as specialized AML cell subpopulations, the cancer stem cells. They aim to gain a better understanding of the development, relapse processes and therapy resistance in AML patients. To this end, the scientists turn off single genes of these cells in cell cultures and animal models using high throughput technologies. This way they can study the role of these genes in AML.
Apart from the cancer cells themselves, cells in the surrounding of the tumor are suspected to also play a role in the development of the disease and of relapses. They can “protect” cancer cells from the chemotherapy. Therefore, Claudia Baldus’ team in Berlin investigates how these cells differ in AML patients in comparison to healthy people and how the cells interact with the cancer cells. Discoveries from this functional study with cancer cells of AML patients shall be implemented into new therapeutic strategies such as the identification of novel target structure on cancer stem cells or in the tumor microenvironment.
Prof. Dr. Christian ThiedeMedizinische Klinik und Poliklinik I Universitätsklinikum Carl Gustav Carus an der TU Dresden
Prof. Dr. Karsten Spiekermann
Ga-PSMA-11 in high-risk prostate cancer
With 173 recruited and treated patients in 8 out of 11 participating centers the international D-A-CH multicenter PSMA-DKTK Trial (phases-I/-II) "[68Ga]Ga-PSMA-11 in high-risk prostate Cancer” completed for patient enrollment. Global end of study was submitted with date of 03-Jul-2020. Currently all central assessments are in progress, the reading phase is ongoing. This translational study can be recognized as master example and success story of an academically driven prospective multicenter clinical study within DKTK. Within the frame work of DKTK we started the clinical development of a new PET tracer within the early phases-I / –II, meaning the evaluation of the safety and efficiacy of the novel radiopharmaceutical [68Ga]Ga-PSMA-11 for the primary diagnosis of prostate cancer by means of noninvasive PET/CT and PET/MR imaging. The usage of PSMA-PET/CT imaging with involved fields Radiopharmacy / Nuclear Medicine / Urology / Pathology is one of its kind and is already being used internationally for directing the patient suffering from prostate cancer into the optimal state-of-the-art therapy regimen. Radiopharmaceutical industry covering the radiopharmaceutical drug development of theranostic radiotracers take notice of this trial. Corresponding industry is just starting to take over this new radiotracer for phase-III clinical trials to finally achieve marketing authorization of this new class of diagnostic PET imaging agent.
Prof. Dr. Frederik Giesel
Prof. Dr. Klaus Kopka
The ImmuNEO MASTER project represents a comprehensive immune analysis of a cross-entity tumor patient cohort included in the DKTK MASTER program. Multi-site sampling of tumor tissue and blood was performed and used for identification of tumor-specific antigens (neoantigens) as well as a comprehensive analysis of the immune microenvironment. We were able to identify neoantigen candidates in around 70% of patients by peptidomics. Flow cytometry and RNA sequencing data indicate that defined immune regulations are present independent of the tumor origin. Integrative analyses are currently ongoing with over 60 data sets to identify potential prospective biomarkers. The tools and results developed within this project will provide a basis for novel diagnostic and therapeutic purposes in cancer immunotherapy. In particular, our bioinformatics algorithms for identification of neoantigen candidates will set the path for novel clinical immunotherapy studies following the adoptive transfer of neoantigen-specific T cells as well as tumor-specific vaccination approaches.
Prof. Dr. Angela KrackhardtKlinikum rechts der Isar III. Medizinischen Klinik
Prof. Dr. Stephan Fröhling
Prof. Dr. Wilko Weichert
INFORM - INdividualized Therapy FOr Relapsed Malignancies in Childhood and Adolescence (now an established international registry study *)
Kindliche Krebserkrankungen können heute in etwa 75% der Fälle geheilt werden. Dies ist insbesondere der systematischen Entwicklung von Kombinationschemotherapien zu verdanken. Bei Kindern mit einem Rückfall (Krebsrezidiv) sind jedoch die Heilungschancen, mit wenigen Ausnahmen, sehr gering: Ihre Krebszellen sind resistent gegen die Chemotherapien geworden. Wissenschaftler haben in den letzten Jahren durch Krebsgenomsequenzierungen zunehmend molekulare Veränderungen bei Kinderkrebs identifizieren können. Dabei wurden zahlreiche neue krebsspezifische Moleküle entdeckt, die sich als Ziel für zielgerichtete Medikamente eignen. Solche Medikamente sind zum Teil für die Behandlung anderer Krebsarten bereits zugelassen oder befinden sich noch in der Entwicklung, werden aber bisher nicht für kindliche Tumorrezidive eingesetzt. Hierfür müssten die für jeden kleinen Patienten charakteristischen molekularen Veränderungen der Krebszellen zunächst bestimmt werden.
Mit INFORM („INdividualized Therapy FOr Relapsed Malignancies in Childhood and Adolescents“) soll ein innovativer klinischer Prozess etabliert werden, der Tumorzellen von Kindern mit Krebsrezidiven untersucht, um im Falle entsprechender molekularer Veränderungen eine maßgeschneiderte Behandlungsstrategie anbieten zu können. Dies erfordert die Entnahme einer Tumor- und einer Blutprobe, deren Aufarbeitung, verschiedene Sequenzierungsmethoden mit anschließender Computerauswertung der komplexen Daten zur Bestimmung der individuellen molekularen Veränderungen der Krebszellen und der Erstellung einer personalisierten Behandlungsempfehlung. Bei INFORM engagieren sich Experten für 11 verschiedene Kinderkrebsarten, wie Hirntumoren, Blutkrebs und Knochenkrebs. In einer ersten Phase, der Registerstudie, werden die oben genannten Abläufe deutschlandweit unter Beteiligung aller Kinderkrebszentren etabliert. Die Sequenzierungen erfolgen an einem Standort und damit in einheitlichen Prozessen. Die Ärzte und Wissenschaftler wollen damit die erforderlichen standardisierten Prozesse mit möglichst kurzer Umlaufzeit etablieren. In der zweiten Phase, der klinischen Studie, nutzen die Kinderonkologen diese Abläufe der Molekulardiagnostik, um Kinder mit Krebsrezidiven deutschlandweit maßgeschneiderte Therapien soweit es geht zu ermöglichen. Diese neuen Behandlungsverfahren werden von Wissenschaftlern begleitet, die untersuchen werden, wie genau die Krebszellen der Patienten auf die verschiedenen Medikamente ansprechen. Eine einmalige Chance, um die Therapie von Krebs bei Kindern weiter zu verbessern.
Prof. Dr. Angelika Eggert
Prof. Dr. Olaf WittDeutsches Krebsforschungszentrum Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), University Hospital Heidelberg
Prof. Dr. Peter Lichter
Prof. Dr. Stefan Pfister
The clinical 'IvacALL' study is currently investigating the effectiveness of tumour vaccines in children suffering from leukaemia. Relapses after chemo or stem cell therapy are a major problem. Here, customized vaccines open up new treatment options: Children's immune systems are able to recognize the protein changes in tumour cells and to fight them. Therapeutic vaccines using altered protein fragments, or peptides can direct immune cells specifically to the tumour.
As a first step the DNA of both the patient's tumour and their normal healthy tissue extensively analyzed in order to identify the cancer-specific alterations. Following on from that, each patient is vaccinated with a personalized peptide cocktail. The tumour database, which was developed in the course of the study forms the basis of improved treatment options for children in the long-term. The technical progress in genome sequencing in recent years has made these large datasets available for individual therapies.
Prof. Dr. Hans-Georg Rammensee
Prof. Dr. Peter LangUniversitätsklinik Tübingen Klinik für Kinder- und Jugendmedizin, Abteilung I
Prof. Dr. Stefan Pfister
Molecular Diagnostics for Pediatric Cancers
Cancer is the second most common cause of death in children in Germany, after road accidents. In many cases, young cancer patients cannot be cured or suffer from complications as a result of the intensive treatment they receive. There is therefore a need for new cancer therapies to be developed. One problem is that children suffer from a wide range of different types of cancer, but each type occurs only rarely. Until now, this has made it difficult to develop new treatments. Thanks to cutting-edge technology, including next-generation sequencing, physicians and researchers can now sequence the genetic makeup of a patient’s cancer cells (cancer genome sequencing). This paves the way for targeted cancer treatment. The first step is molecular diagnostics – identifying the characteristic individual changes (mutations) in the cancer genome for each young patient. The idea is that in future, physicians will be able to use the mutations in the cancer genome to draw up a specific treatment plan for each child. The advantage of this precision oncology in children, is that their cancer cells often present fewer mutations than those found in adults. This makes it easier to identify the mutations that drive the cancer’s growth and which present suitable targets for cancer treatment.
The seven DKTK sites involved in this collaborative project are setting up a network of children’s cancer centers that will offer their patients cancer genome sequencing. The participating researchers will start by looking for characteristic genome mutations in different types of childhood cancer. This requires collaboration between the university hospitals within the DKTK – in order to obtain enough cases of rare cancers to enable them to draw meaningful conclusions. The cancer genomes of patients at all the participating centers will be sequenced using DKTK-wide standardized processes. Specialists at the various sites will then evaluate the results. For instance, samples of childhood liver tumors will be evaluated in Munich, while retinal tumors will be evaluated in Essen. The researchers and pediatric oncologists are particularly interested in the possibility this will open up for a joint analysis of all the different types of childhood cancer. They want to identify mutations that may occur infrequently in individual types of cancer but which play a role in a number of different cancers. The researchers are hopeful that they will then be able to offer young patients new therapies, or that they will be able to predict which established treatment is most likely to be successful.
An additional knowledge gain from this project is that the researchers can identify hereditary gene defects that trigger the onset of cancer in children. In future, physicians will use evidence of such hereditary genome mutations to improve preventive strategies and start treatment earlier, thereby increasing the likelihood of success.
Berlin, Essen/Düsseldorf, Frankfurt/Mainz, Freiburg, Heidelberg, München, Tübingen
Prof. Dr. Peter Lichter
Prof. Dr. Stefan Pfister
Prostate cancer is one of the most common types of cancer in men. By the time it becomes noticeable, it is often so far advanced that a cure is no longer possible. Scientists hope to use a cancer vaccination to activate the patients’ immune system so that it targets and attacks the cancer. They inject the cancer patients with peptides from proteins that occur in particularly high quantities – or exclusively – in cancer cells, together with immunostimulants. Like vaccinations against childhood diseases, where the immune system is stimulated against virus proteins, for example, the idea here is that the immune system will recognize the cancer cells and destroy them. However, if cancer cells are produced that no longer contain the target protein, the tumor may grow again.
The DKTK scientists working on this project are therefore pursuing a strategy of multi-peptide vaccination. The aim is to activate the immune system against a number of different cancer proteins. If this is successful, tumor cells will no longer be able to escape destruction by the immune system so easily. A previous trial produced the desired activation of the immune system and there were indications that it was having an impact on the tumors. However, that trial involved patients with selected immune characteristics. Motivated by the results, the scientists are now looking for a broad spectrum of peptides for a vaccine cocktail with maximum effectiveness that can be used in all prostate cancer patients. In addition, modern infrastructure and processes are being developed to produce the peptides. Because of the legal requirements, the manufacturing process has to meet extremely high purity and quality standards. Between them, the participating centers have the necessary scientific, technical and administrative expertise. The resulting multi-peptide vaccine is to be offered to prostate cancer patients as part of a DKTK trial (MultiPro).
Prof. Dr. Hans-Georg Rammensee
Next Generation Molecular Diagnostics of Malignant Gliomas
Malignant gliomas are the most common tumors in the brain and are extremely difficult to treat. New research has found evidence of numerous genetic changes in glioma cells. A thorough analysis of these complex changes has enabled scientists to identify tumor subtypes that share the same molecular characteristics. These molecular characteristics can in turn be used to improve diagnosis and the prognosis accuracy and help predict the individual patient’s response to particular types of treatment.
In this collaborative project, the DKTK scientists are establishing new diagnostic methods for malignant gliomas based on molecular markers. These methods are intended to help offer patients personalized treatment plans that present the best chances of success for their molecular tumor subtype. To start with, the scientists are investigating how molecular changes and the associated tumor subtypes have influenced treatment outcomes for glioma patients in the past. For this study they have access to well-documented courses of treatment and tumor samples from large numbers of patients who have previously been treated at the participating university hospitals with the currently available forms of treatment: surgery, radiotherapy and chemotherapy. The patients had given their consent for data relating to the outcome of their treatment and biopsy samples from their tumors to be used for research – for the benefit of future cancer patients. The tumor biopsies are analyzed using a range of high-throughput methods (e.g. genome and transcriptome sequencing, and candidate gene analysis) to identify genetic and epigenetic changes in the tumor cells, i.e. in the cancer genome, and deviations in protein composition in the cancer cells. In addition, the experts analyze epigenetic changes that determine how strongly a gene is expressed. They then correlate the new or known molecular changes they have identified with the course of the disease and with the treatment outcome. In the future, oncologists will be able to use these findings to offer their glioma patients the best treatment for their molecular subtype. The plan is for the DKTK physicians and scientists to offer these new diagnostic methods and associated treatments in controlled clinical trials to start with, to validate their findings. For this purpose, they are already developing and installing new infrastructure and the DKTK-wide standardized processes necessary for taking tissue samples, carrying out routine sequencing and diagnosis and making treatment decisions in clinical practice.
Prof. Dr. Gudio Reifenberger
NonCoMs in Cancer Genomes
Genetic tumor analyses have so far focused on mutations that lead to altered proteins. They are often considered to be the trigger for malignant tumors. The project "Identifying and understanding non-coding mutations in cancer genomes" went an important step further and traced so-called non-coding mutations in cancer cells that do not lead to altered proteins but are located in regions that alter the activity of important cancer genes. Investigations were carried out specifically on tumors of the skin (melanomas) and brain (glioblastomas). Regarding melanomas, a special focus was put on the importance of non-coding mutations in the regulatory regions of the genes TERT and DPH3/OXNAD1. For both genes it was found that the non-coding mutations promote tumor development and can therefore be called "oncogenic" mutations. For gliomas, the oncogenic significance of the non-coding TERT mutations could also be clearly demonstrated. Furthermore, we analyzed deep whole genome sequencing data of a set of oligodendroglioma sample pairs, obtained from primary and matched relapsed samples, with evolutionary models of tumor growth. This study revealed a composition of tumor cell subpopulations, suggestive of ongoing selection of malignant subclones during tumor growth in most cases. We frequently identified distinct predominant subclones under positive selection in primary and recurrent tumors. Ongoing work is directed at estimating the selective advantage conferred by the associated driver mutations.
Prof. Dr. Alfred Nordheim
Prof. Dr. Dirk Schadendorf
Prof. Dr. Peter Lichter
Novel Tools for Functional Analysis of Oncogenic Pathways
Scientists need novel technologies to discover and test oncogenic pathways for different types of cancer. Thanks to high throughput technologies such as “Deep Sequencing” more and more signaling proteins of these pathways can be identified. A crucial limiting factor for understanding the biology of cancers and for developing targeted cancer drugs, however, is the limited knowledge what function the identified signaling proteins have. Quicker and more efficient tools to validate the respective cancer genes on the organismal level are therefore needed.
In this joint funding project is a collaboration of scientists from the DKTK research program “Oncogenic Pathways” and the DKTK research platform “Preclinical Models” located at all partner sites. They aim to establish methods that effectively and reliably inactivate signaling proteins by using high throughput technologies. For that to happen, certain genes are being silenced through molecular-genetic processes such as RNA-interference or CRISPR nucleases. With high throughput technologies hundreds of genes of a certain signaling pathway can be blocked – one gene per petri-dish. If the tumor cells in one petri-dish lose their tumor characteristics, the researchers know that they need to follow up on the relationship between this knocked-out gene or signaling protein and its function. The technology is utilized for different key themes in the research program (cell growth and cell differentiation, tumor microenvironment, apoptosis and epigenetics) as well as various tumor entities. Different two and three dimensional cell cultures as well as mouse tumor models are being used.
As part of the Joint Funding Project, scientists under guidance of Clemens Schmitt, Berlin, will build up a small RNA-interference library to analyze the regulation of tumor suppressors in lymphomas. Specific signaling proteins shall be identified which could be clinically relevant as pharmacological target structures. Additionally, scientists of the Joint Funding Project guided by Roland Rad and Roland Schmid, both Munich, will develop so-called genome editing technologies. These technologies can specifically turn off the genes belonging to identified signaling proteins in animal models or edit in certain variations. The observed impact on cancer development and metastasizing provide important information on the activity of individual signaling proteins and their suitability in diagnostics and therapy. Scientists headed by Cornelius Miething, Freiburg, will implement an RNA-interference library for key enzymes in cellular signal processing, the so-called kinases (>800 genes), phosphatases (>200 genes), peptidases (>400 genes) as well as peptidase inhibitors (>180 genes). To establish relevant animal models, the project closely collaborates with the Helmholtz-Alliance “Preclinical Comprehensive Cancer Center (PCCC)” which is headed by the Heidelberg DKTK scientist Hellmut Augustin.
Prof. Dr. Christoph Peters
Dr. Cornelius Miething
Prof. Dr. Roland Schmid
Overcoming therapy resistance in pancreatic cancers
Pancreatic cancer (PDAC) is one of the most aggressive cancers with a dismal prognosis; effective treatment options are desperately needed. In this Joint Funding Project, DKTK experts have joined forces to rationally develop effective combination therapies against pancreatic cancer by exploring the molecular mechanisms behind the development of therapy resistance in cancer cells. The consortium identified several new mechanisms responsible for the large heterogeneity observed in pancreatic cancer. This included e.g. the discovery of Ras gene dosage variation as a fundamental determinant of pancreatic cancer biology (Mueller et al., 2018 Nature) by human and mouse studies. Additionally, researchers from the team defined two differently aggressive molecular subtypes of PDAC providing the insight that in the more aggressive group of tumors a phenomenon known as "viral mimicry" leads to a cancer-promoting inflammatory reaction (Espinet et al., 2020 Cancer Discov). In another approach, members of the consortium have developed an innovative epigenetic targeting strategy based on dual BET/HDAC inhibitors and showed its potency as a novel chromatin‐targeting approach for future clinical development for treatment of PDAC (Zhang et al., 2020 Int J Cancer).
(1) Espinet, E., Gu, Z., Imbusch, C.D., Giese, N.A., Buscher, M., Safavi, M., Weisenburger, S., Klein, C., Vogel, V., Falcone, M., Insua-Rodriguez, J., Reitberger, M., Thiel, V., Kossi, S.O., Muckenhuber, A., Sarai, K., Lee, A.Y., Backx, E., Zarei, S., Gaida, M.M., Rodriguez-Paredes, M., Donato, E., Yen, H.Y., Eils, R., Schlesner, M., Pfarr, N., Hackert, T., Plass, C., Brors, B., Steiger, K., Weichenhan, D., Arda, H.E., Rooman, I., Kopp, J.L., Strobel, O., Weichert, W., Sprick, M.R., & Trumpp, A. (2020). Aggressive PDACs show hypomethylation of repetitive elements and the execution of an intrinsic IFN program linked to a ductal cell-of-origin. Cancer Discov. doi: http://dx.doi.org/10.1158/2159-8290.CD-20-1202
(2) Zhang, X., Zegar, T., Weiser, T., Hamdan, F.H., Berger, B.T., Lucas, R., Balourdas, D.I., Ladigan, S., Cheung, P.F., Liffers, S.T., Trajkovic-Arsic, M., Scheffler, B., Joerger, A.C., Hahn, S.A., Johnsen, S.A., Knapp, S., & Siveke, J.T. (2020). Characterization of a dual BET/HDAC inhibitor for treatment of pancreatic ductal adenocarcinoma. Int J Cancer, 147(10), 2847-2861. doi: http://dx.doi.org/10.1002/ijc.33137
(3) Mueller, S., Engleitner, T., Maresch, R., Zukowska, M., Lange, S., Kaltenbacher, T., Konukiewitz, B., Ollinger, R., Zwiebel, M., Strong, A., Yen, H.Y., Banerjee, R., Louzada, S., Fu, B., Seidler, B., Gotzfried, J., Schuck, K., Hassan, Z., Arbeiter, A., Schonhuber, N., Klein, S., Veltkamp, C., Friedrich, M., Rad, L., Barenboim, M., Ziegenhain, C., Hess, J., Dovey, O.M., Eser, S., Parekh, S., Constantino-Casas, F., de la Rosa, J., Sierra, M.I., Fraga, M., Mayerle, J., Kloppel, G., Cadinanos, J., Liu, P., Vassiliou, G., Weichert, W., Steiger, K., Enard, W., Schmid, R.M., Yang, F., Unger, K., Schneider, G., Varela, I., Bradley, A., Saur, D., & Rad, R. (2018). Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature, 554(7690), 62-68. doi: http://dx.doi.org/10.1038/nature25459
Prof. Dr. Andreas Trumpp
Prof. Dr. Jens Siveke
Prof. Dr. Roland Rad
Prof. Dr. Ulrich Keilholz
The DKTK project “PARADIGM” investigates the interaction between radio- and immunotherapy in the treatment of patients with metastatic melanoma. In the multicenter clinical study “IRINA” patients with metastatic melanoma will be randomized to perceive either immunotherapy only or in combination with radiation treatment. Increasing reports of cancer patients have shown that radiotherapy can also affect tumors outside the irradiated area – the so-called abscopal effect. This effect might result from radiation-induced activation of the patients’ immune system to attack cancer cells.
The interdisciplinary DKTK team will analyze the patients’ tumors and blood in order to shed light on how radiotherapy induces anti-tumor immunity. The researchers aim to boost the anti-tumor activity in patients by combining radiotherapy with a specific immunotherapy approach - blocking the tumors’ defense mechanisms against an immune attack. Furthermore, the team searches for biomarkers, molecular profiles to identify patients that are most likely to benefit from this new combination therapy. The aim is to unravel the molecular mechanism behind the abscopal effect and exploit it for treatment of melanoma patients by combination therapy in the “IRINA” study. The DKTK study will be performed at all eight DKTK sites bringing together experts in radiotherapy, immunotherapy and molecular diagnostics.
PD Dr. Jessica Hassel
Dr. Dr. Amir Abdollahi
Radiobiological profiling for biochemically stratified radiochemotherapy of HNSCC
Advanced head and neck tumors are usually treated with a combination of surgery, radiotherapy and chemotherapy (radiochemotherapy) or just with radiochemotherapy. However, not all patients respond to this standard treatment. In these cases, the tumor recurs (relapse). In order to personalize treatment and improve the success rate, patients with radiation-resistant tumors are to be identified so that in future they can be offered a more intensive treatment (different radiation dose or more intensive chemotherapy or immunotherapy). Secondly, some patients are currently receiving too much treatment. Identifying this group of patients could lead to treatment-reduction strategies in the future.
In this joint funding project, scientists from all the DKTK sites are working together to make it possible to predict responsiveness in patients with head and neck tumors. To start with, they are retrospectively analyzing tumor samples from patients who have been treated with combined or stand-alone radiochemotherapy. For these patients, the scientists know exactly what treatment they received (e.g. the radiation dose used), and whether they responded to the treatment. The researchers are looking for characteristic biological tumor indicators, or biomarkers, that were particularly resistant or sensitive to radiation. However, before these biomarkers or combinations of biomarkers can be used in routine treatment, the scientists have to confirm their reliability in patients undergoing radiochemotherapy. This DKTK project is therefore currently recruiting patients for a clinical trial of this kind (HNprädBio), which will make use of the DKTK RadPlanBio infrastructure.
Prof. Dr. Michael Baumann
Risk-adapted prevention strategies for colorectal cancer
First-degree relatives of a patient with colorectal cancer have a two to four times increased risk of being diagnosed with this cancer. Therefore, these people are recommended to undergo screening colonoscopy already at age 40. However, very limited information has been available about the proportion of people with such family history and their use of colonoscopy. The RAPS study aimed to assess how many people aged 40-54 have a known family history of colorectal cancer and how many of them have had a colonoscopy.
Of 160,000 persons invited to participate in an online survey in 2015 and 2016 in this multi-centric study (München, Dresden, Stuttgart), 28,711 completed the questionnaire. 2705 persons (9.4%) stated that they had a first-degree relative with colorectal cancer. The proportion of people with a first-degree relative with colorectal cancer increased with age: 7.5%, 9.6%, and 10.9% for people 40-44, 45-49, and 50-54 years, respectively. Although a higher proportion of people with a family history of colorectal cancer had undergone a colonoscopy (54.5%) than people without a family history (25.7%), almost half of people with a family history were not in compliance with the guidelines.
The RAPS study provides novel and urgently needed results for further improvement of colorectal cancer prevention in Germany: 1 in 10 persons in Germany aged 40-54 years has a first-degree relative with colorectal cancer. Strategies are needed to increase adherence to recommendations of early use of screening colonoscopy in this high risk group.
(1) Weigl K, Tikk K, Hoffmeister M, Hampe J, Igel S, Kolligs F, Klug SJ, Mansmann U, Müller O, Nagel JM, Pichler M, Schwab M, Schweigler D, Stephan AM, De Toni EN, Brenner H. Prevalence of a First-Degree Relative With Colorectal Cancer and Uptake of Screening Among Persons 40 to 54 Years Old. Clin Gastroenterol Hepatol 2020;18(11):2535-2543
(2) Weigl K, Tikk K, Hoffmeister M, De Toni EN, Hampe J, Kolligs F, Klug SJ, Mansmann U, Nasseh D, Radlovic J, Schwab M, Schweigler D, Stephan AM, Brenner H. A Web-based survey among adults aged 40-54 years was time effective and yielded stable response patterns. J Clin Epidemiol 2019;105:10-18
(3) Tikk K, Weigl K, Hoffmeister M, Igel S, Schwab M, Hampe J, Klug SJ, Mansmann U, Kolligs F, Brenner H. Study protocol of the RaPS study: novel risk adapted prevention strategies for people with a family history of colorectal cancer. BMC Cancer 2018;18(1):720
Prof. Dr. Hermann Brenner
Resistance Mechanisms to Cytotoxic Chemotherapies in Lung Cancer
Most cancer-related deaths in the western world are linked to lung cancer. A fundamental problem is the resistance of lung cancer to chemotherapy, which continues to be the standard treatment for the vast majority of patients concerned. In this translational project, scientists are researching molecular mechanisms that lead to resistance to chemotherapy. They are analyzing tumor biopsies and blood samples from 130 lung cancer patients participating in a cross-regional clinical trial being run by the working group on internal oncology (AIO), which is testing an improved route of administration for chemotherapy. Tumor and blood samples from the treated patients are prepared centrally for the molecular trials at the DKTK site in Essen and are then analyzed by experts from several DKTK sites. In Essen, for instance, scientists are investigating whether signal molecules that are produced or modified in greater numbers in the tumors correlate with resistance or with a positive treatment outcome. They are analyzing tissue samples from the tumor and tumor cells detected in the blood. In Tübingen, scientists are checking whether characteristics of liquid blood components can be used to predict a patient’s response to chemotherapy. In Heidelberg, scientists are researching to what extent tumor cells in the blood contribute to tumor resistance and the development of metastases. In cooperation with the University of Cologne, complete cancer genomes are being analyzed for some patients using modern sequencing methods to detect previously unknown genome modifications that might influence a patient’s response to treatment.
This project will identify tumor characteristics at molecular and cellular level. In future, these findings can be used to help identify lung cancer patients who will respond particularly well to chemotherapy. The physicians are also hoping to develop improved treatment strategies for other tumors, including colon, stomach, breast and ovarian cancer, which are treated with the same or similar chemotherapies as lung cancer. Ultimately, this trial will also be able to identify individual lung cancer patients who could benefit from new targeted therapies because of specific molecular changes.
Essen/Düsseldorf, Frankfurt/Mainz, Freiburg, Heidelberg, Tübingen
Prof. Dr. Martin Schuler
For most patients with metastatic colorectal cancer, a combination of chemotherapy and targeted monoclonal antibody constitutes the standard of care treatment. However, a significant fraction of patients does not exhibit tumor response or at least stabilization due to primary resistance. Further, in case of initial tumor response or stabilization, nearly all patients develop a resistant disease during the further course of treatment, named as secondary resistance. Most of these patients finally succumb to the progressive metastatic disease. Hence, there is an urgent medical need to better understand the primary and secondary resistance against systemic treatment in patients with metastatic colorectal cancer.
This is exactly where REVEAL steps in. This project is coordinated at the DKTK partner sites in Munich and Berlin. With the analysis of genetic information as well as gene expression profiles of colorectal cancer specimens, the researchers aim at identifying molecular causes for resistance against treatment. Further, the prospective, multicenter REVEAL study evaluates tumor specimens derived from liver metastases, which are collected during standard first-line systemic treatment. This approach is complemented by the analysis of blood samples, in which the tumor-associated genetic alterations can be easily tracked during the course of treatment (liquid biopsy).
The aim of REVEAL is to unravel molecular mechanisms of primary and secondary resistance against systemic treatment in metastatic colorectal cancer. With this knowledge, oncologists might better anticipate the individual benefit patients derive from specific antineoplastic drugs. Once validated in further clinical trials, this might help to optimize patient management and ameliorate the limited prognosis of patients with metastatic colorectal cancer.
Between 2014 and 2018, REVEAL recruited successfully at six German cancer centers a total of 70 patients. With an adequate follow-up time and completion of the molecular analyses in late 2020, first results of REVEAL are foreseen in 2021.
Dr. med. Julian Holch
Prof. Dr. Reinhold Schäfer
Prof. Dr. Volker Heinemann
Therapeutic targeting of Myc
Oncogenic activation of MYC transcription factors is one of the most common genetic events observed in cancer genomes. Despite early discovery of MYC oncogenic activities, > 30 years of research have failed to identify clinically effective compounds capable of directly inhibiting MYC activity. MYC is considered to be undruggable. However, direct MYC targeting can be by-passed through pharmacological inhibition of its regulatory partners or target genes. Within the DKTK JF project “Therapeutic targeting of Myc”, we successfully established a MYC targeting pipeline for efficient pre-clinical drug testing and drug development filling an important gap between molecular target identification and clinical trials. Results from this project show that targeting epigenetic proteins including histone deacetylases (HDACs) and BET proteins as well as regulators of MYC family transcript and protein stability via aurora kinase A (AURKA) are among the most promising (combination) strategies for indirect MYC inhibition. Based on the results of this project the new INFORM2 clinical phase I/II trial “INFORM2-NivEnt” (IIT) was initiated in July 2019.
Prof. Dr. Angelika Eggert
Prof. Dr. Jens Siveke
Prof. Dr. Olaf WittDeutsches Krebsforschungszentrum Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), University Hospital Heidelberg
Translation of molecular based treatment approaches in ALL
Treatment resistance and high morbidity associated with conventional chemotherapeutic treatments ask for new therapeutic approaches for relapsed acute lymphoblastic leukemia (ALL). To explore novel treatment options we set up the collaborative research project “Functional modeling of molecular based treatment approaches in relapsed acute lymphoblastic leukemia”. Most important achievements within this research project were the establishment a RNAseq pipeline for the comprehensive molecular characterization of relapsed ALL in conjunction with the setup of mouse and zebrafish models for drug response prediction. This allowed us demonstrate the synergistic effect of two new drugs (Venetoclax and CX-4945) for the treatment of relapsed ALL. These data and models, which were generated within this DKTK project will be clinically applied in future trials for resistant relapsed ALL, such as the international Hem-Smart Trial for pediatric malignancies.The consortium focussed on clinical translation and data exchange within the infrastructure of the German Multicenter Study Group for Adult ALL (GMALL) between research groups were newly established and thereby the essential translational infrastructure of the study group was optimized. Overall three proposals for clinical trials were prepared and submitted to pharmaceutical companies: Venetoclax, Ponatinib and a CD38 antibody. The trial with Ponatinib in Ph+ ALL already received IRB approval. The trial with Venetoclax is short before contract signature. The trial with the CD38 antibody was cancelled due to lack of efficacy of the antibody.
Prof. Dr. Claudia D. Baldus
Prof. Dr. Hubert Serve
UniCAR NK cells
Patient-derived T cells that carry chimeric antigen receptors (CARs) demonstrate remarkable clinical activity against malignancies of different origins. Aim of this DKTK project was the development of a versatile approach for cancer immunotherapy that bypasses the need for patient-individual cell products. Thereby, natural killer (NK) cells are employed as alternative effectors, which carry a universal CAR (UniCAR) and can be safely used in an allogeneic setting. The UniCAR is only activated in the presence of a so-called target module (TM), a soluble adapter which contains a tumor-specific binding domain and a peptide recognized by the UniCAR. This increases safety by allowing to tightly control duration and magnitude of CAR activation. Important results from this project bringing together nine research groups from four DKTK partner sites include the identification of suitable target structures most frequently presented on the surface of melanoma cells, the development of a novel design for TMs with increased half-life, and proof-of-concept for this strategy in preclinical tumor models. These data may aid the further development of this approach towards clinical application of UniCAR-NK cells as a novel therapy for melanoma.