“DKTK Joint Funding” Program
DKTK has implemented the Joint Funding Program, an intramural competition to trigger and support outstanding research networks on innovational translational and clinical projects in oncology, in order to foster interaction between partner sites and strengthen DKTK’s overall research portfolio. The proposals are evaluated in a two-step procedure involving DKTK’s international Scientific Advisory Board. Successful projects will be supported for up to 3 years. Since 2012 20 Joint Funding projects have been funded.
Clonal hematopoiesis is a hallmark of hematologic malignancy, but can also be seen in healthy elderly people. This so-called “clonal hematopoiesis of indeterminate potential” (CHIP) is considered as a risk factor for stem cell-driven hematological diseases, including the myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In this project, DKTK scientists join forces to investigate the role of the bone/bone marrow niche in the evolution of CHIP in elderly patients. The aim of the interdisciplinary study is to comprehensively characterize all components of the stem cell niches in the bone marrow in blood-healthy elderly people and patients with MDS/AML. For this purpose, an extensive collection of biosamples from the BoHemE study (Bone and Hematology in the Elderly) is available. With the help of high-throughput technologies, the CHOICE team will trace the molecular and cellular changes in the hematological compartment and the bone marrow microenvironment in CHIP towards MDS/AML. The researchers aim to define factors and key mechanisms that drive clonal hematopoiesis and malignant evolution of the mutant blood stem cells. The project also aims to elucidate the relationship between bone health and impaired hematopoiesis. Functional investigations using patient-derived xenograft models and 3D cell culture models are planned to evaluate the impact of an altered microenvironment on stem cell clonal evolution. The findings from the CHOICE project could help to better predict and perhaps prevent the transformation of a pre-leukemic clone to leukemia in CHIP patients.
Precision medicine in oncological surgery: Identification of predictive biomarkers for individualized surgical treatment of gastrointestinal tumors.
In the treatment of gastrointestinal tumors, especially in colorectal and pancreatic cancer (CRC and PDAC), local recurrences and long-distance metastases present a major clinical challenge. By now research has focused primarily on molecular biomarkers to initiate a personalized treatment in the sense of precision oncology. However, these treatments are almost exclusively of systemic nature, while localised forms of therapy such as surgery or radiotherapy are much less individualized. Surgical resection as part of a multimodal therapy concept is the central element of the treatment of gastrointestinal tumors. It is known that tumors prone to local recurrence can often be curatively removed by radical surgery, while tumors prone to distant metastases may be treated better by more gentle surgery in combination with early systemic therapy. However, the technique of surgical resection is largely independent of the patient.
The aim of this DKTK-wide research project is to introduce personalized oncology in surgery. To this end, molecular biomarkers that predict the recurrence behavior of GI tumors at an early stage need to be identified, so that this knowledge can be incorporated into the surgical decision. Despite the enormous clinical potential, the area is heavily under-researched. To address this enormous task, all surgical departments of the DKTK framework as well as selected non-surgical groups with unique expertise have formed a consortium which is unparalleled in surgical expertise and annual caseload. Parallel transcriptomic, proteomic and immunopeptidomic analyses from a large cohort of surgical patients together with a detailed follow-up allow to build up a comprehensive database. In specific scientific projects, the "DKTK Surgery" initiative will identify and validate molecular biomarkers in primary tumors as well as circulating tumor cells that allow the physician to predict the recurrence pattern (local vs. distant) in CRC and PDAC. This will enable patient-tailored surgical treatments for two of the most common and deadly solid cancers.
Project „Translation of molecular based treatment approaches in ALL“
Acute lymphatic leukemia (ALL) patients who suffer relapses have poor prognoses. The project “Translation of molecular-based treatment approaches in ALL” engages molecular profiles with active substance screenings in patient-specific in vitro and in vivo models to identify genotype specific drug response signatures. The aim of the project is to identify genotypes to be used for individual treatment decisions about the effectiveness of defined combination treatments in ALL patients.
In the multicenter “AMPLIFY NEOVAC” clinical study DKTK investigators explore a combination immunotherapy for treatment of aggressive brain tumors, malignant glioma. The approach is to boost tumor vaccination, previously developed within DKTK, with so-called immune checkpoint inhibitors (ICIs), which have shown impressive therapeutic activity for other tumors by unblocking the patient’s own immune system. In this trial the immunotherapy will be initiated before a planned resection. The aim of the study is to assess efficacy and to analyze intratumoral anti-tumor immune effects of the combined vaccination/ICI treatment using detailed molecular and immunological studies. These analyses are expected to reveal important mechanisms of response and resistance to targeted immunotherapy in brain tumors.
Immune checkpoint inhibitors have shown high efficacy in a broad variety of advanced tumor entities with bad prognosis. Molecular testing of tumor probes seems to gain importance for the application of immunotherapies in future. High tumor mutation burden has been demonstrated to be associated with response to immune checkpoint inhibitors in some tumor entities as these may result in neoantigens which can be detected by patient`s onw T cells. On the other hand, defined mutations may be associated with lack of response to immunotherapies. The ImmuNEO Master project bases on mutation profiles and gene expression patterns of tumors analyzed in the DKTK MASTER program and focuses on the characterization of the neoantigen repertoire, respective immune responses as well as relevant aspects of the immune environment.
The aim of the research project is to identify biomarkers that predict successful treatment with immune checkpoint inhibitors and to define characteristics of antigens suitable for tumor rejection. Moreover, this project investigates the interdependence of molecular and immune related tumor determinants. The results are aimed to be used for the development of novel targeted immunotherapeutic as well as combinatorial therapies.
Project „UniCAR NK cells“
The DKTK Project “UniCAR NK cells” aims to develop and validate a novel approach for adoptive cancer immunotherapy with immune cells genetically modified to specifically recognize and attack cancer cells. Chimeric antigen receptor (CAR) engineered T cells have already shown remarkable activity against malignancies of B-cell origin. Nevertheless, manufacture of such cells as a patient-individual product is highly complex, time-consuming and expensive, requiring in each case isolation of autologous T cells, genetic modification with a CAR vector to introduce selectivity for a given cancer type, and subsequent quality control and safety testing before re-infusion into the patient. In the project "UniCAR NK cells", the contributing DKTK researchers bring together technologies developed at different DKTK partner sites to establish a cell therapy approach that is more widely applicable in the clinical context: They equip continuously expanding natural killer (NK) cells, which in contrast to T cells can be safely used in an allogeneic setting, with a universal chimeric antigen receptor (UniCAR) that recognizes a defined peptide epitope not present on the surface of cells from normal tissues. For tumor-specific cell killing, they combine these UniCAR NK cells with adapter proteins ('target modules') that contain a tumor-specific binding domain of choice, fused to the peptide epitope recognized by the UniCAR. While the NK cells stay inactive in the absence of an adapter molecule, linkage to cancer cells through UniCAR and target module triggers CAR activation and target-cell lysis. The aim is to make advanced and safe cell therapies more quickly accessible for a larger patient group by combining such universally applicable “off-the-shelf” UniCAR NK cells with pre-manufactured tumor-specific adapter proteins, thereby bypassing the need for complex patient-individual procedures.
The “Targeting Myc” Project
Many cancers in adults and children can be traced back to defects in a family of proteins all similar to the protein giving this family its name, Myc. Myc proteins control the activity of large numbers of other genes, creating an attractive target to attack many processes driving and maintaining cancer cells. Drugs inhibiting Myc have not yet been found that successfully treat cancers. The DKTK team working on the Targeting Myc project is looking for new effective active substances to treat Myc-driven cancers. Active substances are systematically analyzed in studies that assess their ability to either disable genes regulated by Myc proteins or to disable the Myc proteins themselves by blocking their interactions with functional partners or marking them for destruction in the cancer cell. The researchers are using preclinical models, which the DKTK makes available for numerous Myc-driven cancers, and is also developing a new generation of substances capable of blocking Myc protein activities. The aim is to identify effective active substances or combinations of substances that will then be tested in clinical trials.
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.
Project “Ga-PSMA-11 in high-risk prostate cancer”
The clinical study 'Ga-PSMA-11 in high-risk prostate cancer' developed by DKFZ scientists has also received an award. This research project is based on a completely new method for the early diagnosis of prostate cancer. The prostate-specific membrane antigen (PSMA) is a transmembrane protein which is enriched in prostate cancer cells. Using a radioactive substance that specifically binds to PSMA, this enrichment can be visualized with positron emission tomography (PET), precisely marking the tumour tissue and any metastases.
Currently there are no reliable early non-invasive diagnostic method for prostate cancer. The Joint Funding now enables DKTK scientists to test PSMA diagnostics in a clinical study at the DKTK sites. The DKTK investigators will look at a large number of tissue samples from prostate cancer patients and compare the findings using PSMA diagnostics. This method also presents a potential clinical approach for cancer therapy: If labeled with a strongly radioactive marker, the PSMA-binding substance could also specifically destroy cancer cells.
Prof Dr Frederik Giesel
University Hospital Heidelberg
Project “NonCoMs in Cancer Genomes”
So far, the focus of genetic tumour analysis has been on mutations that result in altered proteins. They are often considered to be the trigger for malignant tumours. Identifying and understanding non-coding mutations in cancer genomes is a project that goes an important step further and traces mutations in tumour cells that do not lead to altered proteins, but are located in regions that change the activity of important cancer genes. Plans include investigations particularly on skin tumours (melanoma) and brain tumours (glioblastoma). Being able to identify these mutations in a collaborative effort represents a major chance to track down the causes of cancer.
Project “Molecular Stratification Program”
The DKTK project 'Molecular Stratification Program' at the National Center for Tumour Diseases (NCT) in Heidelberg focuses on customized therapies. The term 'stratification' refers to the initiative to assign patients with the same initial diagnosis to subgroups according to molecular results in order to be able to offer them a tailored therapy. The project promotes the development of a central database containing gene defects and changes in gene activity of tumour cells. The tumour profiles will help hospitals to tailor therapy for individual patients.
Project “Overcoming therapy resistance in pancreatic cancers”
Pancreatic cancer is one of the most aggressive cancers with a dismal prognosis and for which effective treatment options are desperately needed. In this Joint Funding Project DKTK experts in molecular oncology, animal model development, drug development and clinical oncology join forces for rationally developing effective combination therapies against pancreatic cancer. To this end, the team explores molecular mechanisms that are responsible for the resistance that pancreatic tumors possess or develop to established therapies. These mechanisms are studied in sophisticated cell culture and animal models of different molecular subtypes of pancreatic cancer that the DKTK investigators recently described. Notably, these subtypes were found to respond differently to anticancer drugs. Based on the understanding of molecular mechanisms of treatment resistance, the research team explores new drugs and develops combination therapies tailored to each pancreatic cancer subtype with the goal to effectively kill resistant cancer cells or avoid the development of secondary resistance that established monotherapies induce. The overall aim is to establish drug combinations that break tumor resistance as novel treatment options for pancreatic cancer patients.