“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.
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.
Project “Elucidating the basis of primary resistance to first-line combined anti-EGFR /chemotherapy and establishment of a tumor repository for analysis of secondary resistance in metastatic colorectal cancer"
Antibodies are increasingly being used as targeted therapies for treating cancer patients. They can recognize specific molecules on the surface of cancer cells and block their function specifically, or activate the patient’s immune system to attack the tumor. Antibodies are also administered in combination with chemotherapy, for instance in cases of advanced colon cancer. Even with this combination treatment, however, physicians are seeing primary and secondary therapy resistance: some patients do not respond to the treatment and in some patients success is only temporary. The sequencing of tumor samples is increasingly helping scientists identify genetic modifications in cancer cells. However, it is not yet known which of these changes are responsible for therapy resistance in colon cancer patients.
This multicenter project aims to uncover the molecular causes of primary and secondary therapy resistance in colon cancer. When planning treatment, oncologists would then be able to take into account which cancer drugs a patient is resistant to or is highly likely to develop resistance to. The scientists are pursuing two approaches: in order to understand primary tumor resistance, they are analyzing tumor samples from patients who have already been treated with a combination of antibody therapy and chemotherapy and for whom the outcome is known. They are isolating DNA from the samples and sequencing around 500 genes associated with colon cancer to identify genetic changes. At the same time, they are establishing whether cells from the immune system have migrated to the tumor, since DKTK scientists have observed indications that this kind of immune cell infiltration correlates with a better treatment outcome. The researchers are concentrating primarily on changes that are significantly different between patients who responded particularly well or particularly poorly to treatment. In the subsequent, second approach, the scientists at the two participating sites will take tumor biopsies from 60 patients before treatment and in the event of a recurrence. These samples will be analyzed for molecular changes, as in the first approach. The results will enable the researchers to verify their conclusions from the first approach and, for the first time, to investigate the causes of secondary therapy resistance (by comparing the biopsies taken before and after treatment from patients who suffer a relapse). In future, genetic and immune analyses will be used as a routine diagnostic method so that every colon cancer patient can be offered the best treatment option for them.
Project “Novel risk adapted prevention strategies among people with higher risk profiles for colorectal cancer (RaPS)”
People between the ages of 40 and 60 have a two to four times higher risk of developing colon cancer if they have first-degree relatives affected by the disease. Experts recommend that people in this risk group take part in early colon cancer screening programs. In Germany, however, colonoscopies for colon cancer prevention are only offered as standard from the age of 55 onwards.
The aim of the joint project is firstly to establish how frequently people aged 40–55 who have family members with the condition present signs of colon cancer or its precursor stages that can be identified via a colonoscopy and removed. For this part of the project, the participating physicians are offering colonoscopies to 1200 test subjects between the ages of 40 and 54 who have close relatives affected by colon cancer. The data can then be used to develop improved preventative measures for this risk group. In addition, the scientists hope to establish new, less invasive detection methods for early cancer diagnosis. They are examining blood and stool samples for molecular risk factors and biomarkers that would be suitable for early cancer diagnosis.
The aim is for this study to produce new findings that can improve colon cancer prevention in the risk group of people with family members already affected by the disease. This could enable a considerable proportion of the 15,000 or so cases of colon cancer that occur each year in Germany among people below the age of 65 to be prevented or identified early and treated effectively.