Our mission: to identify new and effective treatment options for affected children through the development of innovative biotechnologies and application of cutting-edge research methods.
Malignant brain tumors are the leading cause of childhood death in Germany, with Diffuse Intrinsic Pontine Glioma (DIPG) as the deadliest of all pediatric brain tumors.
Despite tremendous advances in research and treatment of other childhood malignancies, DIPG is still associated with a median survival rate of only 11 months after diagnosis. 90% of children die within 18 months of their diagnosis. To date there is no cure nor a significantly life-prolonging treatment. It is our mission to identify new and effective treatment options for affected children through the development of innovative biotechnologies and application of cutting-edge research methods. Here is an overview of our ongoing DIPG research projects.
In order to assess the effect of novel drugs on DIPG cells we treat millions of tumor cells each week with a large variety of compounds.
The tumor cells are seeded into culture plates using a pipetting robot. Each compound is then added to the tumor cells in up to eight different concentrations. Certain compounds are also added simultaneously in order to assess combination therapies for DIPG. We then measure the effect of each treatment condition using viability and proliferation assays. Our compound libraries comprise already approved drugs as well as experimental substances and natural products such as food homologues. Through our screening process we can quickly identify substances that can either inhibit growth and proliferation in DIPG cells or kill them off completely. Drug screening is usually the first step in our project before we move on to more sophisticated assays such as side effect assessment, resistance and cross resistance profiles or blood brain barrier penetration studies.
Blood Brain Barrier Testing
The human brain is protected by a the so-called Blood Brain Barrier (BBB). This barrier shields the brain from potentially toxic substances and molecules in the blood and regulates the nutrient and oxygen distribution to the brain.
However, this barrier function also limits most drugs and therapeutic compounds to penetrate into the brain and prevents them from reaching their targets such as malignant brain tumors. Our group developed a new model of the human Blood Brain Barrier with unprecedented accuracy of distinguishing BBB-permeable from BBB impermeable compounds and drugs. This model enables us to test promising drugs identified by our screening efforts for BBB permeability. The ability to assess brain penetration potential of drugs is creates invaluable information regarding the clinical usefulness of drugs for their treatment application in DIPG. Patients will only benefit from a drug that is effective against DIPG cells if the drug is able to reach the tumor in the first place.
Many compounds are able to kill off tumor cells quite effectively when added directly to the cells grown in a plastic dish.
Unfortunately, most of these compounds are not exclusively targeting tumor cells and have profound effects on non-cancerous cells, too. When these drugs are administered to patients the off-target effects often result in severe side effects. This results in a dose limitation which means that patients cannot be given sufficient doses that are needed to effectively fight the tumor. Since DIPG patients are typically children, it is of the utmost importance to identify dose limiting and potential developmentally harmful toxicities. To this end we are developing complex cellular models for the most important organ systems. These models are based on diverse cell types we derive from human induced pluripotent stem cells (hIPSCs). Among these cell types are heart muscle, lung, liver and kidney cells. However, our main toxicity related focus is on neurotoxicity as we are favouring drugs that can cross the BBB. Although these drugs can reach tumors protected by the BBB such as DIPG, they also have a high potential of causing severe damage to neurons and other cell types of the central nervous system. This is why we assess the neurotoxic potential of every drug by treating hIPSCs derived neurons with clinically relevant doses of those drugs. Our toxicity analysis provides valuable information to physicians in the clinic and identifies potentially less toxic therapy options for brain tumor patients.
Drug combinations and drug resistance
There are specific indications as to why current DIPG treatment options remain unsuccessful. One of the underlying principles is patient to patient variability and unique therapy responses between patients with the seemingly same disease.
Another major obstacle is the rapid development of resistance to drugs by DIPG cells. To address this problem, we are creating drug and radiation resistant DIPG cells in the lab and expose these resistant cells to a variety of compounds in order to identify therapeutics that can overcome this resistance. The goal of this project is to identify drug combinations that promise to be effective by showing a low level of cross resistance as well as strong independent effects. Identifying such combination regimens is crucial, as it is unlikely that a monotherapy of any compound or treatment modality will facilitate an effective treatment let alone a cure for DIPG.
Advanced Tumor Models
DIPG is a highly complex tumor. It diffusely infiltrates the surrounding tissue and interacts with its microenvironment.
In addition, DIPG consists of heterogeneous tumor populations that are coexisting within the complex tumor architecture and follow a certain developmental hierarchy. In order to identify novel therapeutic options for DIPG, the tumor models in the lab need to closely recapitulate the tumors composition and architecture. To provide a more realistic tumor microenvironment to DIPG cells, we derive so called cerebral organoids from hIPSC and coculture them with patient derived DIPG cells. Cerebral organoids are three dimensional structures that consist of a variety of human CNS cell types, including neural progenitor cells and neurons. By labelling the tumor cells with a fluorescent protein, we are able to observe the tumor cells in real time and distinguish them from normal brain cells. We then subject these advanced tumor models to potential therapeutics or radiation and analyze the effect on DIPG cells as well as on normal brain cells.