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Neurology & Oncology – Matthias Endres
Neurotoxic sequelae are among the most common side effects of tumor therapy. They may include the development of a chemotherapy-induced neuropathy (CIN) or more diffuse symptoms regarding changes in cognition (post-chemotherapy cognitive impairment, PCCI). In addition, immune-related adverse events (irAE) have recently gained interest as tumor immune therapies become a frequent part of cancer treatment. The pathophysiology remains often largely unclear and currently there are no or only limited and often unsatisfactory treatment options available. Due to a severe decrease in quality of life, neurologic sequelae result in alterations or limitations of cancer treatment.
1. Mechanisms of cell death
Different pathomechanisms have been described to play a role in the toxicity towards dorsal root ganglia neurons and the development of a chemotherapy-induced neuropathy. However, the pathomechanism of toxicity often differs from the primary cytostatic effect for many cytostatic substances, which holds the promise that neuroprotection can be achieved without impairment of the antineoplastic effect. We were able to demonstrate that alterations of calcium homeostasis play an important role in the apoptotic cascade after chemotherapy exposure in dorsal root ganglia neurons and neuronal precursor cells. We are working to identify molecular targets of cell death and apoptosis and to establish and validate preventive neuroprotective treatments.
2. Patient-specific disease models for the individualized prediction of nerve damage
At present, a precise prediction of patients who will suffer neurological sequelae due to tumor therapy and to what extent is not possible. Using induced pluripotent stem cells (iPSC) from patients with neurological sequelae after chemotherapy, we are developing individual patient-specific human disease models of CIN and PCCI to explore molecular targets and new predictive markers of nerve damage.
3. Neuro-immune interaction
In the recent past, it was repeatedly shown that, in addition to classical cell death mechanisms, the induction of a secondary neuro-immune interaction contributes to further neuronal damage after chemotherapy. Furthermore, in the context of immune-related adverse events (irAE) after tumor immunotherapy, immune cells attack various structures of the nervous system and can lead to damage of the brain, peripheral nerves and muscles. We are therefore investigating the role of different immune cells and how they contribute to the damage of nerve and muscle cells in both chemotherapy and immunotherapy.
4. Clinical trials
Chemotherapy induced cognitive alterations in recruits with ovarian and breast cancer (CICARO, NCT02753036):
A prospective longitudinal observatory trial that systematically investigates cognitive functions, neuropathy, quality of life and immunological changes in breast cancer and ovarian cancer patients before and after chemotherapy with paclitaxel.
Tumor immune therapy associated neurological immune-related adverse events (TITAN2, DRKS00012668):
Patients treated with immune checkpoint inhibitors can develop debilitating neurological side effects. This prospective longitudinal observatory trial aims at evaluating the frequency of neurological immune related adverse events (irAE) and establishing biomarkers for early recognition of irAEs.
Registry for tumor immune therapy associated neurological immune-related adverse events (TITAN-Reg):
Neurological immune-related adverse events (irAE) of tumor immunotherapies occur rarely (3-5% of cases), but are usually all the more severe and require immediate diagnosis and therapy. For a better understanding of the frequency of neurological irAE as well as the triggering factors, the data of patients with neurological irAE are collected in a registry. In addition, data on patients with irAE after tumor immunotherapies are being compiled throughout Germany in cooperation with the Paul Ehrlich Institute (SERIO Registry, http://serio-registry.org/), which establishes an urgently needed interdisciplinary approach in the treatment of these patients.
Serial Serum Neurofilament measurements for the diagnosis and prediction of chemotherapy-induced polyneuropathy (SENSE-CIPN, DRKS00027898):
This observational study involves the prospective longitudinal investigation of tumor patients receiving neurotoxic chemotherapy ([nab-]paclitaxel, docetaxel, cisplatin, oxaliplatin, carboplatin, vincristine, bortezomib) regarding the development of chemotherapy-induced nerve damage (i.e. chemotherapy-induced polyneuropathy [CIPN]). Blood samples will be taken at defined time points before, during, and after chemotherapy and will be analyzed for potential markers of nerve damage. The aim of the study is to establish neurofilament proteins as biomarkers in the diagnosis and prognosis of CIPN.
5. Novel patient care structures
Routine tumor patient care regularly ends after a defined interval. However, studies of patients evaluated many years after tumor diagnosis and tumor therapy show that a large percentage of these long-term survivors continue to suffer from permanent sequelae of tumor therapy. Within the framework of this novel health care research project - the Charité Survivorship Clinic - the effects of such sequelae on the quality of life of long-term survivors are investigated. At the same time, we evaluate whether routine care of long-term survivors can be improved by an interdisciplinary diagnostic and treatment approach in a specialized outpatient clinic. For more information on the project and the partners involved, please visit https://survivorship-clinic.de/.