Receptor biochemistry

We are aiming to evaluate the therapeutic potential of regulatory (neuro)peptides of the galanin family in immunity and inflammatory diseases, regeneration and obesity. The data obtained so far and the tools generated (several transgenic mouse lines, animal models) have laid the basis for our future research to demonstrate the therapeutic potential of galanin receptor selective ligands.

Tumor Metabolism

With the depth analysis of the alterations of the mitochondrial energy metabolism (Warburg effect) in solid tumors we aim to provide the basis for our preclinical and clinical trials to target the tumor metabolism.

Research conducted within the topic receptor biochemistry is focused on the neuropeptide galanin and members of the galanin peptide family [galanin-message-associated peptide (GMAP), galanin-like peptide (GALP), Spexin and alarin], and their receptors (GAL1-3R). Galanin, a 29- or 30-amino acid neuropeptide, is widely distributed in the central and peripheral nervous systems and in non-neuronal tissues. The physiological functions of galanin are diverse and include roles in feeding, nociception and inflammation. The variety of functions of galanin peptides are ascribed to the different tissue distributions and ligand affinities of the galanin receptors (GAL1-R, GAL2-R, GAL3-R), which belong to the G-protein coupled receptor family.

Affinity of endogenous galanin peptides and signal transduction of galanin receptors

Our data indicate that galanin and its receptors are expressed by immune cells. Furthermore, the galanin system is regulated during inflammation and affects the severity of inflammation in different animal models. For example, we showed that galanin modulates interferon-? production by natural killer cells, and increases neutrophil sensitivity toward the chemokine CXCL8. Thus, we have established that the galanin system has diverse functions especially in inflammation and the innate immune response.

Major findings:

• Evidence that GAL3-R may be an important therapeutic target in psoriasis, as in GAL3-R KO mice the psoriasis activity score is lower than in wild type animals
• Evidence that GAL3-R may be an important therapeutic target in anxiety and depression, as GAL3-R KO mice exhibit an anxiety-like phenotype
• Demonstration that the GAL3-R is involved in the progression of arthritis and inflammatory bowel disease
• Demonstration that galanin effects sweat glands function via GAL3-R
• Evidence that galanin and its receptors are expressed on human and rodent immune cells and modulate the cytokine response of neutrophils and natural killer cells and cytokine expression in monocyte and macrophage subtypes
• Identification of GALR selective compounds
• Demonstration that alarin is a potent regulator of energy metabolism (food intake, temperature regulation)
  
  

The anaerobic use of glucose as an energy source through glycolysis is a feature common to most solid tumors, in turn leading to a lesser dependence on OXPHOS, which is called the Warburg effect. The down regulation of OXPHOS in tumor cells seems to be achieved by different mechanisms, which has been analyzed by us in detail in a range of solid cancers.

We observed a variety of different changes, which can be categorized into the following subgroups:

• Combined alterations of several OXPHOS complexes in astrocytomas, meningioma, schwannoma
• Isolated complex I deficiency in papillary thyroid carcinoma combined with compensatory upregulation of mitochondrial biogenesis
• Intestinal gastric carcinomas are frequently characterized by loss of complex I of the OXPHOS
• Variable but distinct metabolic signature in melanoma and prostate cancer
  

Targeting cellular metabolism is emerging as a promising strategy in cancer treatment. Tumor cells depend critically on glucose for energy production. Thus, ketogenic diet and/or calorie restriction are supposed to target the increased glucose-dependence of cancer cells to selectively "starve them out". Ketogenic diet is high in fat and low in carbohydrate and protein and mimics starvation or prolonged exercise without restricting energy intake.

Cancer cells should be less able to utilize ketone bodies due to their lower OXPHOS capacity. Furthermore, ketogenic diet lowers insulin and insulin-like growth factor (IGF-1) levels. In the context of carcinogenesis, the most important functions of the IGF family involve increse of cell proliferation and inhibition of apoptosis. Therefore, we are using preclinical cancer xenograft models to demonstrate the feasibility of ketogenic diet as adjuvant treatment of different solid cancers.

Number of preclinical studies from other research groups and our lab, which investigated the effect of a ketogenic diet on different types of cancer. Colors of the bars represent the result of each study as indicated in the color key. Studies on KD and cancer were collected by a literature search covering through mid of 2018. R indicates studies with a calorie-restricted KD; T indicates use of a KD as an adjuvant therapy to classic therapy.

Major findings in preclinical cancer models:

• Ketogenic diets, especially medium chain fatty acid enriched ketogenic diets, synergize with classical chemotherapy in treatment of neuroblastoma and the effect is independent of amino acid restriction
• Adjuvant therapy with ketogenic diets is not feasible in a subset of renal cell carcinoma, as tumor induced liver inflammation is enhanced by intervention with ketogenic diets
• Ketogenic diets synergize with classical chemotherapy in treatment of triple negative breast cancer

Furthermore, in collaboration with the Department of Dermatology, we have initiated a small clinical trial to test the feasibility of ketogenic diet in skin cancer patients.