The immune system offers sophisticated molecular solutions to avoid the threat of infections and cancer. Based on these molecular solutions, novel therapeutic concepts can be developed and adjusted to meet urgent clinical needs. Therapeutic manipulation of innate immunity therefore offers an alternative to failing antibiotics and cancer therapies but is underexplored, due to issues of specificity. We have identified novel, specific molecular activation nodes and effector molecules that distinguish protective from destructive effects of innate immune activation in infections and cancer. With this approach, we can design therapeutics, to selectively attenuate destructive innate immune responses to infection without jeopardizing the anti-bacterial defense. We will also explore natural molecules of the innate immune system for antibacterial effects and in cancer therapy. These studies are essential, in view of the global increase in drug-resistant bacteria and cancer-associated mortality, especially in the aging population.
The Svanborg laboratory focuses on the pathogenesis of infectious diseases, with Urinary Tract Infection as a model.
In early work we defined molecular mechanisms used by microbes to infect host cells, ‘’Cellular microbiology’’. We subsequently defined how the host response, quantitatively and qualitatively, determines if infection will result in disease or asymptomatic bacterial carriage, which was later described as ‘’innate immunity’’. We have defined how immune response dysfunctions lead to pathology and chronic kidney disease. Recent work on genetic determinants of human disease susceptibility closes the circle and demonstrates the human relevance of this approach. Throughout this translational work, clinical studies are integrated with molecular and cellular technologies. Ongoing studies define the genetic repertoire that determines UTI susceptibility and the effects of the host environment on bacterial genome evolution and host gene expression.
Rather than targeting the bacteria directly, we propose to strengthen the defense of the patient against bacterial infection. By selectively boosting the protective innate immune response we aim to exploit molecular ‘’tricks’’ to kill bacteria and avoid tissue damage.
- boosting the antimicrobial effectors of the innate immune system; boosting of IRF3 in acute pyelonephritis.
- inhibiting destructive effectors of the innate immune system; IRF7 shRNA therapy in acute pyelonephritis, pharmacological IL-1b and MMP-7 inhibitors in acute cystitis.
Since 1995, the Svanborg laboratory has also been pursuing the discovery of HAMLET; a human milk complex with broad tumoricidal activity.
HAMLET is the first member in a new and expanding family of lipid-bound partially unfolded proteins with tumoricidal activity and offers an interesting new tool in tumor biology. Furthermore, HAMLET has therapeutic activity against experimental and human tumors. In a placebo-controlled clinical study, topical administration of HAMLET removed skin papillomas, without side effects. In patients with bladder cancer, HAMLET triggered rapid shedding of tumor cells into the urine and caused a reduction in tumor size. Recent work has shown that the broad sensitivity of tumor cells to HAMLET relies on the oncogene repertoire, especially on c-Myc expression levels. Furthermore, the tumor killing effect of HAMLET reflects the metabolic state of the tumors, defined by specific glycolytic enzymes. Ongoing studies focus on the ‘’switch’’ turned on by HAMLET in tumor cells, to initiate the death response. Therapeutic models include colon cancer, with promising results. One of the main goals is to elucidate the structural basis of HAMLET and the difference is HAMLET sensitivity between tumor cells and healthy cells.
HAMLET, is a human molecule that kills cancer cells. we have characterised the molecule and its mechanism of action and have shown in clinical trials that HAMLET works in patients.
HAMLET is a new drug candidate with astonishing but well-documented properties.
- HAMLET kills a broad range of tumor cells but spares healthy, mature cells (Proc. Natl. Acad. Sci, 1995 and 2000).
- HAMLET kills more than 40 different types of tumour cells, including those most difficult to treat with available drugs.
- HAMLET kills tumour cells by a natural non-toxic mechanism. Thus, unlike most current cancer drugs, HAMLET does not appear to damage healthy tissues.
- HAMLET occurs naturally in human milk, and may contribute to the lowered cancer incidence in breast-feeding mothers and their children.
- HAMLET can be produced in large quantities at drug quality.
We will develop the concept of innate immunotherapy in cancer, using HAMLET as a model. Studies of structure and mechanism of action will be combined with proof of concept studies of therapeutic efficacy in animal models and patients.