Imidazoquinolines and cytostatics, a new approach in multiple myeloma treatment

Multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells distributed within the bone marrow. It is the second most common hematological malignancy. Symptoms are amongst others the destruction of bone structure, kidney failure and neurological dysfunction. Current treatments increase life expectancy and reduce symptoms, but are unable to cure the disease. In previous studies within context of the special research program SFB021 ("Cell Proliferation and Cell Death in Tumors", FWF) we were able to show that imidazoquinolines selectively induce apoptosis in MM-cells (independently of Toll-like-recptors, TLRs). In normal cells a strong apoptosis inducing function by imidazoquinolines is not known, indicating that it is specific for MM cells. In our studies Imiquimod, an imidazoquinoline, was tested in detail in a MM mouse xenotransplantation model. Treatment of the mice with Imiquimod by subcutaneous injection led to tumor regression and to a decelerated growth of the tumors. A patent covering the apoptosis inducing effect of Imiquimod in MM has been filed, and a publication is in preperation. In addition, Imiquimod was tested in cell culture in combination with different drugs and signal transduction inhibitors presently used in MM treatment. A significant apoptosis inducing effect was observed with combinations of Imiquimod with Melphalan or Akt-Inhibitors. The mechanisms involved in the antitumor effects caused by Akt-inhibitors are not yet understood, and therapeutic effects have so far not been clearly demonstrated in clinical trials. Hence, Melphalan and other cytostatics are successfully applied in MM-treatment since the 1960s. For that reason we decided to focus investigations within this proposal on Imiquimod/cytostatics combinations. Aim of our project is to optimize the use of Imiquimod in the MM mouse xenotransplantation model in terms of dosage and mode of application. Furthermore, the combination of Imiquimod and cytostatics will be evaluated in detail in tissue culture, and then tested in the mouse model. This will be accompanied by a detailed inquiry on how imidazoquinolines induce apoptosis in MM-cells but not in others. This is on one hand of scientific interest and on the other hand a successful identification of the responsible molecular factor will also mean the identification of a potential new drug target. This will serve as basis for a further development of the here proposed MM treatment strategy. The project would be carried out at the Biocenter, Innsbruck Medical University and would be associated as so called "non-K-project" with the Tyrolean center of personalized cancer therapy, ONCOTYROL, a competent alliance of basic and clinical research.

Multiple myeloma (MM) is a cancer of the bone marrow; in particular the antibody producing plasma cells (B cells) of the immune system. The disease leads to bone lesions, organ failures (especially the kidney), and a disturbed blood circulation that can also lead to neurological problems. Currently approved therapies lead to a prolongation of life, but only in very rare cases achieve a cure. Therefore, there is a highly unmet medical need for novel therapies that lead to an eradication of the disease. Before a novel substance is allowed to be used in human patients it has to demonstrate its effectiveness and tolerability in disease models. To this end, there are on the one hand cell culture models, in which tumor cells derived from patients are cultured in nutritional media. Subsequently, novel substances have to show their benefit also in animal models of the disease and even more importantly prove that they are non-toxic at the same dose. During a previous project we had discovered that a compound family that was so far not associated with myeloma therapy, the imidazoquinolines, could potently induce the death of MM cells in a cell culture model. Furthermore, we had shown that the compound was additive in its effect in cell culture with established MM therapeutics such as melphalan. The efficacy for one of the imidazoquinolines (Imiquimod) could also be demonstrated in a mouse model of MM. During this project we could promote the development of imidazoquinolines as a novel therapy against MM by: Identifying an optimal dosing schedule for another imidazoquinoline (Gardiquimod) in a mouse model of MM, at which the compound was effective but not toxic, Confirming the additive effect of Gardiquimod with Melphalan in this mouse model of MM, and Identifying a possible novel mode of action for imidazoquinolines which is another prerequisite for applying this substance group as novel therapy against MM