Malignant hematological diseases are a heterogeneous group of myeloid or lymphoid clonal proliferations characterized by morphological, immunological features and genetics. The clinical course can be chronic and indolent or acute. In general, acute diseases (leukemias and aggressive lymphomas) can be cured in approximately half of the patients, while the other patients die from their disease. Of course, variations in subentities with higher or lower cure rates do exist. Chronic leukemias and indolent lymphomas can be well controlled for years in most cases and sometimes do not even require therapy. However, the cure rate of these patients is low and the course of the disease is characterized by frequent recurrence.
Current treatment options include
- conventional chemotherapy (alkylating agents, anthrocyclines, steroids, etc.),
- small molecules (e.g. kinase inhibitors), and
- immunotherapy (autologous and allergenic stem cell transplantation).
For most diseases combination or sequential therapy is required to achieve optimal results. Low cure rates and frequent relapses show that novel agents for mono or combination therapies have still to be explored.
In recent years, many advances have been made to discover naturally occurring bioactive small molecules and their synthetic derivatives as clinical trial candidates. Widely known are the groups of flavonoids and chalcones which have been shown to display cytotoxic activity in a variety of cancer cell lines and patient primary cells, including leukemic cells. Flavopiridol (alvocidib) is a synthetic flavone derivative and acts as potent growth inhibitor by inhibition of cyclin-dependent kinases of diverse human tumor cell lines by induction of apoptosis also including hematopoietic cell lines.
In the course of a previous project, we identified highly active synthetic chalcones derived from the chalcone scaffold. These cytotoxic compounds were found and developed by modifying the chalcone lead structure concurrent with in vitro tests to evaluate their cytotoxic potential in different cancer cell lines. Experimental data were fed back into the chemical model to further optimize the structure of the molecules thus attaining derivatives with the highest possible activity with only few modifications necessary.
In a next step, the compounds were thoroughly tested regarding their efficacy in inhibiting proliferation and viability in cancer cell lines of the hematopoietic system. From these tests, three representatives emerged showing high cytotoxicity at low concentrations thus displaying promising potential as novel anti-cancer drugs.
In the course of the research cluster, these three compounds will be further optimized with regard to selectivity against tumor cells (cell lines representing hematopoietic malignancies and primary patient cells). Furthermore, their potential as novel drugs alone and in combination with established treatment regimens will be studied.
In addition, novel drugs will be developed and tested on cell lines of the hematopoietic system. Here, we will focus on the development of substances active against cells characterized by genetic aberrations which confer resistance to conventional therapeutic regimens. Patients belonging to diseases subgroups and entities with such genetic changes are in particular need of novel therapeutic options.