Novel metal-based therapeutics against problematic tumors

The development of a successful treatment and early diagnosis of cancer has increased dramatically the overall survival rate of patients in the last decades. Metal-based cytotoxic agents (consisting of Pt(II) complexes) are applied in more than 50% of anticancer regimens including first line chemotherapy in 12 neoplasms. However, the success of treatment varies significantly for different tumors. For example, lung, pancreatic, stomach, and brain tumors show low response to chemotherapy and have generally poor prognosis with a five-year relative survival under 15 %. Within this project, we aim to develop in a rational manner novel multifunctional metal-based drugs for treatment of the above mentioned problematic neoplasms. Our approach is to tether appropriate bioactive molecules to the axial ligands of suitable platinum(IV) scaffolds yielding prodrugs that should be able to overcome the chemoresistance of cancers with poor prognosis. The Prestwick Chemical Library will be used as a source of drug candidates for coupling to the platinum centre. Applying the selective optimization of side activities (SOSA) approach in a high throughput screening manner, the library alone and in combination with the clinically used platinum complexes, will be screened for cytotoxicity in a range of relevant cancer cell lines. Where synergistic effects between the platinum and the organic drug are observed, the hit will be considered for further development of novel multifunctional anticancer agents after verification by means of re-testing. The appropriate Pt(IV) framework will be chosen according to its kinetic inertness in blood, which can be controlled by careful selection of the ligands, and other relevant pharmacological properties. Further tuning of the lead compounds will be accomplished through exploring tumor targeting via glycolysis in order to increase tumor accumulation. All novel complexes will be characterized by 1D and 2D multinuclear NMR spectroscopy, MS, FTIR, elemental analysis, HPLC, X-ray crystallography and DFT calculations. Their pharmacological behavior in vitro will be examined using a variety of biological, biochemical and bioanalytical approaches. Preliminary in vivo screening of the antitumor activity of the most promising compounds will be performed using the chicken embryo chorioallantoic membrane (CAM) model. Based on the obtained results certain complexes will be selected for further evaluation of their toxicity and anti- cancer activity in animal experiments.

The focus of the project was the development of new strategies for improving the chemotherapy of problematic cancers, such as pancreatic and lung carcinoma. Currently, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate treatment for these malignancies, which remain amongst the most deadly diseases with 5-year survival rate under 10%.As a first step, we have developed and validated a screening assay that identifies new potential chemotherapeutics for the treatment of lung and pancreatic cancers, based on drugs already approved for other applications (approach referred as drug repurposing). A library containing 1280 chemically and pharmacologically diverse compounds (drugs or drug-like molecules) was screened against cells derived from lung and pancreatic carcinoma, providing a list of more than 100 compounds that could be active against these problematic cancers. After the respective validation steps, several promising candidates for repositioning emanated, including antiparasitics, cardiac glycosides, as well as few anticancer drugs which are currently not used in the treatment of lung and pancreatic cancers.Subsequently, the screening methodology was expanded with the aim to identify drug-like molecules that can synergistically potentiate the activity of the clinically applied platinum drugs (some of the most widely used and successful chemotherapeutics) against lung and pancreatic carcinoma. Several promising synergistic combinations were found during the screens and the combination effects were further evaluated in various assays. Examples for compounds, which enhance the activity of (or synergize with) one or more of the platinum drugs, include hycanthone (antiparasitic), spironolactone (diuretic), deferoxamine (iron chelator) and the more recent anticancer drugs vorinostat and topotecan. These findings could provide a rational base for selection of new drug combinations for treatment of lung and pancreatic cancers. Furthermore, our methodology could be applied also to optimize drug combinations for clinical trials of new drug candidates.Finally, one of the synergistic combinations identified during the study served as a foundation for the development of a series of new compounds, designed as prodrugs for the platinum drug carboplatin and the iron chelator deferoxamine. Such type of dual-action compounds has potential to overcome the resistance in some malignancy types and is currently examined in different cancer models