Multiple Myeloma (MM) is a malignant hematological neoplasm that causes considerable and rapidly increasing morbidity, mortality, and health care expenditures. Although the last decade has seen considerable improvements in overall and progression-free survival, all patients will ultimately develop clinical resistance to all presently available drugs and drug combinations and thus, MM remains a fatal incurable disease. Consequently, novel therapeutics that enable a cure for MM patients are an unmet medical need. Many drug candidates that had shown significant activity against myeloma cells in preclinical studies failed to demonstrate any activity in clinical trials (DeFeCTs = Drugs that failed in clinical trials). However, most of these preclinical studies focused on analyzing the effect of drug candidates on purified tumor cells ignoring the evidence that the tumor microenvironment sustains most of the hallmarks of cancer and in consequence significantly influences drug sensitivity.
Thus, innovative three dimensional in vitro assays, in which the targeting of cancer cells within their respective microenvironment can be modeled, hold the best promise to identify novel therapeutics, which eradicate all tumor cells and subsequently cure this disease.
In the direction of developing predictive screening assays, we have investigated parameters that contribute to myeloma cell drug resistance including elements of the bone marrow microenvironment (BMM) and have thereby gained expertise in establishing a three dimensional cellular architecture, in which myeloma cells are cultured under conditions typical for the bone marrow. This assay has been optimised with a training set of ten DeFeCTs that had been previously shown to be effective in the traditional preclinical myeloma test system, i.e. purified tumor cells cultured with serum containing medium. In the course of these experiments the improved assay has been successful to predict the failure of the majority of these DeFeCTs. We have used this improved composite MM-BMM screening assay to discover, develop, and optimize a novel lead compound: OTVICICLIB