The project addresses the identification and validation of new aims for a combinatorial therapy of Mcl-1-dependent types of cancer

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Basic research has made crucial discoveries in understanding what triggers cancer development. As a result specific defects in cancer cells are now the target of new therapeutic drugs. However, each type of cancer harbours unique genetic alterations, creating the challenge to match a targeted therapy to a specific cancer indication. Also, gene mutations result in resistance to prevailing therapies. Traditionally, a very time-consuming process addresses the hurdles of human clinical trials to determine which patients will benefit from a drug combination. Another approach to address this issue is the principle of synthetic lethality. This refers to the identity of two genes whose knockouts individually are benign, but together their elimination results in cell lethality. For cancer therapy, the combination of two or more drugs could be used to impede the pathways of two synthetically lethal genes leading to cancer cell death. An example is bortezomid treatment of multiple myeloma and mantle cell lymphoma, which is an approved agent that targets the proteasome. As the pro-survival protein Mcl-1 rapidly turns over via the proteasome, this results in Mcl-1 induction and resistance to bortezomib. Combining bortezomib with the agent obatoclax that targets Mcl-1, results in strong synergies, suggesting a rational clinical development strategy. The project will analyze the role for synthetic lethality opportunities in cancer therapy, targeting Mcl-1. This protein is the ideal candidate, as cancer cells have evolved pathways to preserve antiapoptotic Mcl-1. The project will employ an RNAi screen to identify signal transduction pathways that act in synergy with Mcl-1 to provide pro-survival signals and therefore represent new therapeutic opportunities for drug development. Finally, prioritized hit validation assays will be carried out with identified targets.