Given the complex nature of cancer and the cell's ability to effectively compensate for individual perturbation through evolutionarily honed adaptive mechanisms, there is strong expectation that combination therapy approaches may be required to address the limitations that have emerged from single agent therapy. Synthetic lethality provides strong biological rationale supporting this observation, although mechanisms of compound synergy and sensitization are in general more complex than individual gene-pair interactions. Synthetic lethal genes have been elucidated mainly via large-scale screens in model organisms, or by pooled shRNA/CRISPR screens in cells harboring specific genetic events, or based on mechanistic understanding of specific pathways. These methodologies are laborious, expensive, and prone to significant false positive and negative rates due to the nature of pooled screens. More importantly, results are often idiosyncratic, depending on the specific genetic and epigenetic context of the cellular models used in the analysis.
To address these challenges, we have developed network-based methods to identify master regulator proteins that are responsible for maintaining tumor state, despite being rarely mutated using only patient-derived data. Master regulators are highly enriched in synthetic lethal interactions that can be elucidated computationally, via protein-target analysis. Furthermore, the approach can be trivially extended to elucidate synergistic drug interaction, based on perturbational assays of individual compounds. In this presentation, we will address the discovery of synthetic lethal genes and synergistic compounds in several tumor contexts, including lymphoma, breast cancer, prostate cancer, and glioma, which has led to the design and implementation of novel clinical trials. We will also discuss integration of these methodologies into an N of 1 protocol, which is currently enrolling 260 patients across 14 distinct malignancies.
Citation Format: Andrea Califano. Systematic, network-based elucidation of synthetic lethal proteins and synergistic compounds [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA21.