The study of cancer therapeutics in mouse models is impaired by our limited understanding of whether the regulatory mechanisms that mediate their activity are conserved in human patients. To address this limitation, we have constructed a mouse prostate cancer regulatory model (interactome) based on in vivo drug-based perturbations of 15 transgenic models of prostate cancer as well as a human interactome from a large-scale set of molecular profiles of patient derived tissue. For the mouse interactome, we performed molecular perturbations by treatment with small molecules, including inhibitors of the androgen receptor, tyrosine kinase receptors, MAPK, Akt/mTOR, JAK/STAT, and NF-KB signaling pathways as well as several chemotherapeutic agents. We then used a cross-species analysis to independently identify and match master regulators of cancer progression with the therapeutic compounds that optimally abrogate their activity both in the human and in the mouse regulatory models. Cross-species interactome interrogation represents a new paradigm for ‘human to mouse to human’ (H2M2H) analyses, aimed at maximizing translational potential. By interrogating our regulatory models using molecular profiles of cancer progression, we identified two genes, FOXM1 and CENP-F, that are synergistically required for the maintenance of aggressive, metastatic prostate tumors and are predictive of clinical outcome. Indeed, lentivirus mediated shRNA co-silencing of these master regulators dramatically decreases tumorigenesis in vivo. Interrogation of these interactomes using small molecule signatures further identified candidate combinations that successfully abrogate the activity of the FOXM1/CENPF axis in metastatic prostate cancer GEM models, and significantly reduce tumor and metastatic burden in vivo, thus improving survival significantly over standard of care chemotherapy. Our findings suggest that simultaneous targeting of FOXM1 and CENPF may be especially beneficial in patients who have failed conventional chemotherapy.
Citation Format: Antonina Mitrofanova, Alvaro Aytes, Celine Lefebvre, Michael Shen, Cory Abate-Shen, Andrea Califano. Cross-species analysis of genome-wide regulatory models elucidates master regulators of prostate cancer progression and treatment response. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr A26.
- ©2013 American Association for Cancer Research.