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Predicting targeted drug combinations based on Pareto optimal patterns of coexpression network connectivity.

ABSTRACT: Molecularly targeted drugs promise a safer and more effective treatment modality than conventional chemotherapy for cancer patients. However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes. Combination therapies can overcome resistance but finding the optimal combinations efficiently presents a formidable challenge. Here we introduce a new paradigm for the design of combination therapy treatment strategies that exploits the tumor adaptive process to identify context-dependent essential genes as druggable targets.We have developed a framework to mine high-throughput transcriptomic data, based on differential coexpression and Pareto optimization, to investigate drug-induced tumor adaptation. We use this approach to identify tumor-essential genes as druggable candidates. We apply our method to a set of ER(+) breast tumor samples, collected before (n?=?58) and after (n?=?60) neoadjuvant treatment with the aromatase inhibitor letrozole, to prioritize genes as targets for combination therapy with letrozole treatment. We validate letrozole-induced tumor adaptation through coexpression and pathway analyses in an independent data set (n?=?18).We find pervasive differential coexpression between the untreated and letrozole-treated tumor samples as evidence of letrozole-induced tumor adaptation. Based on patterns of coexpression, we identify ten genes as potential candidates for combination therapy with letrozole including EPCAM, a letrozole-induced essential gene and a target to which drugs have already been developed as cancer therapeutics. Through replication, we validate six letrozole-induced coexpression relationships and confirm the epithelial-to-mesenchymal transition as a process that is upregulated in the residual tumor samples following letrozole treatment.To derive the greatest benefit from molecularly targeted drugs it is critical to design combination treatment strategies rationally. Incorporating knowledge of the tumor adaptation process into the design provides an opportunity to match targeted drugs to the evolving tumor phenotype and surmount resistance.

SUBMITTER: Penrod NM

PROVIDER: S-EPMC4062052 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Predicting targeted drug combinations based on Pareto optimal patterns of coexpression network connectivity.

Penrod Nadia M NM Greene Casey S CS Moore Jason H JH

Genome medicine 20140430 4

<h4>Background</h4>Molecularly targeted drugs promise a safer and more effective treatment modality than conventional chemotherapy for cancer patients. However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes. Combination therapies can overcome resistance but finding the optimal combinations efficiently presents a formidable challenge. Here we introduce a new paradigm for the design of combination therapy ...[more]

PMID: 24944582

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Project description:The FITExP profiling approach was used to identify protein hits from cells incubated with RAPTA-T or RAPTA-EA. Validation experiments with paclitaxel and cisplatin underlined the reliability of the method and hit lists for both test compounds (and?) gave physiologically viable anti-cancer mechanisms. The hit proteins for paclitaxel match with those published and the ones obtained for cisplatin were related to DNA repair, which is in line with the principal mechanism of cisplatin cytotoxicity involving the formation of nuclear DNA lesions. RAPTA-T treatment leads to upregulation of multiple hits suggesting a broad mechanism of action involving both metastasis and tumorigenicity. In contrast, hit proteins identified after incubation with RAPTA-EA are linked to regulation of the oxidative stress response and are therefore thought to be conferred by the EA moiety in the drug. From a therapeutic standpoint, RAPTA-EA could be explored in cancers where EA alone has shown potency, such as chronic lymphocytic leukemias,91 or where EA combined with another agent shows synergy, such as the combination of EA with afatinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitors for breast cancers.92 On the other hand, due to its broad mechanism of action, RAPTA-T could potentially be more useful if used concomitantly with drugs that target specific cancer pathways and could also play a role in therapies for later stage cancers due to its anti-metastatic properties. Here, application of the FITExP allowed us to gauge the mechanistic pathways involved in the action of two novel ruthenium(II) metallodrugs with very different phenotypic characteristics and from this knowledge infer their role in therapy. Potentially, future application of the FITExP approach in this manner could be useful for identification of cancer chemotherapy drug combinations, where commonly cancer clinical trials fail at phase II where drug combinations are first tried and tested.

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Predicting targeted drug combinations based on Pareto optimal patterns of coexpression network connectivity.

Publications

Predicting targeted drug combinations based on Pareto optimal patterns of coexpression network connectivity.

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