Predicting new drug indications for prostate cancer: The integration of an in silico proteochemometric network pharmacology platform with patient-derived primary prostate cells.

BACKGROUND: Drug repurposing enables the discovery of potential cancer treatments using publically available data from over 4000 published Food and Drug Administration approved and experimental drugs. However, the ability to effectively evaluate the drug's efficacy remains a challenge. Impediments to broad applicability include inaccuracies in many of the computational drug-target algorithms and a lack of clinically relevant biologic modeling systems to validate the computational data for subsequent translation. METHODS: We have integrated our computational proteochemometric systems network pharmacology platform, DrugGenEx-Net, with primary, continuous cultures of conditionally reprogrammed (CR) normal and prostate cancer (PCa) cells derived from treatment-naive patients with primary PCa. RESULTS: Using the transcriptomic data from two matched pairs of benign and tumor-derived CR cells, we constructed drug networks to describe the biological perturbation associated with each prostate cell subtype at multiple levels of biological action. We prioritized the drugs by analyzing these networks for statistical coincidence with the drug action networks originating from known and predicted drug-protein targets. Prioritized drugs shared between the two patients' PCa cells included carfilzomib (CFZ), bortezomib (BTZ), sulforaphane, and phenethyl isothiocyanate. The effects of these compounds were then tested in the CR cells, in vitro. We observed that the IC50 values of the normal PCa CR cells for CFZ and BTZ were higher than their matched tumor CR cells. Transcriptomic analysis of CFZ-treated CR cells revealed that genes involved in cell proliferation, proteases, and downstream targets of serine proteases were inhibited while KLK7 and KLK8 were induced in the tumor-derived CR cells. CONCLUSIONS: Given that the drugs in the database are extremely well-characterized and that the patient-derived cells are easily scalable for high throughput drug screening, this combined in vitro and in silico approach may significantly advance personalized PCa treatment and for other cancer applications.

Systems biology, complexity, and the impact on antiepileptic drug discovery.

The number of available anticonvulsant drugs increased in the period spanning over more than a century, amounting to the current panoply of nearly two dozen so-called antiepileptic drugs (AEDs). However, none of them actually prevents/reduces the post-brain insult development of epilepsy in man, and in no less than a third of patients with epilepsy, the seizures are not drug-controlled. Plausibly, the enduring limitation of AEDs' efficacy derives from the insufficient understanding of epileptic pathology. This review pinpoints the unbalanced reductionism of the analytic approaches that overlook the intrinsic complexity of epilepsy and of the drug resistance in epilepsy as the core conceptual flaw hampering the discovery of truly antiepileptogenic drugs. A rising awareness of the complexity of epileptic pathology is, however, brought about by the emergence of nonreductionist systems biology (SB) that considers the networks of interactions underlying the normal organismic functions and of SB-based systems (network) pharmacology that aims to restore pathological networks. By now, the systems pharmacology approaches of AED discovery are fairly meager, but their forthcoming development is both a necessity and a realistic prospect, explored in this review.