Toll-like receptors (TLRs) are expressed by a wide variety of cell types including immune cells. They play a crucial role in the inflammatory and host defense response against microorganisms, and triggering TLRs can mediate the activation of innate immunity. Furthermore, research suggests that various TLRs may function differently on different tumor cells. The change in TLR activity may elicit an anti-tumor activity in hepatocellular carcinoma (HCC) cells and may serve as a novel therapeutic target for HCC therapy. Areas covered: This review discusses the role of the TLR family in HCC and the underlying signaling pathway of TLRs as a form of pattern recognition receptor in mediating inflammation and HCC immunity responses. Agonists and antagonists of TLRs, which render TLRs as potential therapeutic targets, activate downstream molecules, subsequently causing HCC cell survival. The proliferation or protection against the development of HCC is also described. Expert opinion: A series of studies have highlighted a crucial role of TLRs in HCC and consider TLR signaling pathways as potential therapeutic targets for HCC. However, the conclusions of these studies are in part paradoxical and controversial. Thus, it is necessary to extend further research to help determine the signaling pathways involved.

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The family of inhibitor of apoptosis proteins (IAPs) plays a key role in the suppression of proapoptotic signaling; hence, a small molecule that disrupts the binding of IAPs with their functional partner should restore apoptotic response to proapoptotic stimuli in cells. The continued publication of new patent applications of IAP antagonists over the past 4 years is a testament to the continued interest surrounding the IAP family of proteins.
This review summarizes the IAP antagonist patent literature from 2010 to 2014. Monovalent and bivalent Smac mimetics will be covered as well as two new developments in the field: IAP antagonists coupled to or merged with other targeted agents and new BIR2 selective IAP antagonists.
In addition to the well-explored scaffolds for monovalent and bivalent Smac-mimetics, some companies have taken more drastic approaches to explore new chemical space – for example, fragment-based approaches and macrocyclic inhibitors. Furthermore, other companies have designed compounds with alternative biological profiles – tethering to known kinase binding structures, trying to target to the mitochondria or introducing selective binding to the BIR2 domain. An overview of the status for the four small molecule IAP antagonists being evaluated in active human clinical trials is also provided.

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It is challenging to evaluate how tumour pathophysiology influences nanomedicine therapeutic effect; however, this is a key question in drug delivery. An advanced analytical method was developed to quantify the spatial distribution of drug-induced effect in tumours with varied stromal morphologies. The analysis utilises standard immunohistochemistry images and quantifies the frequency of positive staining as a function of distance from the stroma. Two stromal morphologies – Estuary and Tumour Island – were classified in 28 tumours from a lung cancer explant model in mice treated with liposomal doxorubicin. Analysis demonstrated that Estuary-like tumours presented a highly convoluted tumour-stroma interface, with most tumour cells in close proximity to vessels; these tumours were 8.8-fold more responsive to liposomal doxorubicin than were Tumour Island-like tumours, which were nearly unresponsive to liposomal doxorubicin. SDARS analysis allows the relative treatment effect to be assessed in tumours individually, and enables investigation of nanomedicine delivery in complex tumour pathophysiologies.
Advances in nanotechnology have brought about many novel treatment modalities for cancer. Nonetheless, there is no standard evaluation technique for tumor cells’ drug response. The authors here utilized patient-derived tumour xenograft (PDTX) models to have a more translatable pre-clinical evaluation platform for nanomedicine drugs. They then used advanced imaging acquisition technique to analyze tumor stromal morphology, which they named Spatial Distribution of Apoptosis Relative to Stroma (SDARS). The findings would have significant clinical impact as it would help predict the eventual clinical drug response.
Copyright © 2015 Elsevier Inc. All rights reserved.

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Pharmacy benefits management companies have emerged as the national standard for the management of prescription drugs in the United States. The objective of this study was to estimate the annual costs per treated patient of 8 biologics indicated for select immune-mediated inflammatory diseases: moderate to severe rheumatoid arthritis, moderate to severe plaque psoriasis, active psoriatic arthritis, and/or active ankylosing spondylitis.
Using the Medco pharmacy benefits-management database, data from patients aged 18 to 63 years with ≥1 claim for abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, or ustekinumab, dated between January 1, 2008 and August 31, 2011, were collected. Eligible patients were continuously enrolled for ≥180 days before and 360 days after the date of the first biologic claim (index date), and had ≥1 claim associated with a diagnosis of rheumatoid arthritis, moderate to severe plaque psoriasis, active psoriatic arthritis, and/or active ankylosing spondylitis in the 180 days before or 30 days after the index date. The annual total costs per treated patient were calculated as the total dose of the index biologic and all other biologics for which there was a claim in the postindex period, multiplied by the wholesale acquisition cost as of October 1, 2013, plus the costs associated with administrations (calculated as number of infusions multiplied by the 2013 Medicare Physician Fee Schedule costs).
Within the study population (N = 8306; 5356 (64.5%) women, 2950 men (35.5%), average age: 42.3 years (SD: 10.0)), the most commonly used biologics were etanercept (43.1%), adalimumab (31.0%), and infliximab (17.0%), which accounted for 91.1% of all biologic prescriptions. Total costs per treated patient across indications were as follows: adalimumab, $23,427 to $26,304; infliximab, $22,824 to $28,907; and etanercept, $21,468 to $27,748, whereas abatacept, certolizumab, golimumab, rituximab, and ustekinumab were associated with a larger range: $17,017 to $41,888.
The present study provides insight into the prescribing patterns and cost differences among 8 biologic agents used for the treatment of immune-mediated inflammatory diseases. This information may prove useful when designing a pharmacy benefits-management formulary.
Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

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