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Purpose: Ireland's Sláintecare health plan is placing an increased focus on primary care. A community oncology nursing programme was developed to train community nurses to deliver care in the community. While the initial pilot was proven to be clinically safe, no cost evaluation was carried out. This study aims to compare the costs of providing cancer support services in a day-ward versus in the community. Methods: 183 interventions (40 in day-ward and 143 in community) were timed and costed using healthcare professional salaries and the Human Capital method. Results: From the healthcare provider perspective, the day-ward was a significantly cheaper option by an average of €17.13 (95% CI €13.72 - €20.54, p

Purpose Cancer patients are a particularly vulnerable population group, facing an increase in physical, mental, logistical and financial difficulties. This, as well as Ireland's increased focus on primary care with the Slaintecare health plan, led to the development of the Community Oncology Nursing Programme, where community nurses are trained to provide cancer care in the community. This paper sought to explore the lived experiences of the patients and nurses involved in this programme in order to examine its impact as well as determine facilitators and roadblocks for future development. Methods A qualitative examination of the service was carried out by interviewing cancer patients receiving care as part of the programme as well as the nurses delivering care, both in the community and hospital day-ward. Thematic analysis was used. Results Themes of improved patient experience, nurse-patient relationship, the importance of location and roadblocks to further implementation of the programme emerged. There was a universal belief that the programme offered benefits to the patient and improved their care in some manner. Conclusions The Community Oncology Nursing Programme has been well received by both nurses and patients. The service provided by community nurses as part of this programme offers benefits to patients and an improved cancer service.

Background and Objective The inhibition of fatty acid amide hydrolase 1 (FAAH) has been proposed as a novel mechanism for treating pain syndromes by increasing the levels of endogenous cannabinoids (ECs). This study describes the safety, tolerability, pharmacokinetics and pharmacodynamics of V158866, a reversible FAAH inhibitor, after first administration to man. Methods 51 healthy male subjects were recruited into this double-blind, randomised, placebo-controlled, adaptive dose, phase I single (Part A) and repeated ascending dose (Part B) study. The primary outcome was the safety and tolerability of V158866. Secondary outcomes were (1) pharmacokinetics of V158866 and (2) pharmacodynamics of V158866, as assessed by changes in plasma EC concentrations. Results Single oral doses of 5–300 mg and repeated oral doses of 50–500 mg were evaluated. V158866 was well tolerated, with no apparent treatment-related effects on laboratory variables. V158866 was rapidly absorbed with a mean terminal elimination half-life of 9.6–18.3 h (Day 7; Part B). V158866 reached steady state within 2–3 days of administration, with an accumulation ratio, based on AUC0–24h, of approximately 2 on Day 7. V158866 showed a linear relationship between dose and AUC across the entire dose range. V158866 caused reversible, dose-related increases in plasma ECs. At hemi-equilibrium, there was a sigmoidal maximum effect relationship between plasma V158866 concentrations and changes in plasma ECs. Conclusions V158866 is well tolerated, with linear pharmacokinetics suitable for once-daily administration, and reversible effects on plasma ECs. Maximum increases in plasma ECs occur with V158866 doses of 300–500 mg/day. Electronic supplementary material The online version of this article (doi:10.1007/s40268-016-0127-y) contains supplementary material, which is available to authorized users.

On sustaining damage to their DNA, cells employ a sophisticated mechanism of detection and repair, termed the DNA damage response (DDR). As a critical component of the DDR and G2/M checkpoint, Chk1 kinase represents an attractive target for cancer therapy. We have utilized a structure-based drug design approach to identify and develop VER-250840, a novel, orally active inhibitor of the checkpoint kinase, Chk1. VER-250840 exhibited sub-nM potency against Chk1 kinase with exquisite selectivity over an extensive and diverse panel of kinases. In vitro, VER-250840 inhibited Chk1 autophosphorylation with an IC50 of 1.0 nM and increased the number of S-phase tumor cells staining positive for pan-nuclear γH2AX with an EC50 of 7 - 27 nM. Accumulated genomic DNA damage by Chk1 inhibition led to irreversible cell cycle arrest, inhibition of tumor cell proliferation, increased replication stress, and cell death in both 2D culture and multicellular tumor spheroids. In an in vivo A2058 tumor xenograft PD study, VER-250840 demonstrated rapid and sustained inhibition of Chk1 auto-phosphorylation within 30 minutes of oral administration. Doses of 10 mg/kg and higher PO resulted in greater than 90% inhibition of tumor pChk1 (S296) over 24 hours. In SKOV3 in vivo models, VER-250840 inhibited Chk1 auto-phosphorylation, modulated other biomarkers of replication stress and DNA damage, and exhibited moderate antitumor activity with minimal toxicity when administered orally on a 21-day once-daily schedule. Work is ongoing to further optimize in vivo efficacy. In conclusion, VER-250840 demonstrates potent and selective activity as a monotherapy both in vitro and in vivo. From these findings, further evaluation and optimization of this novel kinase inhibitor is justly merited. Citation Format: Joanne Wayne, Stephen Stokes, Nicolas Foloppe, Helen Browne, Teresa Brooks, Karen Benwell, Lisa Baker, Zoe Daniels, Andrea Fiumana, Christopher Graham, Alba Macias, Daniel Maddox, Sean McKenna, Christopher Northfield, Stuart Ray, Heather Simmonite, Emma Stefaniak, Paul Webb, Mike Wood, Andrew Massey. Identification and preclinical characterisation of VER-250840, a potent, selective Chk1 inhibitor with in vivo oral single-agent antitumor activity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B163.

The anti-apoptotic function of the 70 kDa family of heat shock proteins and their role in cancer is well documented. Dual targeting of Hsc70 and Hsp70 with siRNA induces proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition.We have previously described the discovery and synthesis of novel adenosine-derived inhibitors of the 70 kDa family of heat shock proteins; the first inhibitors described to target the ATPase binding domain. The in vitro activity of VER-155008 was evaluated in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors.VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI(50)s in the range 5.3-14.4 microM, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 cells. VER-155008 potentiated the apoptotic potential of a small molecule Hsp90 inhibitor in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level.These data suggest that small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/Hsp70 inhibition remain to be determined.

// Andrew J. Massey 1 , Stephen Stokes 1 , Helen Browne 1 , Nicolas Foloppe 1 , Andrea Fiumana 1 , Simon Scrace 1,3 , Mandy Fallowfield 1 , Simon Bedford 1 , Paul Webb 1 , Lisa Baker 1 , Mark Christie 2 , Martin J. Drysdale 1,4 and Mike Wood 1 1 Vernalis Research, Granta Park, Cambridge, UK 2 Akranim Ltd, Maidstone, UK 3 Horizon Discovery, Cambridge Research Park, Waterbeach, Cambridge, UK 4 Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, UK Correspondence to: Andrew J. Massey, email: // Keywords : Chk1, V158411, fragment, drug discovery, colon cancer Received : June 17, 2015 Accepted : September 14, 2015 Published : September 30, 2015 Abstract Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro , p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation.

The role of the 70 kDa heat shock protein isoforms (Hsc70 and Hsp70) in cancer development and progression through their ability to inhibit apoptosis and via their role as Hsp90 co-chaperones has been well documented. Dual targeting of Hsc70 and Hsp70 with siRNA has previously been demonstrated to induce proteasome-dependent degradation of Hsp90 client proteins and extensive tumor specific apoptosis as well as the potentiation of tumor cell apoptosis following pharmacological Hsp90 inhibition. The design and synthesis of novel adenosine-derived inhibitors of Hsp70, guided by modelling and X-ray crystallographic structures of these compounds in complex with Hsc70/BAG-1, has been described.1 These were the first inhibitors described to target the ATPase binding domain of this family of chaperones. Many of these compounds exhibited submicromolar affinity for Hsp70, were highly selective over Hsp90, and displayed in vitro activity against a variety of human tumor cell lines. We further describe the in vitro mode of action of one of the most potent analogues, VER-155008 in HCT116, HT29, BT474 and MDA-MB-468 carcinoma cell lines. Cell proliferation, cell cycle, cell apoptosis and caspase 3/7 activity was determined for VER-155008 in the absence or presence of small molecule Hsp90 inhibitors. VER-155008 inhibited the proliferation of human breast and colon cancer cell lines with GI50s in the range 5.3 to 14.4 M, and induced Hsp90 client protein degradation in both HCT116 and BT474 cells. As a single agent, VER-155008 induced caspase-3/7 dependent apoptosis in BT474 cells and non-caspase dependent cell death in HCT116 and HT29 cells. VER-155008 potentiated the apoptotic potential of the small molecule Hsp90 inhibitors VER-821602 and 17-AAG in HCT116 but not HT29 or MDA-MB-468 cells. In vivo, VER-155008 demonstrated rapid metabolism and clearance, along with tumor levels below the predicted pharmacologically active level. These data suggest that as a single agent, small molecule inhibitors of Hsc70/Hsp70 phenotypically mimic the cellular mode of action of a small molecule Hsp90 inhibitor and can potentiate the apoptotic potential of a small molecule Hsp90 inhibitor in certain cell lines. The factors determining whether or not cells apoptose in response to Hsp90 inhibition or the combination of Hsp90 plus Hsc70/Hsp70 inhibition remain to be determined. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A212.

Conventional chemotherapeutic agents such as gemcitabine, cisplatin or irinotecan induce DNA damage and activate cell cycle checkpoints. P53 defective tumors lack a functional G1 checkpoint and rely heavily on the S and G2 checkpoints, and the effector kinase Chk1, for protection against this DNA damage. Inhibiting Chk1 potentiates the anti-tumor effects of these cytotoxic chemotherapeutic agents. Targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor efficacy of DNA damaging cytotoxic chemotherapeutic drugs without increasing their toxicity to normal cells. Elaboration of a designed kinase directed fragment core utilizing X-ray structure guided design lead to the identification of a potent pyridone series of Chk1 inhibitors. Further profiling identified V158411 as the lead candidate. X-ray crystallography identified V158411 as being bound to the ATPase site in the kinase domain of Chk1. V158411 potently inhibited Chk1 and Chk2 with IC50s of 4.4 and 4.5nM respectively. The addition of V158411 to gemcitabine or camptothecin treated cells abrogated the cell cycle checkpoints induced by these agents resulting in the expected modulation of cell cycle proteins and increased apoptosis. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient but not proficient human tumor cell lines in vitro. V158411 could be formulated in a simple aqueous form suitable for i.v. dosing. In nude mice, V158411 was well tolerated as a single agent (MTD >100mg/kg) and in combination with irinotecan. Intravenous administration to rats and mice resulted in low plasma clearances (20mL/min/kg) and long half-lives (2.9–3.7h). In tumor bearing animals, V158411 was detected at high concentrations in the tumor (tumor:plasma AUC ratio of 4.7) with a long tumor elimination half life of 22 hours. No pharmacologically relevant in vivo drug-drug interaction with irinotecan was identified. V158411 potentiated the anti-tumor activity of gemcitabine and irinotecan in a variety of human tumor xenograft models without additional systemic toxicity. These results demonstrate the potential of combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Based on this data, the clinical development of V158411 is currently being actively pursued. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C207.