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Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).

Purpose This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax ® ) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. Methods Twenty-one patients with peritoneal malignancies received Nanotax ® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50–275 mg/m 2 ) of Cremophor-free Nanotax ® were administered intraperitoneally for one to six cycles (every 28 days). Results Intraperitoneal (IP) administration of Nanotax ® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration–time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450–2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax ® IP treatment. Conclusions Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax ® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.

Developing a functional and productive relationship between a contract research organization (CRO) and a sponsor company can be an intricate and delicate endeavor. Time, strategy, effective communication, and plain hard work on the part of both companies are required to lay a solid foundation for a smooth outsourcing contract. After a CRO has established a business partner-type relationship with a customer, the client's desired end goal should be carefully described and identified. The next step is to put together a core team of individuals from both the CRO and the client's organization who will be principally involved with the project. Once the core team is chosen, the team members should collaborate to map out the best route to the desired goal. One of the pitfalls that a CRO and client can encounter is unrealistic or unspoken expectations. After the customer's expectations have been disclosed, a CRO should assess all of the acquired information and begin to create a written document of the services that the project will require.

Ewing sarcoma (ES) are aggressive pediatric bone and soft tissue tumors driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. Treatment of ES patients consists of up to 9 months of alternating courses of 2 chemotherapeutic regimens. Furthermore, EWS-ETS-targeted therapies have yet to demonstrate clinical benefit, thereby emphasizing a clinical responsibility to search for new therapeutic approaches. Our previous in silico drug screening identified entinostat as a drug hit that was predicted to reverse the ES disease signatures and EWS-FLI1-mediated gene signatures. Here, we establish preclinical proof of principle by investigating the in vitro and in vivo efficacy of entinostat in preclinical ES models, as well as characterizing the mechanisms of action and in vivo pharmacokinetics of entinostat. ES cells are preferentially sensitive to entinostat in an EWS-FLI1 or EWS-ERG-dependent manner. Entinostat induces apoptosis of ES cells through G0/G1 cell cycle arrest, intracellular reactive oxygen species (ROS) elevation, DNA damage, homologous recombination (HR) repair impairment, and caspase activation. Mechanistically, we demonstrate for the first time that HDAC3 is a transcriptional target of EWS-FLI1 and that entinostat inhibits growth of ES cells through suppressing a previously unexplored EWS-FLI1/HDAC3/HSP90 signaling axis. Importantly, entinostat significantly reduces tumor burden by 97.4% (89.5 vs. 3397.3 mm3 of vehicle, p < 0.001) and prolongs the median survival of mice (15.5 vs. 8.5 days of vehicle, p < 0.001), in two independent ES xenograft mouse models, respectively. Overall, our studies demonstrate promising activity of entinostat against ES, and support the clinical development of the entinostat-based therapies for children and young adults with metastatic/relapsed ES.Key messages• Entinostat potently inhibits ES both in vitro and in vivo.• EWS-FLI1 and EWS-ERG confer sensitivity to entinostat treatment.• Entinostat suppresses the EWS-FLI1/HDAC3/HSP90 signaling.• HDAC3 is a transcriptional target of EWS-FLI1.• HDAC3 is essential for ES cell viability and genomic stability maintenance.

Abstract Background: Inhaled chemotherapeutics may enhance pulmonary drug exposure to malignant lesions in the lung without substantially contributing to systemic toxicities. The pharmacokinetic profile of inhaled submicron particle paclitaxel (NanoPac®) in healthy rodent plasma and lung tissue is evaluated here to determine administration proof-of-principle. Methods: Healthy male Sprague Dawley rats received paclitaxel in one of three arms: intravenous nab-paclitaxel at 2.9 mg/kg (IVnP), inhaled NanoPac low dose (IHNP-LD) at 0.38 mg/kg, or inhaled NanoPac high dose (IHNP-HD) at 1.18 mg/kg. Plasma and lung tissue paclitaxel concentrations were determined using ultraperformance liquid chromatography tandem mass spectrometry from animals sacrificed at 10 time points ranging up to 2 weeks after administration. Peak concentration (Cmax), apparent residence half-life (T1/2), exposure (AUC(last)), and dose-normalized exposure (AUCD(last)) were determined. Pulmonary histopathology was performed on rats sacrificed at the 336-hour time point. Results: Paclitaxel was detectable and quantifiable in the rat lung for both inhaled NanoPac arms sampled at the final necropsy, 336 hours postadministration. Substantial paclitaxel deposition and retention resulted in an order of magnitude increase in dose-normalized pulmonary exposure over IVnP. Inhaled NanoPac arms had an order of magnitude lower plasma Cmax than IVnP, but followed a similar plasma T1/2 clearance (quantifiable only to 72 hours postadministration). Pulmonary histopathology found all treated animals indistinguishable from treatment-naive rats. Conclusion: In the rodent model, inhaled NanoPac demonstrated substantial deposition and retention of paclitaxel in sampled lung tissue. Further research to determine NanoPac's toxicity profile and potential efficacy as lung cancer therapy is underway.

Abstract Background: This study evaluated the antineoplastic and immunostimulatory effects of inhaled (IH) submicron particle paclitaxel (NanoPac®) in an orthotopic non-small cell lung cancer rodent model. Methods: Male nude rats were whole body irradiated, intratracheally instilled with Calu-3 cancer cells and divided into six treatment arms (n = 20 each): no treatment (Group 1); intravenous nab-paclitaxel at 5.0 mg/kg once weekly for 3 weeks (Group 2); IH NanoPac at 0.5 or 1.0 mg/kg, once weekly for 4 weeks (Groups 3 and 4), or twice weekly for 4 weeks (Groups 5 and 6). Upon necropsy, left lungs were paraffin embedded, serially sectioned, and stained for histopathological examination. A subset was evaluated by immunohistochemistry (IHC), anti-pan cytokeratin staining AE1/AE3+ tumor cells and CD11b+ staining dendritic cells, natural killer lymphocytes, and macrophage immune cells (n = 2, Group 1; n = 3 each for Groups 2–6). BCL-6 staining identified B lymphocytes (n = 1 in Groups 1, 2, and 6). Results: All animals survived to scheduled necropsy, exhibited no adverse clinical observations due to treatment, and gained weight at the same rate throughout the study. Histopathological evaluation of Group 1 lung samples was consistent with unabated tumor growth. Group 2 exhibited regression in 10% of animals (n = 2/20). IH NanoPac-treated groups exhibited significantly higher tumor regression incidence per group (n = 11–13/20; p < 0.05, χ2). IHC subset analysis revealed tumor-nodule cluster separation, irregular borders between tumor and non-neoplastic tissue, and an increased density of infiltrating CD11b+ cells in Group 2 animals (n = 2/3) and in all IH NanoPac-treated animals reviewed (n = 3/3 per group). A single animal in Group 4 and Group 6 exhibited signs of pathological complete response at necropsy with organizing stroma and immune cells replacing areas presumed to have previously contained adenocarcinoma nodules. Conclusion: Tumor regression and immune cell infiltration were observed in all treatment groups, with an increased incidence noted in animals receiving IH submicron particle paclitaxel treatment.