The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors indicate the need for a new generation of drugs. Therefore, we focused on developing an oral proteasome inhibitor with improved efficacy and safety profiles.
The in vitro inhibition of the 20S proteasome catalytic activities was determined in human multiple myeloma (MM) cellular lysates with fluorogenic peptide substrates specific for each catalytic subunit. Cell cytotoxicity was assessed with the ATP bioluminescence assay using human cell samples from tumor cell lines, MM patients or normal healthy donors. In mice bearing human MM xenografts, a single dose of LC53-0110 was administered orally, and concentration-time profiles of LC53-0110 and the 20S proteasome catalytic activities in plasma, blood, and tumor were determined. The efficacy of repeat-dose compound with regard to tumor growth inhibition in vivo was also evaluated in the same MM xenograft models.
LC53-0110 is far more specific for the chymotrypsin-like proteolytic (β5) site of the 20S proteasome as compared to bortezomib, carfilzomib, or ixazomib. LC53-0110 treatment showed accumulation of ubiquitinated proteins, inhibited cell viability with a low nM range potency in various tumor cell lines, and showed potent activity on CD138(+) cells isolated from MM patients who are resistant/refractory to current FDA-approved drug treatment. When a single dose was administered orally to tumor-bearing mice, LC53-0110 showed both greater maximum and sustained tumor proteasome inhibition as compared with ixazomib in MM xenograft models. The robust pharmacodynamic responses in tumor correlated with tumor growth regression. In addition, LC53-0151, an analog of LC53-0110, in combination with pomalidomide, a third-generation immunomodulatory drug, showed synergistic inhibition of tumor growth both in vitro and in the xenograft mouse model.
In view of the in vitro, in vivo, and ex vivo profiles, further investigation of additional LC compounds in preclinical studies is warranted for the nomination of a clinical development candidate.

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Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60-80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis.

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Chondroblastoma is a benign tumor classically located within the epiphysis of the long bones. The tumor is believed to arise from immature cells of the epiphyseal plate. Purely metaphyseal or diaphyseal chondroblastoma is exceedingly uncommon, occurring in approximately 2% of chondroblastoma cases. In all of these non-epiphyseal-based cases, the tumor has been intramedullary.
We describe the histologic and imaging features of the first detailed description of a surface-based chondroblastoma.
The tumor was located in the anteromedial midshaft of the tibia in a 47-year-old male.
We discuss the diagnostic considerations and possible etiology of chondroblastoma given this unusual location.

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Local infiltration of inflammatory cells is regulated by a number of biological steps during which the cells likely penetrate through subendothelial basement membranes that contain heparan sulfate proteoglycans. In the present study, we examined whether administration of heparastatin (SF4), an iminosugar-based inhibitor of heparanase, could suppress local inflammation and degradation of heparan sulfate proteoglycans in basement membranes. In a carrageenan- or formyl peptide-induced dorsal air pouch inflammation model, the number of infiltrated neutrophils and monocytes was significantly lower in mice after topical administration of heparastatin (SF4). The concentration of chemokines MIP-2 and KC in pouch exudates of drug-treated mice was similar to control. In a zymosan-induced peritonitis model, the number of infiltrated cells was not altered in drug-treated mice. To further test how heparastatin (SF4) influences transmigration of inflammatory neutrophils, its suppressive effect on migration and matrix degradation was examined in vitro. In the presence of heparastatin (SF4), the number of neutrophils that infiltrated across a Matrigel-coated polycarbonate membrane was significantly lower, while the number of neutrophils passing through an uncoated membrane was not altered. Lysate of bone marrow-derived neutrophils released sulfate-radiolabeled macromolecules from basement membrane-like extracellular matrix, which was suppressed by heparastatin (SF4). Heparan sulfate degradation activity was almost completely abolished after incubation of lysate with protein G-conjugated anti-heparanase monoclonal antibody, strongly suggesting that the activity was due to heparanase-mediated degradation. Taken together, in a dorsal air pouch inflammation model heparastatin (SF4) potentially suppresses extravasation of inflammatory cells by impairing the degradation of basement membrane heparan sulfate.
Copyright © 2016 Elsevier B.V. All rights reserved.

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Concurrent and sequential cisplatin-based chemoradiotherapy regimens are standard therapeutic approaches in cancer treatment. Recent clinical data suggest that these different dosing schedules may adversely affect antigen-specific immunotherapy. The goal of the present preclinical study was to explore the effects of concurrent and sequential cisplatin/radiotherapy on immune status in a lung cancer mouse model. A total of 150 C57BL/6 mice were randomized into six treatment groups: control; 8 Gy thoracic radiotherapy (dose schedules 1 and 2); cisplatin 2.5 mg/kg i.p.; cisplatin + radiotherapy (concurrent); and cisplatin + radiotherapy (sequential; n = 25, all groups). At the end of the study (week 41), serum cytokines were assessed by multiplex immunoassay, surface markers of spleen-derived lymphocytes were assessed by immunostaining and flow cytometry, lung tumor expression of programmed death ligands 1 and 2 (PD-L1/2) was evaluated by immunohistochemistry, and miRNA profiling was performed in serum and lymphocytes by quantitative real-time PCR. Lung whole mounts were prepared to assess treatment effects on lung tumor foci formation. The results showed that sequential chemoradiotherapy (two cycles of cisplatin followed by 8 Gy radiotherapy) had equivalent antitumor activity as concurrent therapy. However, sequential cisplatin/radiotherapy resulted in significant differences in several immune response biomarkers, including regulatory T cells, miR-29c, expression of costimulatory molecule CD28, and serum IFNγ. PD-L1 and PD-L2 were strongly expressed in tumor foci, but no trend was seen between groups. These results suggest that monitoring immune status may be necessary when designing treatment regimens combining immunotherapy with chemoradiotherapy.
©2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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