Cathepsin S has been implicated in a variety of malignancies with genetic ablation studies demonstrating a key role in tumor invasion and neo-angiogenesis. Thus, the application of cathepsin S inhibitors may have clinical utility in the treatment of cancer. In this investigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of cathepsin S, originally developed to target cathepsin S in inflammatory diseases, in both in vitro and in vivo tumor models.
Validation of cathepsin S selectivity was carried out by assaying fluorogenic substrate turnover using recombinant cathepsin protease. Complete kinetic analysis was carried out and true K i values calculated. Abrogation of tumour invasion using murine MC38 and human MCF7 cell lines were carried out in vitro using a transwell migration assay. Effect on endothelial tube formation was evaluated using primary HUVEC cells. The effect of inhibitor in vivo on MC38 and MCF7 tumor progression was evaluated using cells propagated in C57BL/6 and BALB/c mice respectively. Subsequent immunohistochemical staining of proliferation (Ki67) and apoptosis (TUNEL) was carried out on MCF7 tumors.
We confirmed that this inhibitor was able to selectively target cathepsin S over family members K, V, L and B. The inhibitor also significantly reduced MC38 and MCF7 cell invasion and furthermore, significantly reduced HUVEC endothelial tubule formation in vitro. In vivo analysis revealed that the compound could significantly reduce tumor volume in murine MC38 syngeneic and MCF7 xenograft models. Immunohistochemical analysis of MCF7 tumors revealed cathepsin S inhibitor treatment significantly reduced proliferation and increased apoptosis.
In summary, these results highlight the characterisation of this nitrile cathepsin S inhibitor using in vitro and in vivo tumor models, presenting a compound which may be used to further dissect the role of cathepsin S in cancer progression and may hold therapeutic potential.

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OnApril 22, 2016 Provectus Biopharmaceuticals, Inc. (NYSE MKT: PVCT, www.pvct.com), a clinical-stage oncology and dermatology biopharmaceutical company ("Provectus" or "the Company"), reported that researchers from Moffitt Cancer Center in Tampa, Florida, presented a poster titled, "T cell Mediated Immunity After Combination Therapy with Intralesional PV-10 and Co-Inhibitory Blockade in a Melanoma Model," at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016, held at the Ernest N. Morial Convention Center in New Orleans, Louisiana (Press release, Provectus Pharmaceuticals, APR 22, 2016, https://www.pvct.com/pressrelease.html?article=20160422.1 [SID:1234511391]).

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In the poster, authors Amy M Weber, Hao Liu, Krithika Kodumudi, Amod A Sarnaik and Shari Pilon-Thomas state that "treatment with IL PV-10 and anti-PD-1 antibody results in a delay in tumor growth and enhanced T cell activation in the M05 tumor model." They also conclude that "the effect of combination therapy with IL PV-10 and PD-1 blockade is mediated by CD8+ T cells, and depletion of either CD4+ T cells or CD25+ Tregs enhances anti-tumor immunity in the M05 melanoma model." The abstract of the poster (number 4978) may be viewed at View Source;sKey=2923b796-8c3a-4376-8adb-7b669b666d8f&cKey=727ae663-75cd-4102-8a98-34de39d3a95f&mKey=1d10d749-4b6a-4ab3-bcd4-f80fb1922267.

Shari Pilon-Thomas, Ph.D., who leads the research team at Moffitt, noted, "Our results show that combining intralesional PV-10 with anti-PD-1 co-inhibitory blockade not only suppresses tumor growth vs. either agent alone but also yields marked increases in tumor-specific T cell activation against injected tumor."

Eric Wachter, Ph.D., Chief Technology Officer of Provectus, observed, "The nonclinical data reported by our collaborators at Moffitt reaffirm the crucial role T cells play in response to tumor ablation with intralesional PV-10, and further demonstrate the potential value of combining PV-10 with T cell directed checkpoint inhibition, such as the anti-PD-1 agent pembrolizumab. Intriguingly, these data also highlight possible strategies for augmenting this paradigm by harnessing additional targets in T cell signaling."

Provectus is currently enrolling patients in a phase 3 study of PV-10 as a single agent therapy for patients with locally advanced cutaneous melanoma (Clinical Trials ID NCT02288897) and in a phase 1b study of PV-10 in combination with the immune checkpoint inhibitor pembrolizumab in patients with metastatic melanoma (Clinical Trials ID NCT02557321).

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The mission of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) is to prevent and cure cancer through research, education, communication, and collaboration. Through its programs and services, the AACR (Free AACR Whitepaper) fosters research in cancer and related biomedical science; accelerates the dissemination of new research findings among scientists and others dedicated to the conquest of cancer; promotes science education and training; and advances the understanding of cancer etiology, prevention, diagnosis, and treatment throughout the world.

The AACR (Free AACR Whitepaper) is the oldest and largest scientific organization in the world focused on every aspect of high-quality, innovative cancer research. Its reputation for scientific breadth and excellence attract the premier researchers in the field. The programs and services of the AACR (Free AACR Whitepaper) foster the exchange of knowledge and new ideas among scientists dedicated to cancer research, provide training opportunities for the next generation of cancer researchers, and increase public understanding of cancer.

On April 22, 2016 Adaptimmune Therapeutics plc (NASDAQ:ADAP), a leader in the use of TCR engineered T-cell therapy to treat cancer, reported that they have hosted an Investor and Analyst meeting in New York and presented clinical and corporate updates that included progress with pipeline development and manufacturing process optimization (Press release, Adaptimmune, APR 22, 2016, View Source;p=RssLanding&cat=news&id=2159734 [SID:1234511272]).

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"At today’s event, we were delighted to present an overview of our T-cell therapy and Adaptimmune’s position within the exciting immune-oncology field," said James Noble, Chief Executive Officer. "We also reported on our upcoming goals and took the opportunity to announce MAGE-A4 as the company’s next target with the objective of achieving IND acceptance in 2017."

The presentations included updates on the company’s synovial sarcoma and multiple myeloma studies, as well as on progress with optimization of manufacturing processes and the construction of a dedicated manufacturing plant in Philadelphia scheduled to open in 2017.

Adaptimmune also announced the establishment of its scientific advisory board, to be chaired by cancer immunotherapy expert, Crystal Mackall, M.D., Professor of Pediatrics and Medicine and Associate Director of the Stanford Cancer Institute, and the adoption of the name SPEAR T-cells (Specific Peptide Enhanced Affinity Receptor T-cells) to describe its proprietary technology.

In addition to James Noble, CEO, the presenters were:

Helen Tayton-Martin Ph.D., MBA, Chief Operating Officer, Adaptimmune
Bent Jakobsen, Ph.D., Scientific Founder, Adaptimmune
Stephan Grupp, M.D., Ph.D, Novotny Professor of Pediatrics, University of Pennsylvania Perelman School of Medicine
Aaron Rapoport, M.D., Professor of Medicine, Gary Jobson Professor in Medical Oncology, University of Maryland Marlene and Stewart Greenebaum Cancer Center
Rafael Amado, M.D., Chief Medical Officer, Adaptimmune
Gwendolyn Binder-Scholl, Ph.D., Chief Technology Officer, Adaptimmune
A summary of clinical and corporate highlights presented at the Investor and Analyst Day is set out below. The slide presentation and a replay of the webcast from the event will be available on the company’s website for 30 days following the event at ir.adaptimmune.com.

Clinical and corporate highlights through April 2016:

Proprietary SPEAR T-cell technology that uniquely delivers:
Correctly identified targets
Specificity and optimal affinity TCRs
‘Supra-natural’ TCRs to accelerate programs
Enhanced effectiveness of TCRs: Generation 2 and 3
Multiple clinical responses in synovial sarcoma, a solid tumor
New images presented showing resolution of large solid lesions
Cohort 2 suggests responses in low expressers
Cohort 3 suggests importance of fludarabine
Cohort 4 starting shortly

Over 90% response rate in multiple myeloma study in conjunction with ASCT
Median overall survival of ~3 years (as of January 2016)
Pivotal studies in sarcoma to start in 4Q16/1Q17
Company INDs open for NY-ESO, MAGE-A10 and AFP
Next IND in 2017: MAGE-A4
Generation 2 INDs from 2017

These TCRs all derive from Adaptimmune’s proprietary technology
Active programs give broad coverage of tumors

Milestones met through April 2016
Expanded into autoimmune
Expanded strategic immunotherapy collaboration with GSK
Secured NY-ESO breakthrough therapy designation in synovial sarcoma
Secured NY-ESO orphan drug designation
IND opened for AFP in hepatocellular cancer

Manufacturing processes optimized
Proprietary T-cell expansion method
Commercial-ready process in place
EU and US contract manufacturers in place

Progressed construction of a dedicated manufacturing plant in Philadelphia
Manufacturing plant scheduled to open in 2017
Potential to enable treatment of up to 1,200 patients per year

Financial position confirmed
Total liquidity position of $248 million as of December 31, 2015
Current capital can fund the business through mid-2018

Novel techniques for high-throughput steady-state metabolomic profiling yield information about changes of nearly thousands of metabolites. Such metabolomic profiles, when analyzed together with transcriptional profiles, can reveal novel insights about underlying biological processes. While a number of conceptual approaches have been developed for data integration, easily accessible tools for integrated analysis of mammalian steady-state metabolomic and transcriptional data are lacking. Here we present GAM (‘genes and metabolites’): a web-service for integrated network analysis of transcriptional and steady-state metabolomic data focused on identification of the most changing metabolic subnetworks between two conditions of interest. In the web-service, we have pre-assembled metabolic networks for humans, mice, Arabidopsis and yeast and adapted exact solvers for an optimal subgraph search to work in the context of these metabolic networks. The output is the most regulated metabolic subnetwork of size controlled by false discovery rate parameters. The subnetworks are then visualized online and also can be downloaded in Cytoscape format for subsequent processing. The web-service is available at:View Source
© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

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On April 22, 2016 Adaptimmune Therapeutics plc (NASDAQ:ADAP), a leader in the use of TCR engineered T-cell therapy to treat cancer, reported that the company has adopted the name SPEAR T-cells (Specific Peptide Enhanced Affinity Receptor T-cells) to describe its proprietary technology (Press release, Adaptimmune, APR 22, 2016, View Source;p=RssLanding&cat=news&id=2159628 [SID:1234511273]).

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The SPEAR T-cells brand is intended to symbolize the vital role that Adaptimmune’s enhanced affinity T-cell receptors play in targeting cancer.

Adaptimmune has a history of scientific leadership in the field of T-cell engineering and the company’s proprietary T-cell engineering platform, developed over the last 15 years, has generated a strong pipeline of T-cell therapies.

"Affinity optimized T-cell receptors are essential to the fight against cancer," said James Noble, Adaptimmune’s Chief Executive Officer. "Our SPEAR T-cell technology is unique in delivering correctly identified targets and enhanced affinity TCRs that have the potency needed to attack tumors, but also the optimum specificity to minimize risks of cross-reactivity. Our proprietary technology provides us with ‘supra-natural’ TCRs that enable the acceleration of our programs and also facilitates our development of second generation TCRs."