ENTERPRISES/0618/056

A Fully Autologous Cell-based System for Delivery of Molecular Therapeutics to Brain Malignancies

BRAIN-THROUGH introduces a sound, credible and feasible innovative system for fully autologous cell-based Delivery of Molecular Therapeutics to Brain Malignancies, epitomized by Malignant Gliomas (MG). Glioblastoma Multiforme (GBM) is the most frequent (3-5/100,000) and morbid one with median survival 15months. The grim prognosis relates to resistance to available therapies and treatment failure, greatly attributed to the (i) significant tumor heterogeneity and biologic complexity, (ii) difficulty in delivery of therapeutics across the Blood-Brain- Barrier (BBB) and the brain tumor microenvironment (TME), including the extracellular matrix (ECM) and (iii) lack of precise tumor imaging, presenting unique challenges for comprehensive management of the disease. The individualized medicine market is exponentially increasing^[1] reaching $ 90 B. in 2023, while there is a projected tremendous increase of the GBM market niche alone from 670 M$ in 2014 to 3.4.B $ in 2024. Thus, there is a compelling need and unique challenges for a carefully-targeted and personalized drug regime for each patient. The proposed Research for Enterprises project, is aiming to: Primarily, make notable advances in the management of a detrimental and economically unbearable disease by exploiting converging driver mutation pathways throughout tumorigenesis, within a dynamic interplay between the TME and transmigrating, therapeutically engineered cell populations such as the Neural Stem Cells (NSCs). Such an advancement can become available from biomimetic models of NSCs induced from fibroblasts (iNSCs) with effective reprogramming while therapeutic attributes can be endowed with effective gene transfer of multipotent micro-RNA sequences, attacking multiple driver (i.e. oncogenic) pathways. The appreciation that successful delivery of multipotent micro-RNA sequences within iNSCs would favourably modify drug delivery in both localised and distantly invading tumour niches. This is achieved due to the tumour-homing potential of iNSCs and assures faster clinical translation. The therapeutic iNSC-based systems will be designed and engineered around cellular, biological and physiological processes involved in the brain ECM within three-dimensional organoids grown on natural polymers, offering a service that overcomes insufficient robustness and cost ineffectiveness of the currently available small-scale production processes of cell-based therapies, leading to a next generation brain tumour management system and transforming the brain tumour market. Secondly, contribute effectively to the ongoing financial crisis by assuring enhancement of the competitiveness of the Cypriot enterprises with the development and swift commercial exploitation of a new pipelines in both highly expanding markets and emerging market niches.  This will be achieved with the intensification of the participation of Cyprus enterprises in research and development activities, such as the fully autologous platform for cell construct (organoid) and disease preclinical models supported by minimally invasive and image processing tools, assuring faster translation. This is expected to further advance the contribution of the private sector to Research, Technological Development and Innovation. Ultimately, respond to the alarmingly high fragmentation of efforts and resources with thoughtfully designed exploitation of competencies and complementarities within disciplines and across sectors facing the major challenges and addressing the requirements of S3Cy Priority Area ‘Health” with the “Development of Safe and Efficacious Drugs”. BRAIN-THROUGH integrates the essential constituent basic knowledge and unique infrastructures, prototype compounds and validating systems, available at each team by introducing Key Enabling Technologies, monitoring, quantifying and delineating the response to cell-based therapies with high effectiveness and safety for better prognosis, totally fulfilling the scope of this call. This will enable the entrepreneurial partner to respond effectively to the requirements of a unified European and globalized market within an interdisciplinary and coherent framework of Open Innovation. BRAIN-THROUGH will face the unemployment challenge with the creation of new positions and will further equip the next generation of creative researchers with the tools to face current and future challenges and convert knowledge and ideas to products and services towards developing therapies for an intractable and economically burdening disease, thus bringing substantial economic and social benefits, in full accordance with the program’s objectives.

[1] Precision Medicine Market, Global Market Insights, Inc. (Available online)

Duration: October 2013 - September 2017

Funding: € 3,178.803

Lead of Training: A. Odysseos

Nanomedicine offers capability to significantly change the course of treatment for lifethreatening diseases. Many of the most significant current therapeutic targets, to be viable in practice, require the efficient crossing of at least one biological barrier. However, the efficient and controlled crossing of the undamaged barrier is difficult. The range of small molecules that can successfully do so (via diffusive or other non-specific processes) is limited in size and physiochemical properties, greatly restricting the therapeutic strategies that may be applied. In practice, after several decades of limited success, there is a broad consensus that new multidisciplinary, multi-sectoral strategies are required. Key needs include detailed design and understanding of the bionano-interafce, re-assessment of in vitro models used to assess transport across barriers, and building regulatory considerations into the design phase of nanocarriers. The overarching premises of the PathChooser ITN are that (i) significant advances can only be made by a more detailed mechanistic understanding of key fundamental endocytotic, transcytotic, and other cellular processes, especially biological barrier crossing; (ii) elucidating the Mode of Action / mechanism of successful delivery systems (beyond current level) will ensure more rapid regulatory and general acceptance of such medicines. Paramount in this is the design and characterization of the in situ interface between the carrier system and the uptake and signalling machinery. (iii) inter-disciplinary knowledge from a range of scientific disciplines is required to launch a genuine attack on the therapeutic challenge. The PathChooser ITN program of research and training will equip the next generation of translational scientists with the tools to develop therapies for a range of currently intractable (e.g. hidden in the brain) and economically unviable diseases (e.g. orphan diseases affecting a limited population).

FP7-PEOPLE-IAPP: NANORESISTANCE 286125

Duration: November 2011 - October 2015

Funding: € 1,400.000

Principal Investigator: A. Odysseos.

NANORESISTANCE introduces for the first time (i) receptor -independent targeting of Epidermal Growth Factor Receptor-kinase activity, (ii) nuclear delivery of anti-Epidermal Growth Factor Receptor therapy with novel grafting techniques and (iii) the deciphering of resistance and lack of responsiveness to anti-EGFR therapies in the preclinical setting with mathematical models of interstitial biodistribution. This work defines an unprecedented integrated approach for the comprehensive management of failure to anti-EGFR therapy and treatment monitoring. This partnership will play a structuring role by allowing researchers to acquire key skills equally relevant to the public and private sectors including cutting edge nanobiotechnology techniques for fabrication of nanotheranostic conjugates for targeted nuclear drug delivery and imaging, pioneering approaches for intracellular targeting with carbon nanotubes (CNT), innovative mathematical models and assessment of biodistribution, state-of-the-art Surface Plasmon Resonance for assessing drug-target interactions, emerging technologies for in vivo protein-protein and theranostic compound-protein interaction with Bimolecular Fluorescence Complementation Assays (BIFCs).These parallel approaches provide a promising innovative solution in the multifaceted challenge of the overall resistance to anti-EGFR therapies. This will be achieved with the development of multimodal CNT-based nanoplatforms carrying the fluorescent conjugates of EGFR inhibitors intracellularly independently of EGFR extracellular recognition. This system will further deliver anti-EGFR and fluorescent attributes to the nucleus. The partnership offers and a well-structured scheme of complementary skills highly inspired by the entrepreneurial spirit of academicians and research commitment of the industrial partners securing significant impact on their employability in their sector.

Duration: June. 2012 - May. 2014

Funding: € 178.803

Project Coordinator: C. Pitris ; Partner: A. Odysseos

This project brings together expertise in medical optics and optoelectronics, magnetics, coordinate Lanthanide chemistry, bio-organic synthesis and molecular oncology, aiming at introducing a break-through solution for the overall management of colorectal cancer and potentially other malignancies expressing the epidermal growth factor family of receptors (EGFR). The solutions is based on prototype metal-based functionalized compounds engaging cutting-edge synthetic and complexation approaches. Initially, a panel of kinetically stable prototype lanthanides complexes with potent (a) optical (e.g near infrared spectroscopic) and (b) magnetic /relaxation properties will be designed and synthesized as building blocks for heterometallic arrays and subsequently the lanthanide complexes will be functionalized to a series of biologically active bimodal theranostic agents with anti-EGFR recognizing and inhibiting properties. Functionalization of the probes with the recognizing and therapeutic ligands (i.e. anilinoquinazolines) will increase the molecular size, thus optimizing proton relaxivity and magnetic efficacy. Diagnostic specificity will be assessed by ERB-B1 recognition and internalization of the compounds on (a) cell monolayers and (b) 3-dimensional tissue phantoms of cell lines differentially expressing ERB-B1 under inverted NIR microscope. Highly sensitive and efficacious compounds will be considered for further development as theranostic agents for early detection and therapy of CRC in subsequent pre-clinical models with the application of multimodal Molecular Imaging. This approach enables the quantitative imaging of defined cancer biomarkers in a non-invasive manner, aiding in lesion detection, patient stratification, new drug development and validation, dose optimization and treatment monitoring.