Novel precision technological platforms to promote non-invasive early diagnosis, eradication and prevention of cancer relapse: proof of concept in the bladder carcinoma

Despite years of awareness, as of today, there is no screening program for the early detection of bladder cancer (BCa). The unmet clinical needs in the management of BCa are the prevention of tumor onset, relapse and progression, and therapy of the aggressive bladder carcinoma in situ (Cis), requiring frequent and endless follow-up and weekly treatments, with a consequent poor quality of  life   and the  highest   cost   per patient among all cancers. Therefore public health programs crave for early BCa detection protocols, to improve performance in the management of this devastating disease. 

EDIT will develop advanced transformative technology combining newly developed targeted imaging technologies (high-resolution ultrasound elastography and photoacoustic imaging) on the bladder using plasmonic gold sensors for enhanced resolution.

Structural and mechanical modification of the collagen rich extracellular matrix is a common denominator for invasive breast, colorectal, prostate and bladder cancers.
The EDIT platforms will also pave the ways for the earlier management of other bladder-related pathologies and solid tumors, with a profound impact on the quality of life and well-being of millions
 

The EDIT approach exploits the structural and mechanical properties of the bladder extracellular matrix (ECM) as a unique biomarker of the early onset/progression/relapse of carcinoma, through engineered novel gold nanorods (GNRs) used as intravesical photoacoustic antennas targeted at the ECM within the cellular microenvironments and consequently generating an ad hoc visualization platform. GNRs will be further utilized as heat-releasing effectors at nanoscale for targeted cancer photo-thermal therapy.

EDIT is designed to detect pre-neoplastic area and eradication of local areas at few cells resolution with high sensitivity and specificity.

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EDIT Outcomes will revolutionize the management of BCa with the introduction of sensing and effector nanotechnologies combined with non-invasive organ imaging with high resolution/definition 3D ultrasound and photoacoustic imaging.

OBJECTIVES

1. Early prognosis: The leading hypothesis that pre-conditioning of the extra cellular matrix (ECM) in the form of fibrillary collagen-rich matrix predisposes a soil needed for the onset/progression/relapse of bladder cancer.
Increased stiffness of ECM associates with progression of breast cancer and correlates with poor survival. EDIT will pursue an innovative application of specific effectors, provided by novel functionalized nanoparticles developed within the project, to be employed as intravesical source of ultrasound through photoacoustic effect.

2. Early eradication is envisaged by exploitation of the superior targeting properties of locally delivered nanoparticles able to thermal ablating Cis cells upon near-infrared laser irradiation, allowing to recognize and eradicate cluster of few neoplastic cells <1 mm.

3. Novel biomarkers will assess sub-aims, implementing i) characterization of markers that identify pre-conditioning of the ECM allowing the seed of cancer cells (onset, relapse and tumor progression), ii) novel targets for the identification of Cis cells (specific integrins and cellular markers), and iii) new ligands for expanding the armamentarium for targeted delivery of gold nanorods, increasing the opportunities for the “bench to bedside” translational approach of EDIT.

The concept of EDIT

Rome, Italy

Milan, Italy

Bologna, Italy

Rehovot, Israel

Milan, Italy

Rehovot, Israel

The University of Milan

OSM DAN Ltd

The Weizmann Institute

of science

Ascend Technologies Ltd

FUJIFILM Sonosite BV (VisualSonics)

LIME Technology P.C.

Southampton, United Kingdom

Amsterdam, Netherland

Ioannina, Greece

NEWS AND EVENTS

The University of Bologna

Istituto di Fisiologia Clinica-Consiglio Nazionale delle Ricerche 

Ospedale San Raffaele

On the 25th-26th of October , 2019 the Kick of meeting of EDIT, took place at OSR, Milan. It was hosted by OSR. 44 persons from the 9 partners of the consortium participated at this meeting. All meeting goals were realized.

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PUBLICATIONS

EDIT at the 6 Months meeting
6-7 March 2019, Amsterdam Hosted by FUJIFILM Sonosite BV
Excellent experience of high science, networking and collaboration

Our partners at IRCCS Ospedale San Raffaele are working with the Vevo LAZR-X (VisualSonics), exploring all the great advantages of this multimodal high frequency ultrasound and photoacoustics platform!

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Summer school - EDIT partners OSR and IFC-CNR participated to the “Photoacoustic summer school”, September 10-12, 2019, Amsterdam, Netherlands, organized by partner FFSS for European scientists.

1    REVIEW MEETING M12

On the 21st of November the EDIT P1 Review Meeting took place in Brussels at the EU premises Four reviewers reviewed the project results and the achievements of the project were appreciated by the reviewers. Their comments were addressed in the amendment of P1 technical report

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2 Innovations

2 Innovations related to EDIT project have been selected by The European Commission's Innovation Radar team

• -Targeted gold nanorods
  https://www.innoradar.eu/innovation/36003

• -3D Reconstruction and visualization of the bladder and the bladder tumour combining US and PA images

      https://www.innoradar.eu/innovation/36008

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EDIT in a nutshell

https://we.tl/t-Mhcqbupel4

24M Meeting – online

The 24M meeting was online on the 31 on September 2020.

Although online the agenda was fulfilled, and constructive discussions were accomplished.

The advisors, Dr Vito Lorusso and Dr. Richard Bryan participated at this meeting.

Dr Lorusso delivered a workshop named Molecular Imaging: Applications in Oncology with focus on Bladder Cancer

2nd  REVIEW MEETING M30

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The very succesful and highly appreciated  by the reviewers Review meeting of Periond 2 of EDIT took place online, on the May 18th, 2021,

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The sicentific work was mentioed being very advanced and with promissing resutls

PUBLICATIONS

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Book: COLLAGEN Methods and protocols, ISBN 1493990942, 9781493990948, Springer New York, 2019, USA editors Sagi I (The WEIZMANN INTITUTE), Afratis, Nikolaos A.​

Two papers in the above book

• V.R. Krishnaswamy “Multi-well Fibrillation Assay as a Tool for Analyzing Crosslinking and Stabilization of Collagen”

• E. Shimshoni, I Sagi “Sample Preparation of Extracellular Matrix of Murine”.

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Current concepts in nanostructured contrast media development for in vivo photoacoustic imaging, Mirko Maturi, Erica Locatelli, Ilaria Monaco, Mauro Comes Franchini, Review Article, Biomaterial Science, Issue 5, 2019,

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A Stapled Chromogranin A-derived Peptide is a Potent Dual Ligand for Integrins αvβ6 and αvβ8, Chemical Communications, Francesca Nardelli, Michela Ghitti, Giacomo Quilici, Alessandro Gori, Qingqiong Luo, Andrea Berardi, Angelina Sacchi, Matteo Monieri, Greta Bergamaschi, Wolfgang Bermel, Fuxiang Chen, Angelo Corti, Flavio Curnis and Giovanna Musco, Issue 98, 2019, 10.1039/c9cc08518a.

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Mechanotransduction in Neuronal Cell Development and Functioning, Biophysical Reviews, in press Matteo Chighizola, Tania Dini, Cristina Lenardi, Paolo Milani, Alessandro Podestà, Carsten Schulte, 10.1007/s12551-019-00587-2.

Patent - Chromogranin A-derived peptides and uses thereof (EP 19209484.5)

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Application filed by: Ospedale San Raffaele (OSR), November 14th, 2019 Inventors: Curnis F, Nardelli F, Ghitti M, Gori A, Corti A, Musco G; Affiliation of the inventors: Ospedale San Raffaele (OSR, Milan, Italy) and Consiglio Nazionale delle Ricerche (CNR, Milan, Italy); Name of the inventors of the OSR team present in EDIT: Curnis F.

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Influence of natural convection on gold nanorodsassisted photothermal treatment of bladder cancer in mice, Ean H. Ooi, Viktor Popov, Massimo Alfano & Jason K. K. Cheong, International Journal of Hyperthermia 37, 2020.

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Adhesion force spectroscopy with nanostructured colloidal probes reveals nanotopography-dependent early mechanotransductive interactions at the cell membrane level, M. Chighizola, A. Previdi, T. Dini, C. Piazzoni, C. Lenardi, P. Milani, C. Schulte, A. Podestà, Nanoscaale, 2020,12, 14708-14723

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Exosomes as a storehouse of tissue remodeling proteases and mediators of cancer progression, Alakesh Das, Vishnu Mohan, Venkat Raghavan Krishnaswamy, Inna Solomonov, Irit Sagi, Cancer and Metastasis Reviews volume 38, pages455–468(2019)

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LOXL2 Inhibition Paves the Way for Macrophage-Mediated Collagen Degradation in Liver Fibrosis, Mordehay Klepfish, Tamar Gross, Milena Vugman, Nikolaos A. Afratis, Sapir Havusha-Laufer, Eli Brazowski, Inna Solomonov, Chen Varol, Irit Sagi, Immunol., 2020

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MMP9 modulates the metastatic cascade and immune landscape for breast cancer anti-metastatic therapy, Mark Owyong, Jonathan Chou, Renske JE van den Bijgaart, Niwen Kong, Gizem Efe, Carrie Maynard, Dalit Talmi-Frank, Inna Solomonov, Charlotte Koopman, Elin ­Hadler-Olsen, Mark Headley, Charlene Lin, Chih-Yang Wang, Irit Sagi, Zena Werb, Vicki Plaks, 2(6), 2019

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Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody, -L. Cohen, I. Sagi,E. Bigelman, I. Solomonov, A. Aloshin, J.- B. Shoshan, Z. Rozenbaum, G. Keren, M. Entin-Meer, Plos One,2020

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Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts, K. Kim, W. Hu, F. Audenet, N. Almassi, A. J. Hanrahan, K. Murray, A. Bagrodia, N. Wong, T. N. Clinton, S. Dason, V. Mohan, S. Jebiwott, K. Nagar, Gordon, Z. Chen, Y. Dong, P. A. Watson, R. Alvim, A Elzein, S. P. Gao, E. Cocco, A. D. Santin, I. Ostrovnaya, J. J. Hsieh, I. Sagi, E. J. Pietzak, A. A. Hakimi, J. E. Rosenberg, G. Iyer, H. A. Vargas, M. Scaltriti, H. Al-Ahmadie, D. B. Solit, J. A. ColemanJ. Gao, A. Penson, C. Hughes, B, Nature communictions, 2020

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Influence of natural convection on gold nanorodsassisted photothermal treatment of bladder cancer in mice, Ean H. Ooi , Viktor Popov , Massimo Alfano & Jason K. K. Cheong, nternational Journal of Hyperthermia, 37:1, 634-650,

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Large colloidal probes for atomic force microscopy: Fabrication and calibration issues, Matteo Chighizola  Luca Puricelli  Ludovic Bellon  Alessandro Podestà, J. Molecular recognision, 2020

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Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill, Mohan,V., Gaffney,J.P, Solomonov,I., Levin,M., Klepfish,M., Akbareian,S., Grünwald,B.,  Dym,O., Eisenstein,M., Yu,K.H., Kelsen,D.P., Krüger,A., Edwards,D.R, Sagi,I. Cancers 2021, 13(7), 1679

D6.2 - First plan for dissemination and exploitation (using and disseminating the foreground

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The aim of this deliverable is to present the mid version of the dissemination and exploitation plan of the EDIT project. It presents the actions that will be taken to disseminate the EDIT project highlights. Different dissemination avenues are described in relation to the stakeholders to be reached out. Dissemination methods range from the Internet website and social media to journals and conferences. The project website is recognised as a key dissemination medium which brings together all other types of dissemination. Exploitation plan starts with brief explanation of legal boundaries. We propose a set of exploitation tools and identify potential customers of EDIT solutions.

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D7.2  - Data Management plan

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The Data Management Plan (DMP) is a document outlining how research data will be handled during the research project and after it is completed.

It should always include clear descriptions and rationale for the access regimes that are foreseen for collected data sets.

A DMP describes the data management life cycle for all data sets that will be collected, processed or generated by the research project. It is a document outlining how research data will be handled during a research project, and even after the project is completed, describing what data will be collected, processed or generated and following what methodology and standards, whether and how this data will be shared and/or made open, and how it will be curated and preserved.

The DMP is not a fixed document; it evolves and gains more precision and substance during the lifespan of the project.

More elaborated versions of the DMP can be delivered at later stages of the project. The DMP will be updated at least by the mid-term and final review to fine-tune it to the data generated and the uses identified by the consortium since not all data or potential uses are clear from the start.

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D2.2 - Report on GNRs with different PAUS features, GNRs@Chit-Dec and GNRs@Chit-Lig for prognosis and multi-target theranostics nanomedicine

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The use of nano-architectures takes an important role in the development of effective strategies in cancer therapy, giving the opportunity to use them as smart detectors, in terms of contrast agents for diagnostics, but also as efficient therapeutic agents. This duality brings toward theranostic approaches. This Deliverable  reports the characterization on the developed gold nanorods bio-conjugated with different ligands (Dec and Lig systems), tested by photoacoustic techniques for the diagnostics, and laser beams for the therapeutic exploitation. Briefly, chemical conjugation with the ligands, the characterization of the system by cell-adhesion assays have been performed for the two key systems GNRs@Chit-Dec and GNRs@Chit-Lig systems. They have been validated in terms of photoacoustic performances and contrast features for detection and recognition. Finally, the hyperthermic effect of the new nanosystems have been also assessed and a comprehensive description of the experimental set up is herein provided.

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 D3.2 v1_Software Prototype on 3D Visualization platform

The aim of this deliverable is to present the first version of the Software Prototype on 3D Visualization platform of the EDIT project. The first Chapter presents the objectives of the deliverable, while Chapter 2 presents an overview of the input and output data and formats defined in the platform as well as image acquisition procedures utilized. In Chapter 3, the software architecture is being presented in detail and its components are analysed in depth along with their interconnections. A software walkthrough is outlined in Chapter 4 via the use of 4 use cases so that every aspect of the platform is demonstrated. Finally, Chapter 5 contains the references used within this deliverable.

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D4.3 Report on the prognostic power of detecting pre-neoplastic area obtained by instillation of GNRs@Chit-Dec and PAUS approach

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The preclinical experiments of spontaneous bladder cancer (administration of the carcinogen BBN (

 the carcinogen nitrosamine) in the drinking water for 6-8 months) were concluded.

Advances in ultrasound and photoacoustic analysis of BBN model, and stiffness analysis by atomic force microscopy of the bladder from the preclinical models are here reported.