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.

Click here              for download

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!

Click here              for download

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
  

• -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

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

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.

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

Click here     10.1039/d0nr01991g

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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)

Click here   10.1007/s10555-019-09813-5

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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

Click here   10.3389/fimmu.2020.00480

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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

Click here   10.26508/lsa.201800226

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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

Click here   10.1371/journal.pone.0231202

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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

Click here   10.1371/journal.pone.0231202

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