The “Tuscany Health Ecosystem” (THE) is one of the eleven ecosystems nationally funded under the PNRR, the only one dedicated to life sciences. The goal of “THE” is to make Tuscany the “region of health”, directing research and companies towards the development of applications and the production of technologies dedicated to health and well-being. THE intends to respond to the innovation and training needs of the sector, enabling the consolidation of the regional ecosystem and strengthening its competitiveness on a regional, national and global scale.
For more information, refer to the official website https://www.tuscanyhealthecosystem.it/.
Spoke 1: Advanced radiotherapies and diagnostics in oncology
With about four hundred thousand cases every year in Italy, oncological diseases have a huge social and economic impact and are a global challenge for scientific research and technological innovation. Treatment of tumors has specialized using different principles and approaches, reaching today very high levels of effectiveness and complete recovery. Oncological radiotherapy is used in more than a quarter of all cases and in 40% of curable cases of radiosensitive tumors to eliminate or to reduce the size of the tumor before or after surgery, to kill residual tumor cells. The definition of treatment plans for cancer subjects has been inspired by the guiding principle of gradual administration of the therapeutic dose, through several sessions distributed over time. This principle is still considered a key element in controlling the cost-benefit ratio. Recent studies show that this guiding principle may not be optimal. The so-called “FLASH effect”, already anticipated in studies in the 1960s and recently emerged with overwhelming evidence in preclinical and clinical studies, suggests that the administration of the therapeutic dose in a single session and in very short times (< 200 ms and with a ultra-high dose rate ≥40 Gy/sec (ultra-high dose pulse – UHDP) would lead to equivalent effects on the tumor, but much reduced damage to healthy tissues, allowing to widen the therapeutic window. If translated to the clinics, this effect could lead to an increase in both dose and volume of treatment, enabling radiotherapy to be effective also against tumors characterized, to date, by unfavourable prognosis. Also, the duration of the treatment would be reduced to one or very few sessions compared to the many sessions of conventional radiotherapy. This is a potential paradigm shift that could lead to a revolution in radiotherapy, with great clinical, economic, and social benefits.
At present, the radiobiological mechanisms responsible for the FLASH effect have not been fully understood. Also, translation of this effect to clinical practice requires ionizing radiation with unprecedented intensity and spatio-temporal structure, beyond the capabilities of current industry standards. A global effort is ongoing to provide new devices that are now being validated for biomedical use. FLASH dose-rates can now be achieved by modified laboratory electron accelerators and, recently, by upgraded Intraoperative Radiation Therapy devices (e.g., Electron Flash LINAC) capable of delivering multi-MeV beams with high current, for preclinical studies and in view of dermatologic radiotherapy. New devices are being developed for the delivery of Very High Energy Electron (VHEE) accelerators, with energy between 100 MeV and 250 MeV, which are primarily being considered for the treatment of deep-seated tumors. Novel, laser-based accelerators can inherently deliver ultrashort beams of ionizing radiation, including VHEE beams, with a unique instantaneous dose-rate largely exceeding 1E10 Gy/s and high dose per pulse.
This spoke aims at a comprehensive translational (from bench to bedside) approach to advanced radiotherapy, from the models to the clinics, including the most advanced tools and methods based on ionizing radiation known to date, from innovative external beam generators to radiotracers and radiopharmaceuticals (available at CNR and UNIPI), for a step change in diagnostics and therapy of tumors. The project is organized in 8 subprojects (see below) and relies on three advanced experimental facilites. The CPFR center at UNIPI/AOUP, equipped with a world-unique electron Linac, will perform fundamental studies to understand the radiobiological mechanism underlying Flash effect and pre-clinical studies finalized to realize the first clinical trials on skin cancer with low energy (<10 MeV). The ILIL Facility at CNR-INO, National Institute of Optics, Pisa, equipped with a novel Laser-Linac accelerator delivering a Very High Energy Electron beam with energy (>100 MeV) will focus on preclinical investigation of VHEE beams, also in collaboration with CNR-IFC and CNR-ITB. The Officina Farmaceutica (OF), operating at CNR-IFC and authorized by AIFA, will produce radiopharmaceuticals according to GMP.
Theoretical modelling of the effect of ionizing radiation from atomic and molecular level up to cells and tissues will be carried out at CNR-NANO, exploiting a multi-scale approach synergistically combining Monte Carlo and molecular dynamics simulations and low-resolution to reach the macroscopic scales in silico, serving as a quantitative bridge between the physical parameters of the radiation and the radiobiological effects measured in vitro and in vivo. A platform for in vitro and in vivo studies of fundamental radiobiological effects of ionizing radiation will be established based on the long-standing expertise in the study and characterization of different aspects of rodent physiology and pathology (present at CNR-IN, CNR Institute of Neuroscience and CNR-IFC, CNR Institute of Clinical Physiology) to investigate how FLASH radiotherapy affects brain function, mitochondrial function, and cardiovascular system. Studies will include assessment of the risk associated with the treatment to evaluate the efficacy of the treatment and manage the dose optimization. UNIPI researchers will also contribute to novel dosimetry, radiobiology (employing high resolution in vitro microscopy, PET/CT imaging on small animal models, in vivo Cherenkov imaging), preclinical studies in combination with other oncological approaches (chemo, immunotherapy, and targeted therapy), realization of the first clinical protocols of FLASH RT (for skin cancers, using low energy electrons). The project will include advanced data analysis of the high-resolution microscopy images acquired in vitro, aided by the implementation of dedicated AI-based algorithms.
In the path towards clinical implementation of the FLASH radiotherapy, preclinical investigation will also be addressed using radiotracers and radiopharmaceuticals and translated to improve clinical accuracy of imaging tools for diagnosis and follow up of tumor patients. A key objective of the CNR is to integrate the preclinical development of new chemical entities with the industrial production of new radiopharmaceuticals, favouring new paths to promote clinical studies, now limited to one radiotracer (i.e., 18F-Fluoro-deoxiglucose, FDG), in combination with innovative therapeutic approaches. This will be realized with the development of radiopharmaceuticals alternative to FDG and theranostic agents to conduct innovative experimental studies with a specific focus on oncological and metabolic research. The radiopharmaceutical unit (supported by a cyclotron unique in Italy), will develop and produce new oncologic radiopharmaceuticals that will be assessed in the preclinical and clinical models. Radiopharmaceuticals for oncological diagnostics will be available to the THE for both clinical and experimental (clinical and preclinical protocols). The clinical radiopharmaceuticals will be produced in the “Officina Farmaceutica” (OF), while preclinical radiotracers and theranostics will be developed by the Radiochemistry Laboratory, both operating at CNR-IFC. Radiolabelled carriers will be also investigated in this project to study hypoxia, one of the key aspects of tumors and is also being considered one of the mechanisms at the origin of the FLASH effect. The metalloenzyme Carbonic Anhydrase IX (CA IX) developed within the UNIFI research group by means of drug design approaches applied to the obtainment of CA IX/XII selective inhibitors is a freshly validated target for the treatment of human hypoxic tumors since it acts as a pro-survival factor functionally involved in control of cell adhesion/migration and pH regulation. Specifically this proposal makes use of the scientific and technological know-how reached over the years in the field to obtain valuable drug conjugates based on highly selective small molecule CA IX ligands properly functionalized with emitting radionuclides and therefore highly recommended in the management/imaging of highly aggressive hypoxic tumors, paving the way to the development of theranostics and new selective probes for nuclear imaging, that will be validated in a predictive experimental animal model at CNR-IFC.
|SPOKE 1 – SUBPROJECTS||PARTICIPATING UNITS|
|1.1 INNOVATIVE APPROACHES TO ONCOLOGIC RADIOTHERAPY: RADIATION SOURCES||CNR-INO, INFN, UNIPI|
|1.2 SIMULATIONS, MOLECULAR MECHANISMS VALIDATION AND RADIOBIOLOGICAL EFFECT MODELLING||CNR-IFC, CNR-INO, CNR-ITB, CNR-NANO, INFN, UNIPI|
|1.3 RADIOBIOLOGICAL EFFECTS OF IONIZING RADIATION: IN VITRO (CELL CULTURE) AND IN VIVO||CNR-IFC, CNR-IN, CNR-INO,UNIPI|
|1.4 FLASH RADIOTHERAPY: PRECLINICAL||CNR-IFC, CNR-IN,CNR-INO, UNIPI|
|1.5 FLASH RADIOTHERAPY – FROM PRECLINICAL TO CLINICAL||CNR-IFC, CNR-IN,UNIPI|
|1.6 IN SITU ADVANCED DIAGNOSTICS OF RADIATION DEPOSITION AND CONFORMALITY||CNR-IFC, CNR-IN, CNR-INO, INFN, UNIPI|
|1.7 SYNTHESIS AND PRODUCTION OF TUMOR-TARGETED RADIONUCLIDES, RADIOTRACERS AND RADIOPHARMACEUTICALS FOR EXPERIMENTAL STUDIES||CNR-IFC, CNR-IN, UNIFI|
|1.8 SYNTHESIS AND PRODUCTION OF TUMOR-TARGETED RADIONUCLIDES, RADIOTRACERS AND RADIOPHARMACEUTICALS FOR CLINICAL USE||CNR-IFC, CNR-IN, UNIFI, UNIPI|
Leonida A. Gizzi (Spoke 1 – Leader)
Donata Fornaciari (Spoke 1 – Project Management)