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Prostate cancer (PCa) is a major health burden among aging men. Most newly-diagnosed cases of PCa are adenocarcinomas, originating in the glandular epithelial tissue of the prostate. Recently, proton therapy has been applied in the treatment of advanced PCa. The success of this approach is consequence of the precision of proton therapy, which is able to target the cancerous lesion with accuracy. Nevertheless, to take full advantage of proton therapy it is important to correlate the correct size of the tumor with the image obtained by MRI, and to correctly assess prostate cancer malignancy. The implementation of proton therapy in Portugal will contribute to diminishing the prevalence of surgeries. The current clinical management of PCa enables its detection at early organ-confined stages by combining regular screening and patient classification in risk groups. Although these tumors do not usually pose a threat to the patient, the majority of PCa cases are prescribed a radical treatment after diagnosis (e.g., surgery or radiotherapy). The implementation of proton therapy in Portugal will contribute to diminishing the prevalence of surgeries. However, the limited individualization of the clinical management beyond risk-group definition will still lead to significant overtreatment and undertreatment rates, which may adversely impact the patients’ lives and life expectancy, respectively. Thus, PCa is a paradigmatic condition in which an individualized predictive technology could make a crucial difference in clinical practice. Recently, mechanistic and reproducible computational methods to simulate cancer growth and treatment have enabled the personalized prediction of clinical outcomes and the design of optimal therapies, e.g., for breast and brain cancers. This new approach, termed computational oncology, combines the use of mathematical models accounting for key physical and biological mechanisms involved in tumor growth with computer simulations to forecast tumor growth. Personalization of these predictions relies on the parameterization of the model with longitudinal clinical and imaging data from each patient and on simulating tumor growth over the actual anatomy of the patient’s affected organ. In particular, multiparametric magnetic resonance (mpMR) imaging has been providing a wealth of data to describe the tumor morphology, architecture and behavior. Given the increasing use mpMRI data to inform clinical decision-making in PCa, and given the facility of analyzing removed prostates, providing unique insight to yield biologically-relevant model parameterizations, it is timely to validate the predictive capability of state-of-the-art tumor forecasting models for PCa cases against longitudinal patient-specific data. Here, we propose to design and validate a personalized, organ-scale mathematical model able to forecast PCa growth and assist physicians in diagnosis, clinical-decision making and treatment with proton therapy. Our approach relies on 4 key strategies. First, we will leverage phase-field (PF) modeling, a robust and flexible modeling framework extensively used to successfully describe tumor growth phenomena. Second, the resolution of an inverse problem will provide a personalized parameterization of model equations using longitudinal mpMR imaging and clinical data of PCa patients. Third, model validation will be performed against the corresponding histopathological data extracted from each patient’s prostate surgical specimen, which is the current gold standard in PCa research. Finally, we will use patient-specific simulations of the parameterized model to investigate the driving biological mechanisms of tumor growth after proton therapy and derive optimal therapeutic plans (e.g., maximum reduction of tumor burden and progression-free survival with minimum toxicities). The student will integrate an international high-productivity interdisciplinary collaboration with researchers from Portugal (University of Coimbra, University of Porto), Italy (University of Pavia) and USA (University of Texas Austin), which include Physicists, Mathematicians, Engineers, Pathologists and Medical Doctors. This will provide an invaluable learning opportunity to the student and will generate a vast range of international contacts guaranteeing the success of the student’s professional future.

Owing to the favorable physical properties of interaction of protons with matter, application of proton beams in radiation therapy for highly selective cancer treatment is rapidly spreading worldwide. To date, over 90 ion therapy facilities are operational, predominantly with proton beams, and about the same amount is under construction or planning. Over the last decades, considerable improvements have been achieved in accelerator technology, beam delivery and medical physics to enhance conformation of the dose delivery to complex shaped tumor volumes, with excellent sparing of surrounding healthy tissue and critical organs. Nevertheless, full clinical exploitation of the proton beam advantages is still challenged, especially by uncertainties in the knowledge of the beam range in the actual patient anatomy during the fractionated course of treatment, thus calling for continued multidisciplinary research in this rapidly emerging field. To date, there are two main physical channels that may be explored for in-vivo monitoring of the proton therapy treatments. The first one is imaging beta+ decays via dedicated or commercial positron emission tomographs (PET), and the second is prompt gamma (PG) imaging. Both beta+ decaying nuclei or PG emission are produced by nuclear reactions between the penetrating protons and the nuclei of the patient being irradiated. In order to provide valuable feedback to the fractionated treatment, both methods need to compare the measured PET and/or PG distribution with the computed predictions. Studies that our teams have performed show that using off-the-shelf Monte Carlo simulation codes such as Geant4 is too time consuming for daily clinical applications. Timing is still unacceptable even when typical high performance computing clusters available at some clinical centers are utilized. Hence, in this thesis we propose to develop an approach (and realize it in a custom software) that accelerates the simulation of beta+ creation and decay during clinical proton irradiation. The software must take into account the computed tomogram (CT) of the patient and the beam fluency on a voxel-by-voxel basis and estimate the production of beta+ activity based on the stored look-up values determined previously by validated, detailed Monte Carlo simulations. Development of such fast simulation approaches is crucial to fully realize the potential of the PET-based range monitoring systems, including those to be eventually operated at the planned proton facility in Portugal. In addition, the same code will be utilized in the task of monitoring proton treatments at the MD Anderson Cancer Center (MDACC), including the currently ongoing work in the frame of the TPPT cooperation, formed by the University of Texas at Austin, MDACC, PETsys electronics (Lisbon), ICNAS-UC and LIP (host institution).

The current multi-center PhD project will investigate several possible models to explain why high-fraction dose radiotherapy (SBRT) has higher success rates than conventional radiotherapy. These models are based on variable oxygen or reactive oxygen species (ROS) concentrations within or around the tumor cells. An existing dynamic tumor growth software that uses cell-based modelling will be used to implement and model tumor growth and response to photon and proton radiation. The different SBRT models will be compared for both photons and protons and new treatment strategies will be investigated.

Radiopharmaceuticals offer unique opportunities to explore a theranostic approach of cancer, as one targeting biomolecule recognizing a specific molecular target can be labelled either with diagnostic and/or with therapeutic radionuclides, allowing patient-specific treatments with easier monitoring of the disease progression. In the past few years, these advantages prompted the design and the preclinical and clinical study of new target-specific radiopharmaceuticals with very encouraging results in the case of peptides or peptidomimetics radiolabelled with beta emitters, namely for 177Lu-radioconjugates. This progress has led to the recent approval of [177Lu]Lu-DOTA-TATE (Lutathera) and [177Lu]Lu-PSMA-617 (PluvictoTM) by the FDA and/or EMA agencies for the treatment of neuroendocrine tumors and prostate cancer, respectively. Despite these progresses, the use of beta minus emitters in targeted radionuclide therapy (TRT) of cancer has some limitations, such as the nephrotoxicity and beta radiation resistance encountered in a non-negligible number of patients. Targeted alpha therapy can be an alternative, and promising preclinical and clinical data were recently reported for different 225Ac-labeled biomolecules, as for example 225Ac-PSMA-617. Unfortunately, most alpha emitters have a low availability that limits their clinical use. Auger electron (AE) emitters can be a more feasible alternative, as this class of radionuclides has easier availability than alpha emitters and many of them are already commonly used in nuclear medicine imaging (e.g. 67Ga, 99mTc or 111In), enabling therefore the development of theranostic strategies. In particular, Auger electron radiopharmaceutical therapy (AE-RPT) may have the same therapeutic efficacy in oncological small disease compared to alpha or beta particle therapy with lower risks of normal tissue toxicity, as the intense shower of these low-energy AEs deposit their energy in the immediate vicinity of their site of decay. The promise of AE-RPTs as therapeutic agents has not yet been realized with few agents evaluated in clinical trials and none so far becoming part of routine treatment. From a dosimetric point of view, the highest relative biological effectiveness (RBE) of AE emitters results when these radionuclides are internalized into highly radiosensitive organelles, like the cell nucleus or mitochondria. Thus, the design of cancer specific AE-emitting radioconjugates with preferential accumulation in these organelles might lead to better therapeutic outcomes. Towards this goal, this PhD project proposes dual-targeted complexes of AE emitting trivalent radiometals (Indium-111 and Erbium-165) stabilized by DOTA chelators carrying: i) a PSMA-617 derivative for selective uptake by prostate (PCa) cells upon interaction with the PSMA receptor; ii) pharmacophores with well-recognized affinity for the cell nucleus or the mitochondria (e.g. a DNA intercalator such as an acridine orange derivative or a mitochondria-tropic moiety as a rhodamine derivative). Both devised AE-emitters, 111In (T1/2 = 2.81 d; AE/decay = 7.4) and 165Er (T1/2 = 10.36 h; AE/decay = 7.3), allow also SPECT imaging, which might confer theranostic features to their radiopharmaceuticals. However, unlike 111In, 165Er emits no γ-rays but X-rays, being a kind of “pure” AE emitter. This difference should contribute to reduce the deleterious effects in non-target issues in the case of 165Er, and enable more selective radiobiological effects by the emitted short-range Auger electrons. Some of the dual radioconjugates will contain a protease-cleavable linker, either by a cathepsin B or a caspase protein, between the PSMA-617 targeting moiety and the M(DOTA) complex (M = 111In, 165Er). The intracellular cleavage of the linker in the cancer cells is expected to provide smaller radiometallated complexes, carrying the DNA intercalator or the mitochondria-tropic unit with enhanced ability to target the nucleus or the mitochondria, respectively. Altogether, this PSMA targeting strategy should also lead to reduced accumulation in the nucleus or mitochondria of healthy tissues, minimizing therefore undesired side effects (e.g. hematological toxicity, kidney damage or cardiotoxicity), which could be crucial for the success of AE emitters in TRT.

Colorectal cancer (CRC) is the third most frequent cancer worldwide and the second leading cause of cancer-related death. CRC patients die of metastatic disease, therefore effective therapeutic interventions are mostly valuable in this setting in order to improve the wellbeing of patients and extend survival. Cetuximab and panitumumab are monoclonal antibodies (mAb) that target the epidermal growth factor receptor (EGFR) in RAS wild-type metastatic CRC (mCRC). Although effective, these therapies result in about 40% of innate resistance. Unfortunately, even patients that initially respond to cetuximab, finish by developing resistance and progress under these therapies. In this context, novel strategies aiming to overcome resistance are absolutely needed to improve the health of patients. We have recently found that activation of EGFR downstream signalling, mediated by phospholipase C gamma 1 (PLCγ1) and its partner SHP2, is involved in cetuximab resistance. Therefore, combination of cetuximab with SHP2 inhibitors (e.g., SHP099), showed a synergistic effect in bypassing resistance in in vitro and in vivo animal models. PLCγ1 is a predictive marker of cetuximab responses which, not only identifies tumors that do not respond to cetuximab, but also those which benefit from combined EGFR/SHP2-targeted therapy. However, systemic co-treatment is associated with high toxicity. In this context, strategies that allow the delivery of such compounds directly into the tumor tissue have the potential to be highly effective and associated with low toxicity. Nanomedicines can deliver drugs at higher doses with lower side effects by the enhanced permeability and retention (EPR) effect, or through receptor-mediated active targeting. Nanotherapies with enhanced circulation and reduced toxicity are already in clinical use, and others show great promise in clinical development. Among clinical translational nanomedicines, polymeric micelles (PM) have demonstrated unique advantages toencapsulate a wide variety of bioactive molecules in the inner shell and the external surface can be functionalized with ligand moieties directed to specific receptors on the cells to confer specificity and/or conjugate other therapeutic and/or imaging agents, improving therapeutic efficacy and reducing systemic toxicity. Radiopharmaceuticals are particularly suited to provide new in vivo/whole body PET or SPECT imaging protocols for early detection of cancer and design more selective targeted therapies. The non-invasive evaluation of EGFR status by targeted molecular imaging modalities, such as PET or SPECT, may assist the selection of patients who are expected to benefit from anti-EGFR targeted therapy and to monitor their response to personalized cancer treatment. Moreover, efforts are being done towards the design of nuclear theranostic tools that combine potential for targeted specific molecular imaging and personalized systemic targeted radionuclide therapy (TRT) exploring the possibility to radiolabel the same (bio)molecular/supramolecular targeting entity either with diagnostic and/or therapeutic radionuclides. The long-standing goal of theranostics is to gain the ability for early diagnostic and fine-tuning of therapy and dosimetry with unattainable control, leading to personalized medicine. The main goal of this PhD project is to generate and validate new multifunctional targeted drug delivery platforms to explore the synergistic effect of targeted radionuclide therapy combined with EGFR/SHP2-targeted therapy aiming to provide safe and selective drug delivery and ultimately to improve the therapeutic efficacy and overcome resistance in the treatment of metastatic colorectal cancer (mCRC). To achieve this goal, we will develop vehicles (PMs) to deliver radionuclides and drugs to the EGFR(+) tumors and their metastases and to combine in the same nanomedicine: i) an anti-EGFR antibody (e.g., cetuximab, panitumumab or other) to confer specificity and therapeutic effect; ii) specific SHP2-inhibitors (e.g., SHP099) to overcome drug resistance; iii) a bifunctional chelator (BFCA) to stabilize the radionuclides for imaging (111In) or therapy (161Tb/177Lu) envisaging a nanotheranostic approach; Using this strategy, a synergistic effect for this multifunctional targeting approach is anticipated, since the selective and specific mAb should promote specific delivery to the tumor cells, and the SHP2 inhibitor is expected to interact with EGFR downstream pathway inhibiting it and overcoming the resistance to cetuximab therapy. Furthermore, the encapsulation of the inhibitor in the nanoplatform is expected to improve the bioavailability and minimize side effects. Moreover, the possibility to introduce imaging (e.g., 111In) or therapeutic radionuclides (e.g., 177Lu/161Tb) will help to select the best performing nanoplatform and may assist the selection of patients who are expected to benefit from therapy using the same nanoplatform labeled with 177Lu or 161Tb and monitor their response to this personalized cancer treatment.

The project focuses on the investigation of a new silicon-based detector concept for use during proton or electron FLASH irradiation. Silicon sensors are resilient and can be used to estimate the passage of particles. We plan to apply novel technologies being developed, namely at CERN to develop a novel concept for particle radiotherapy dosimetry. The candidate will work in a competitive environment, having access to the latest technologies. Tests will be performed at a reference centre for radiotherapy (DKFZ, Heidelberg, Germany). The novel Si sensors will be developed for conventional and high dose rate delivery such as FLASH radiation with electrons and protons. The novel sensors emanate from the developments being made at CERN. The development will be done at LIP and the testing and integration will be performed at DKFZ, a reference proton therapy centre in Heidelberg.

Proton Radiation Therapy (PRT) is a powerful anticancer tool being the hadrontherapy modality with the strongest growth over the lastest decades. PRT has the unique capability to confine high-doses in small and deep space regions, due to its inverse dose deposition profile. While the reduction of dose in healthy tissue is significant in PRT, its Relative Biological Effectiveness (RBE) is comparable to that of other Radiation Therapy (RT) modalities [1]. Innovative approaches have been recently able to enhance its RBE, adding boron in low concentrations to the body and activating it through proton-induced reactions [2]. Low-dose RT has an hormetic nature, and it produces a wide variety of non-toxic biological effects that have therapeutic potential beyond killing cancer cells. For example, low-dose RT has been successfully applied to treat peripheral protein aggregation diseases known as amyloidosis, which resemble widespread neurodegenerative disorders such as Alzheimer (AD), Parkinson (PD) or Huntington diseases (HD) [3]. However, the therapeutic potential of both conventional and proton RT has been barely explored in this context. We propose to turn novel and powerful PRT approaches for cancer treatment into weapons against neurodegenerative disorders, targeting toxic amyloids with boron- and fluorine-based compounds [4-6] in combination with low-dose PRT. Our hypothesis is that PRT will reduce the aggregation and toxicity of amyloid structures associated with AD, PD and HD, among other disorders, and significantly increase the RBE. The proposed PhD program will have a strong multidisciplinary component, unifying the fields of nuclear physics, biochemistry and bioimaging to lay the groundwork for an increase in the versatility of future PRT facilities.

Glioblastoma multiforme (GBM) is the most common of brain tumors in adults. It is a primary lesion with very aggressive, invasive and undifferentiated characteristics, associated with a poor prognosis. The standard treatment relies on surgical tumor resection followed by combined radiation therapy (RT) and chemotherapy. The average survival is only 15 months and the majority of the patients has a recurrence of disease and eventually dies in a short period of time. The introduction of new approaches for the treatment of GBM is of great importance, and novel therapies are currently under research. The idea of using proton therapy (PT) as a RT alternative in GBM has gain great attention within the scientific community due to the small amount of dose the proton beam delivers when entering the patient’s body and to the dose fall-off after reaching the Bragg peak. The proton beam can be manipulated so that the Bragg peak falls within the tumor site, leading to a higher dose in the lesion while sparing the surrounding healthy tissues. This project aims to evaluate the potential of proton therapy as a therapeutic approach in the treatment of GBM. We will compare the radiobiological effects of X-rays and protons on GBM. For this purpose, a PET-cyclotron-based set-up for proton irradiation will be established at the ICNAS facility. The first stage of radiobiological studies will include the evaluation of viability and survival in human GBM cell lines U87 and U373 when exposed to X-rays. Animal models on GBM will be developed at ICNAS preclinical facility. GBM xenografts will be irradiated with X-rays at CNC and with protons at ICNAS to quantify the effects of radiation in the tumors. In vitro and in vivo studies will be reproduced with a clinical proton beam with energy up to 200 MeV at MD Anderson Cancer Center (MDACC).

This PhD program will focus on the design and evaluation of the biological prospective of multifunctional magnetic nanoplatforms for biomedical applications. They are powerful non-invasive tools for hyperthermia therapy and radiotherapy as radiosensitizers of gamma and proton radiation. These nanoplatforms are based on core–shell magnetic nanostructured iron oxides (Fe3O4) displaying superparamagnetic behavior (SPIONs). The overall goal is to provide essential physicochemical and biological knowledge and contribute to the development of breakthrough strategies for more efficient and selective cancer therapies. This can be considered an emerging partnership for both gamma rays and proton radiation therapies. Recently it was found that gold nanoparticles (AuNPs) functionalized with a DOTA derivative and bombesin peptide analogue (BBN) show a very good affinity towards GRPr with T1/T2 MRI properties and a remarkably internalization into human PC3 cancer cells. In addition, AuNPs can act as radiosensitizers after exposure cells to high-energy radiation. In this regard, a comparison of the potential synergic cell-killing effects for both gamma-rays and proton radiation therapies can be evaluated on biological systems, namely with relevant cancer cell models, in the presence or absence of the magnetic nanoplatforms. These studies may be extended to relevant animal models. The selected candidate will be part of a multidisciplinary team belonging to different research units of IST, Universidade de Lisboa, Centro de Ciências e Tecnologias Nucleares (C2TN), Instituto de Bioengenharia e Biociências (iBB) and Centro de Química Estrutural (CQE), and Instituto Politécnico de Setúbal. This project will benefit from complementary scientific expertise of the supervisors and from a set of experimental infrastructures available at the research units mentioned above. Moreover, it will profit from ongoing collaborations between the team members and IFIMUP, University of Porto, Institut de Ciència de Materials de Barcelona, and Instituto de Microelectrónica de Barcelona (C.S.I.C.).

The regular use of ionizing radiations in applications like radiation therapy, medical imaging, security checking in airports or other buildings, and space industries can led to adverse health effects if radiation protection measures are not properly taken. In proton therapy facilities the main concerns are with secondary radiation, particularly the residual radiation originated from activation, which continues after the beam is shut off, and wearable shielding, commonly based on lead, is normally used for protection. However, the use of lead is becoming problematic, which is not only due to regulatory requests, but also due to its density that makes the wearable shielding quite heavy. In recent years, a great effort to develop efficient light lead free systems has been taken in many companies, universities and research centers. These new systems generally use powders of elements like bismuth, antimony or tungsten that are blended by a polymer, but the frequent formation of aggregates or other inhomogeneity’s decrease the shielding performance. Recently, laminated few-layered antimonene sandwiched between PDMS was observed to increase the radiation attenuation when compared with the powder based systems. Here it is proposed the development of high efficiency shielding systems based on layered materials. Van der Walls compounds constituted by heavy elements, like Bi2Te3, WTe2 and Sb2Te3, which easily break according to well-defined planes, are the basis of such layered shielding systems. When sandwiched between a polymer, they form highly textured homogeneous laminar structures similar to the antimonene case, which is expected to increase the probability of interaction between the ionizing radiation and the shielding material, enhancing the shielding performance. The study of the performance of each material, changing parameters like the grain size, number of layers in the flake, concentration and texture, will allow the optimization of the radiation attenuation and the identification of the shielded energy ranges. This will enable the conceptualization and construction of personal shielding systems for the different energy ranges to be used in hadron therapy facilities. The use of Monte Carlo simulations will be an essential tool to follow the experimental developments and to produce an adequate translation of the experimental data into physical quantities. The development of these novel personal shielding systems creates the opportunity to produce them in Portugal, which is an stimulating step for future activities.

Proton range verification is a critical aspect of proton therapy. It involves verifying the precise location and depth of the proton beam as it travels through the patient's body, ensuring that it reaches the intended target and minimizes exposure to healthy tissue. The need for proton range verification arises due to several factors, including patient safety and accurate treatment. It is a key component of quality assurance in proton therapy, ensuring that patients receive the highest standard of care. It can be done using several techniques, including imaging techniques, such as PET imaging, which can be used to visualize the location and extent of the proton beam in the patient's body; ionization chambers, that measure the energy deposited by the proton beam as it passes through the body; scintillation detectors, to detect the passage of protons, allowing for the determination of the proton range. Each technique has its own strengths and limitations, and a combination of different ones may be used to provide a more complete picture of the proton beam and its location in the patient's body/phantom. One of the advantages in using PET for beam quality assessment in proton therapy is the ability to quickly generate a 3D map of β+ decay and correlate it with the beam interaction in the phantom, which is an improvement over current technologies that utilize stacks of 2D representations of the beam profile. The problem is that in Proton Therapy Centers (PTC), PET systems are not located in the treatment room, which often requires the use of phantoms for beam quality assessments to be carried out to another place in the PTC facilities. The brief half-life of isotopes produced during irradiation, such as carbon isotopes, demands rapid transport to prevent loss of PET signal. Portable and benchtop PET scanners, such as the HadronPET may therefore, offer a significant advantage over traditional, bulky scanners, as they are more versatile and can be integrated into various locations within PTC facilities more easily, facilitating the process. The main goal of the PhD project proposed is to implement time-of flight technology in the HadronPET system, already under development. This implementation represents an important tool in strategies of proton beam quality assessment with PET systems since it contributes significantly to reduce image artifacts in realistic clinical irradiations by including time-of-flight (TOF) information in the reconstruction, and improve the image signal-to-noise ratio on a poor count-rate scenario.

This work will focus on the Real Time measurement of Bragg-Peak (BP) using Prompt-Gammas Ray Timing (PGT) - Compton Camera (CC) combined method with novel semiconductor Cherenkov Charge Induction (CCI) radiation detectors (eg: Thallium Bromide – TlBr), a type of materials that exhibits very interesting timing and energy resolution properties for nuclear medicine. The main objectives are the design and development of a PGT-CC prototype and its characterization in a proton beam line. The workplan activities include Monte-Carlo simulations, to understand and optimize the detectors behaviour, and laboratory work, to operate/develop the required instrumentation and software for detectors data acquisition and processing. It will be carried out at the Physics Department of the University of Aveiro within the I3N – Institute of Nanostructures, Nanomodelling and Nanofabrication - Aveiro Pole, under the supervision of Dr. Pedro Correia, PhD in Physics Engineering and Researcher at University of Aveiro, Portugal, and Prof. Dr. Ana Luísa Silva, PhD in Physics and Auxiliar Professor at University of Aveiro, Portugal, and at the Department of Biomedical Engineering of the University of California at Davis, USA (UCDavis) under the supervision of Dr. Gerard Ariño-Estrada, Researcher at the Biomedical Engineering Department

Owing to the favorable physical properties of interaction of protons with matter, application of proton beams in radiation therapy for highly selective cancer treatment is rapidly spreading worldwide. To date, over 90 ion therapy facilities are operational, predominantly with proton beams, and about the same amount is under construction or planning. Over the last decades, considerable improvements have been achieved in accelerator technology, beam delivery and medical physics to enhance conformation of the dose delivery to complex shaped tumor volumes, with excellent sparing of surrounding healthy tissue and critical organs. Nevertheless, full clinical exploitation of the proton beam advantages is still challenged, especially by uncertainties in the knowledge of the beam range in the actual patient anatomy during the fractionated course of treatment, thus calling for continued multidisciplinary research in this rapidly emerging field. To date, there are two main physical channels that may be explored for in-vivo monitoring of the proton therapy treatments. The first one is imaging beta+ decays via dedicated or commercial positron emission tomographs (PET), and the second is prompt gamma (PG) imaging. Both beta+ decaying nuclei or PG emission are produced by nuclear reactions between the penetrating protons and the nuclei of the patient being irradiated. Our team has been investigating a system that uses orthogonal prompt-gamma rays (a concept we call O-PGI) to determine the distal edge position of the proton beam. It consists of collimator slats interspersed with scintillator slats. Previous simulation results using a full O-PGI system have demonstrated the ability of such a system to detect deviations in the position of the distal edge with a precision of 2 mm FWHM during irradiation of a homogeneous acrylic phantom. We are currently building a small prototype detector that will be tested later this year at the clinical proton cyclotron in Delft, the Netherlands (HollandPTC). Full O-PGI system simulations have recently been extended to include irradiation of the head of an anthropomorphic phantom with a single proton beamlet. The main goal of this proposal is to extend these studies with anthropomorphic phantoms to the irradiation of other anatomical regions (e.g. pelvic irradiation, craniospinal irradiation of pediatric patients), not just with a single beamlet, but including the whole planned irradiation treatment. Such studies will also include the real-time monitoring of moving tumors (e.g., in the thoracic region affected by respiratory or cardiac movements). This work will be carried out using both commercially available digital anthropomorphic phantoms and data from real patient treatment plans (which will include a phantom based on the patient's computed tomography -CT- scan and its irradiation with beamlets based on the planned beams). At the end of this work, we hope to have defined a list of potential applications where the O-PGI system can provide effective feedback on the progress of treatment, both inter-fractionally (between treatment sessions) and intra-fractionally (in real time during treatment). This, together with the forthcoming experimental results, should increase the value of the O-PGI system, which will be a fundamental step towards the construction of a complete system and its future implementation in clinical practice.

The project focuses on a multidisciplinary approach to investigate the impact of combined chemotherapy and radiotherapy (RT) to significantly improve the metastatic cancer treatment. Notably, proton therapy is predicted to result in reduced irradiation of off-target tissue, sparing healthy tissue, and an improved patient prognosis. Combining experimental and theoretical studies, we plan to develop a novel concept for particle radiotherapy applications. The candidate will work in an exciting research environment, having access to the latest technologies. The computational studies will be carried out at C2TN in collaboration with Irina S. Moreira, a top-rated researcher in data-driven and computational tools from University of Coimbra. The proton therapy tests will be performed at a reference centre for radiotherapy (DKFZ, Heidelberg, Germany). The cells models will be irradiated at conventional and high dose rate delivery such as FLASH radiation. The biological assessment will be done both C2TN and DKFZ, a reference proton therapy center in Heidelberg.