logo_cecarep_144x74

Nato da un progetto congiunto tra ALCLI “Giorgio e Silvia” e Polo Universitario di Rieti “Sabina Universitas”, il “Centro Oncologico di Ricerca e Prevenzione della Provincia di Rieti” di seguito indicato con l’acronimo Ce.Ca.Re.P. (Center for Cancer Research and Prevention), entra ufficialmente in funzione nel Gennaio del 2016, a seguito della firma di una apposita convenzione.

Il Ce.Ca.Re.P. è stato istituito con lo scopo di realizzare studi pre-clinici e clinici in ambito oncologico, che apportino un significativo contributo alla comunità scientifica nell’elaborazione di nuove strategie terapeutiche. Tali ricerche, inoltre, possono rappresentare per la ASL territoriale e le associazioni di volontariato, il punto di partenza nell’organizzare campagne di prevenzione e screening specifiche per le patologie neoplastiche più diffuse nella provincia di Rieti.

  • Operating Units

 

  • PERSONNEL

Laboratory of Experimetal Medicine and Environmental Pathology – Rieti University Hub “Sabina Universitas”

  • EXTERNAL COLLABORATORS

Department of Experimental Medicine – “Sapienza” University of Rome

Department of Biotechnological and Applied Clinical Sciences – University of L’Aquila

  • ACTIVITIES
  • Pharmaceutical planning, synthesis and development of new anticancer compounds;
  • Evaluation of pharmacological effects and anti-neoplastic activity of synthetic molecules or natural compounds and comparison with standard oncological therapies;
  • Stem cells and angiogenesis;
  • Studies of stem cells and cancer stem cells secretoma factors;
  • Cellular and Molecular pathways in carcinogenesis;
  • Establish relationships with new partners to expand research fields and to improve innovative approaches in oncological sciences.

     

  • PERSONNEL

Laboratory of Experimetal Medicine and Environmental Pathology Rieti University Hub “Sabina Universitas”

  • EXTERNAL COLLABORATORS

Department of Public Health and Infectious Diseases – “Sapienza” University of Rome

Department of Agricultural, Environmental and Food Sciences – University of Molise

  • ACTIVITIES
  • Profiles of exposure to toxic and carcinogenic pollutants present in the Rieti province;
  • Cancer mortality trend in Latium region (Italy): focus on Rieti province and comparing with the other Latium provinces;
  • Implementation of prevention and screening campaigns for the population of the province of Rieti.
  • establish relationships with new partners.

     

  • PERSONNEL
  • xxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

  • EXTERNAL COLLABORATORS
  • xxxxxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

  • ACTIVITIES
  • xxxxxxxxxxxxxxxxx
  • xxxxxxxxxxxxxxxxx

Center for Cancer Research and Prevention of Rieti Province (Ce.Ca.Re.P.) was created to implement basic and applied research in the oncology field and to give a significant contribution to the scientific community in the development of new diagnostic and therapeutic strategies.

Aims:

  • to create synergies with the departments directly involved in the oncology clinical practice of the O.G.P. “San Camillo de Lellis”, ASL of Rieti, and with other universities and/or research centers for the purpose of developing innovative therapies in the field of oncology;
  • to organize meetings with the population in order to disseminate all the results obtained by the project and to make known how the donations made to the ALCLI have been used;
  • to implement prevention training programs in collaboration with schools in the context of screening campaigns;
  • to establish thesis awards to the best elaboration in the oncological field drawn up by the students of Rieti University Hub “Sabina Universitas”.

 

Project Manager: Prof. Maurizio Sorice

Heparanase is the only known endo-β-glucuronidase in mammals capable of cleaving the side chains of heparan-sulfate, presumably in sites of low sulfation. The enzymatic degradation of heparan sulfate leads to the dismantling of the extracellular matrix (ECM) and is therefore involved in fundamental biological phenomena associated with tissue remodeling and cell invasion, including inflammation, angiogenesis and metastasis. It has been shown that heparanase primarily resides in endocytic vesicles localized in the perinuclear site and or within lysosomes. Autophagy is a highly conserved mechanism in eukaryotic cells, where cytoplasmic waste material is addressed to lysosomes for degradation; can be regulated by different stimuli, including nutritional, metabolic, oxidative, genetic, genotoxic, and proteotoxic. Research in the field of autophagy can help to clarify whether the endogenous or pharmacological regulation of the same can modify the anti-neoplastic response, thus revealing new potential therapeutic targets. In particular, heparanase appears to play a very important role in the autophagy process, although the mechanism by which heparanase induces autophagy is not completely understood. Various evidences show that in many primary solid tumors, such as carcinomas and sarcomas, heparanases are “up-regulated”. Cancer cells that overexpress heparanases are more resistant to stress and chemotherapy and the mechanism is associated with increased autophagy. This consideration encourages the development of heparanase inhibitors. In fact, always Shteingauz et al. and Vlodavsky et al. have shown that the promotion of autophagy by eparanase induces tumor growth and chemo-resistance. Rivara et al. in their study they describe the existence of various heparanase inhibitors, such as heparin, monoclonal antibodies, as well as small newly synthesized chemical compounds. Benzoxazole and benzimidazole derivatives were identified as compounds with submicromolar inhibitory activity against heparanase. The structural requirements responsible for inhibition have been identified by molecular docking studies using the human crystal structures of human heparanases in complexes with oligosaccharides that provide fundamental information on the architecture of the enzymatic binding fissure. These data will allow to synthesize new analogs in order to improve the inhibitory activity of the compounds under examination. The group of prof. Di Santo University “Sapienza” will have the task of synthesizing the chemical structures that have been designed. The chemical synthesis programs will be undertaken in several shifts to optimize the synthesis of the inhibitors. Iterative cycles of enzymatic design and tests (on eparanase) will be implemented. The in vitro tests will be performed in the laboratories of the Experimental Medicine Dept. of the “La Sapienza” University under the direction of prof. Sorice. The compounds with the best activity will be tested for the modulation activity of autophagy and their effects on the growth of neoplastic cells.
The project can be divided into the following main objectives:

  1. pharmacological design, synthesis and development of new compounds with activity of heparanase inhibitors;
    evaluation of the activity of the compounds synthesized by specific enzymatic tests (on eparanase);
  2. evaluation of the effect of the heparanase inhibitors on cytotoxicity, apoptosis and autophagy in tumor cell lines of different origins.

The results of this research will help to identify a new class of potential anti-neoplastic drugs, through the characterization of new therapeutic targets, which can be very useful, both to support the traditional chemotherapeutics, in order to reduce the side effects, both for personalized treatments..

 

Project Manager: Prof. Roberta Misasi

Several studies have shown that cannabinoids reduce tumor growth, inhibit angiogenesis and decrease tumor cell migration. These molecules are well tolerated, so it would be interesting to investigate their potential benefit in the hypothesis of using them in combined antineoplastic therapies. Cannabinoid receptors (CBRs) are specific for endogenous and exogenous cannabinoids. Among the various CBRs, CB2R is expressed almost exclusively in peripheral cells and tissues and, compared to CB1R, the interaction with its ligands not from psychoactivity, a typical side effect of cannabinoids. In particular, the levels of CB1R and CB2R are exclusively upregulated in different tumor cells without necessarily being expressed in the tissue of origin. In the previous three years, our goal was to synthesize a series of selective ligands for CB2R. In a first work already published (Capozzi A. et al., 2018), we evaluated the cytotoxic effect of a series of compounds able to bind CB2R; subsequently, analyzing the obtained data, we selected the 2-oxo-1,8-naphthyridine compound (LV50) as the most active, describing its synthesis and biological effect using the Jurkat cell line of T lymphoblasts. Furthermore, we have shown that this compound reduces cell viability, with an evident pro-apoptotic effect. Therefore, we can suggest a link between the inhibition of cell survival and the proapoptotic activity of the new compound acting as a cannabinoid agonist, hypothesizing its possible use in antineoplastic therapeutic protocols, in combination with classical anti-tumor therapies. Starting from the data already published it would be interesting to continue to study the biological activity of these newly synthesized compounds that bind CB2R and behave like cannabinoid agonists. The objective of our subsequent research project is to analyze the effect of these molecules on a different cell line, in particular glioblastoma tumor stem cells (U87 and U251), analyzing not only the cytotoxic and proapoptotic effects, but also the signal transduction pathways that are able to trigger when binding the receptor. In this regard we will study the activation of molecules such as ERK1 / 2, AKT and p38, involved in cell proliferation and survival signals. The interesting aspect of this new research project is also the use of an allosteric compound of CB2R to be used in combination with agonist compounds both on T lymphoblastoid cells and glioblastoma. In fact, pharmaceutical chemistry approaches have long been aimed at developing molecules that behave like allosteric modulators, because they could offer a new therapeutic approach. CB2R agonists, in combination with their allosteric compound, can be used at a lower concentration than the normally effective one and this could represent a first advantage. Furthermore, potential therapeutic benefits could be obtained by avoiding the intrinsic side effects typical of the orthostatic ligands..

 

Project ManagerDr. Claudio Festuccia

The project involves the analysis of different compounds of natural origin.

  • Olendrine, cardio-active glycoside of great interest because it contrasts the progression of different tumor models and induces apoptosis in PC-3 prostatic tumor cells. Furthermore, recent studies have shown its ability to inhibit the activity of RAD51, which translates into a possible radiosensitizing effect. The aim of the project will be to evaluate the potential of PBI, a cold extract of Oleandrine, on glioblastoma cell lines through the use of in vitro and in vivo models;
  • Crocetina, carotenoid present in the flowers of the genus Crocus (Saffron). Based on previous studies already published, we will evaluate the molecular mechanisms that underlie the anti-humor responses of crocetin;
  • Sulforafano, a molecule present in high concentrations in Cruciferae (broccoli, cabbage, cauliflower) whose extracts, containing sulforaphane, have anti-oxidant and anti-neoplastic activity for intestinal tumors. The aim is to evaluate the molecular mechanisms underlying the antitumor responses of sulforaphane.[/button]

 

Project ManagerProf. Adriano Angelucci 

The project is divided into two phases: first we will evaluate the clinical relevance of the reactive stroma by analyzing prostate cancer tissues and, subsequently, we will analyze the bioenergetic profile of primary prostatic stromal cells and the role of direct interaction between stromal and tumor cells in determining the progression of cancer. In particular, we will evaluate the ability of cancer-stromal stromal cells to modulate proliferation and response to therapy of several prostate cancer cell lines.

 

Project ManagerProf. Simona Delle Monache

Although the relationship between the K-Ras oncogene and the expression of VEGF has been demonstrated, the biological role of oncogene in the production of VEGF by colon cancer cells has not yet been clarified. In this regard, using KRAS colon tumor lines mutated on the G12 codon with respect to non-mutated lines, we will analyze the effect of these mutations on the expression of pro-angiogenic factors and their correlation with possible variations in the activation of the signaling pathways responsible of their expression. Furthermore, through functional biological assays, we will evaluate the ability of the conditioned media from these cell lines to influence the capacity of invasion or tubular formation of human endothelial cells. At the same time, by means of an ELISA test, we will analyze the serum level of pro-angiogenic factors such as in serum samples obtained from mutated and wild type G12_13 KRAS patients 3 and 6 months after treatment with bevacizumab.

 

Project Manager: Prof. Matteo Vitali

During the last three years, the collection of urine samples of pediatric children was performed with the aim of tracing a risk profile of exposure to environmental toxicants and carcinogens in children between the ages of five and eleven living in three specific areas of the province of Rieti: urban, industrial and rural areas. The main factors responsible for this exposure were the degree of urbanization of the area of residence, the traffic in cars and second- and third-intention passive smoking. Thanks to these samples, it was possible to determine the presence of benzene, methyl-terbutyl-ether in the urine and other 12 compounds indicating urban pollution and passive smoke. The first results of the research have already been published while, for the next three years, further processing of the data will lead to the identification of metabolic profiles of the collected samples.

 

Project Manager: Prof. Carmela Protano

Thanks to the work carried out in the previous three years on the trend of cancer mortality in the province of Rieti and Lazio, the project for the new three-year period aims to make such an investigation systematic, using data provided by the National Institute of Statistics (ISTAT) for the calculation of specific and standardized cancer mortality rates. Furthermore, if the Lazio Cancer Registry becomes fully operational, calculations can also be made on the incidence.

 

Project Manager: Prof. Carmela Protano

Exposure to secondhand smoke is a major risk factor for public health, associated with numerous adverse effects, especially when exposure occurs in children, individuals highly susceptible to chemicals. Despite the ban on smoking in public places has reduced the possibility of exposure for non-smokers, the domestic environment is still a risky place, both for passive smoking and for “third hand smoke”, ie what remains in the environment after the cigarette has been turned off. It is an invisible and highly toxic mixture of gas and particles, which remains attached to the hair, to the clothes of those who smoke, as well as to the coverings, carpets and fabrics in general, which remains in the room longer than passive smoke. People may be exposed to third-hand smoke by inhalation, ingestion or contact with the skin. Smoke residues include heavy metals, carcinogens, and even radioactive substances, and not even common cleaning methods have proven effective in reducing contamination. Third-hand smoke added to passive smoking determines blood-related reactions that lead to the formation of cotina and nitrosamine, which have been found in the urine of children living in the homes of smokers. In light of this, the aim of the research for the next three years will be to evaluate, always using urine samples collected from elementary school age children in the province of Rieti, the presence of these substances, which is closely connected with the behavior of parents smoking in the home environment.

 

Project ManagerProf. Pasquale Avino

Following a preliminary study carried out in 2017 over the course of two seasons, summer and winter, it is considered useful and necessary to carry out a more rigorous monitoring campaign for a better and timely assessment of the air quality in terms of aerosols and its composition. The latter aspect is, in fact, relevant for defining the quality contours of the particulate species in relation to the emission sources of an anthropogenic type that can subsequently impact on the composition of the particulate and therefore on human health. Although the area in question is “relatively” anthropized, it is affected by the vehicular circulation, especially the heavy one, as well as the typical problems of high urbanization areas. This study is necessary considering that the evaluation of the quality of atmospheric particulate matter is also important in relation to the health of the population. In 2013, the International Agency for Research on Cancer (IARC) reclassified some substances of the list of known carcinogens and among these has formalized the entry of fine powders (PM) and in general of air pollution by including them in category 1, certainly carcinogenic. Therefore, it is proposed to carry out two seasonal measurement campaigns, aimed at the study of atmospheric particulate both in granulometric terms and in terms of chemical composition. The measurements will be performed in two different seasons: the first series of measurements will be carried out in the summer (warm period) while the second ones in the winter period (cold period). Seasonal variability is necessary to evaluate the effect of weather conditions on atmospheric particulate. The measurements carried out in the two seasonal campaigns of last year have shown interesting preliminary data from the environmental point of view that require further study for a better evaluation: in detail the above evaluation will use tools that allow the evaluation of the particulate fraction up to the particles ultrafine, during the 24-hour period. At the same time PM10 samples will be carried out on filters that will be subsequently analyzed in the laboratory both in terms of organic and inorganic fraction. Sampling will be performed with FAI Instruments’ Smart Sampler: aerosol sampling will be performed in the PM10 fraction using the low flow sampling method for a different time, on average 2-3 months. The collected sample will be brought into the laboratory and subjected to an analytical procedure of extraction, clean-up and analysis by gas chromatography or spectroscopy for the qualitative and quantitative determination of substances of environmental-toxicological interest. At the same time, campaigns will be carried out to measure submicronic particles, and ultrafine particles in particular, with classification of the particles in the various dimensional classes and relative counting. This last approach will allow to significantly deepen the problem linked to atmospheric particles and their effect on human health: in fact a deposition model will be applied in the human respiratory system in order to evaluate the deposited dose. The tools will be made available by the Group of Analytical Chemistry of the University of Molise and the analyzes will be carried out at the same laboratory.

ORGINIAL RESEARCH MANUSCRIPTS

  • Manigrassi M., Protano C., Martellucci S., Mattei V., Vitali M., Avino P. Evaluation of the submicron particles distribution between mountain and urban site: contribution of the transportation for defining the environmental and human health. International Journal of Environmental Research and Public Health. 2019. Under press;

BOOKS

CONFERENCES, CONGRESSES AND SYMPOSIA

In order to support and encourage young students in the study and deepening of oncological diseases, to improve the biomedical knowledge in the aforementioned field through the dissemination of interesting and unprecedented aspects of the neoplastic phenomenon, Ce.Ca.Re.P. establishes the  Thesis Award ALCLI “Giorgio e Silvia” and announces a competition to award a prize for the best degree thesis in the field of oncology developed by students of the Rieti University Hub “Sabina Universitas”.

Competition Notice:

Premio Tesi di Laurea ALCLI “Giorgio e Silvia” – II Edizione

Information playbill:

premio_tesi_di_laurea_2017_locandina