Design, synthesis and biological evaluation of substituted naphthalene diimides as anticancer agents

It has been proved that naphthalene diimide (NDI) derivatives display anticancer properties as intercalators and G-quadruplex-binding ligands, leading to DNA damage, senescence and down-regulation of oncogene expression. This thesis deals with the design and synthesis of disubstituted and tetrasubstituted NDI derivatives endowed with anticancer activity, interacting with DNA together with other targets implicated in cancer development. Disubstituted NDI compounds have been designed with the aim to provide potential multitarget directed ligands (MTDLs), in order to create molecules able to simultaneously interact with some of the different targets involved in this pathology. The most active compound, displayed antiproliferative activity in submicromolar range, especially against colon and prostate cancer cell lines, the ability to bind duplex and quadruplex DNA, to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Tetrasubstituted NDI compounds have been designed as G-quadruplex-binding ligands endowed with anticancer activity. In order to improve the cellular uptake of the lead compound, the N-methylpiperazine moiety have been replaced with different aromatic systems and methoxypropyl groups. The most interesting compound was 1d, which was able to interact with the G-quadruplexes both telomeric and in HSP90 promoter region, and it has been co-crystallized with the human telomeric G-quadruplex, to directly verify its ability to bind this kind of structure, and also to investigate its binding mode. All the morpholino substituted compounds show antiproliferative activity in submicromolar values mainly in pancreatic and lung cancer cell lines, and they show an improved biological profile in comparison with that of the lead compound. In conclusion, both these studies, may represent a promising starting point for the development of new interesting molecules useful for the treatment of cancer, underlining the versatility of the NDI scaffold.

Ruolo dei recettori tirosinchinasici in oncologia animale

Disregolazioni dei recettori tirosinchinasici (RTK) sono di frequente riscontro nei tumori dell’uomo e in molti casi sono indicatori biologici che permettono di definire in maniera più accurata la prognosi dei pazienti. Possono rappresentare inoltre marker predittivi per la risposta a terapie antitumorali con farmaci a bersaglio molecolare. Numerosi inibitori tirosinchinasici (TKI) sono attualmente in corso di studio o già disponibili per l’utilizzo in oncologia umana, e molti di questi hanno dimostrato una significativa efficacia utilizzati singolarmente o in combinazione a terapie convenzionali. Studi recenti indicano che un quadro analogo di disregolazione dei recettori tirosinchinasici è presente anche nelle neoplasie dei piccoli animali, e ne suggeriscono in molti casi un’implicazione prognostica. Gli inibitori tirosinchinasi sono da poco entrati nell’arena dell’oncologia veterinaria, ma i primi risultati lasciano supporre che siano destinati ad essere integrati definitivamente nei protocolli terapeutici standard. La tesi consiste in una parte introduttiva in cui sono trattate le principali funzioni biologiche dei recettori tirosinchinasici, la loro struttura e il loro ruolo nell’oncogenesi e nella progressione tumorale in medicina umana e veterinaria. Si affrontano inoltre le principali metodiche di laboratorio per l’analisi molecolare in oncologia e i meccanismi d’azione dei farmaci inibitori tirosinchinasici, con un cenno ai prodotti maggiormente utilizzati e alle loro indicazioni. Segue la presentazione e la discussione dei risultati di quattro studi relativi alla valutazione delle disregolazioni del recettore tirosinchinasico Kit (espressione aberrante e mutazioni genomiche) nel mastocitoma cutaneo del gatto e del recettore del fattore di crescita epidermico (EGFR) nel carcinoma squamocellulare cutaneo del gatto e nei tumori polmonari primitivi del cane, con particolare attenzione al loro ruolo prognostico.

Perdite aeree prolungate dopo resezione polmonare

Il tumore del polmone e una delle neoplasie più diagnosticate dal 1985 e rimane ancora oggi la causa più frequente di morte cancro-correlata nel mondo. Una resezione polmonare anatomica completa continua ad essere il cardine della terapia per il tumore non a piccole cellule. Perdite aeree prolungate (PAL) sono la più comune complicanza dopo una chirurgia polmonare e sono state riportate con un’incidenza compresa tra il 3-26%, simile sia nelle resezioni polmonari per via toracotomica sia in quelle per via toracoscopica. Fattori di rischio descritti sono scissure interlobari incomplete, patologie polmonari sottostanti (come enfisema, fibrosi, tubercolosi o neoplasie), aderenze pleuriche, pazienti anziani (>75 anni) e bassa capacita di diffusione. Lo sviluppo di strumentazione all’avanguardia e di nuove tecniche chirurgiche ha contribuito a ridurre l’incidenza di queste complicanze. Considerando l’alto impatto clinico e socio-economico di queste problematiche, e stata inoltre sviluppata una varietà di complementari naturali e materiali sintetici molti utili nella gestione delle perdite aeree.

Molecular target therapy and immunotherapy of rare lung tumors

Lung cancer is an heterogeneous disease, with 1-2% of rare histology. New molecular profiling technologies, such as next generation sequencing (NGS), haverevolutionized the assessment of molecular alteration in clinical practice. We analyzed a cohort of 1408 NSCLC-A patients treated at the Sant'Orsola- Malpighi University Hospital from 2019 to 2021. This analysis was performed using the oncomine focus thermo fischer panel. Of them, 410 (29%) had rare alteration (RET 3%, NTRK 0,2%,FGFR1 2%, MET exon14 skipping 3%, BRAF V600 4%, ALK fusion EGFR exon 20 2%) and 36 (2%)had a uncommon mutation. We enrolled 7 RET- rearranged patients in CRETA and J2G-MC-JZJC clinical trials assessing respectively unselective and selective RET-inhibitors , another 7 patients tested positive for the BRAF V6006 mutation and have been enrolled in the Array clinical trial assessing a novel combination of anti-BRAF and anti-mek agents . Other molecular alterations found are KRAS (Gly12Cys), FGFR1-4 mutation, MET skipping ex14 mutations, respectively eligible for other ongoing open studies such as Amgen 20190009 comparing efficacy of sotorasib vs docetaxel, Fight-207 assessing activity of pemigatinib and CINC280J12201 assessing activity of the novel met inhibitor capmatinib. In 2018 we joined the CHANCE clinical trial,a multicenter study evaluating the efficacy and safety of atezolizumab in patients withrare lung cancer histologies where and 14 patients have been so far enrolled in the Bologna site. Our studies underline the need of tailored approach to NSCLC patients and our results showed that precision medicine is feasible and is an effective approach to cancer treatment.

Indoor and Outdoor Natural Radioactivity in the Vulsini Volcanic District (Central Italy): Estimation of Doses and Radiological Risks

Terrestrial radioactivity for most individual is the major contributor to the total dose and is mostly provided by 238U, 232Th and 40K radionuclides. In particular indoor radioactivity is principally due to 222Rn, a radioactive noble gas descendent of 238U, second cause of lung cancer after cigarettes smoking. Vulsini Volcanic District is a well known quaternary volcanic area located between the northern Latium and southern Tuscany (Central Italy). It is characterized by an high natural radiation background resulting from the high concentrations of 238U, 232Th and 40K in the volcanic products. In this context, subduction-related metasomatic enrichment of incompatible elements in the mantle source coupled with magma differentiation within the upper crust has given rise to U, Th and K enriched melts. Almost every ancient village and town located in this part of Italy has been built with volcanic rocks pertaining to the Vulsini Volcanic District. The radiological risk of living in this area has been estimated considering separately: a. the risk associated with buildings made of volcanic products and built on volcanic rock substrates b. the risk associated to soil characteristics. The former has been evaluated both using direct 222Rn indoor measurements and simulations of “standard rooms” built with the tuffs and lavas from the Vulsini Volcanic District investigated in this work. The latter has been carried out by using in situ measurements of 222Rn activity in the soil gases. A radon risk map for the Bolsena village has been developed using soil radon measurements integrating geological information. Data of airborne radioactivity in ambient aerosol at two elevated stations in Emilia Romagna (North Italy) under the influence of Fukushima plume have been collected, effective doses have been calculated and an extensive comparison between doses associated with artificial and natural sources in different area have been described and discussed.