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A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX and XII is proposed. The induction/stabilisation of G-quadruplex structures by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance and reducing oncogene expression. hCAs IX and XII are well-established anti-tumour targets, upregulated in many hypoxic tumours and contributing to metastasis. The ligands reported feature a berberine G-quadruplex stabiliser scaffold connected to a moiety inhibiting hCAs IX and XII. In vitro experiments showed that our compounds selectively stabilise G-quadruplex structures and inhibit hCAs IX and XII. The crystal structure of a telomeric G-quadruplex in complex with one of these ligands was obtained, shedding light on the ligand/target interaction mode. The most promising ligands showed significant cytotoxicity against CA IX-positive HeLa cancer cells in hypoxia, and the ability to stabilise G-quadruplexes within tumour cells.

A novel series of twelve aromatic bis-ureido-substituted benzenesulfonamides was synthesised by conjugation of aromatic aminobenzenesulfonamides with aromatic bis-isocyanates. The obtained bis-ureido-substituted derivatives were tested against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX and hCA XII). Most of the new compounds showed an effective inhibitory profile against isoforms hCA IX and hCA XII, also having some selectivity with respect to hCA I and hCA II. The inhibition constants of these compounds against isoforms hCA IX and XII were in the range of 6.73–835 and 5.02–429 nM, respectively. Since hCA IX and hCA XII are important drug targets for anti-cancer/anti-metastatic drugs, these effective inhibitors reported here may be considered of interest for cancer related studies in which these enzymes are involved.

In continuation of our previous studies to optimise potent carbonic anhydrase inhibitors, two new series of isatin N-phenylacetamide based sulphonamides were synthesised and screened for their human (h) carbonic anhydrase (EC 4.2.1.1) inhibitory activities against four isoforms hCA I, hCA II, hCA IX and hCA XII. The indole-2,3-dione derivative 2h showed the most effective inhibition profile against hCAI and hCA II (KI = 45.10, 5.87 nM) compared to acetazolamide (AAZ) as standard inhibitor. Moreover, 2h showed appreciable inhibition activity against the tumour-associated hCA XII, similar to AAZ showing KI of 7.91 and 5.70 nM, respectively. The analogs 3c and 3d showed good cytotoxicity effects, and 3c revealed promising selectivity towards lung cell line A549. Molecular docking was carried out for 2h and 3c to predict their binding conformations and affinities towards the hCA I, II, IX and XII isoforms.

We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (Ki within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (Ki > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.

Burkholderia territorii, a Gram-negative bacterium, encodes for the ι-class carbonic anhydrase (CA, EC 4.2.1.1) BteCAι, which was recently characterised. It acts as a good catalyst for the hydration of CO2 to bicarbonate and protons, with a kcat value of 3.0 × 105 s−1 and kcat/KM value of 3.9 × 107 M−1 s−1. No inhibition data on this new class of enzymes are available to date. We report here an anion and small molecules inhibition study of BteCAι, which we prove to be a zinc(II)- and not manganese(II)-containing enzyme, as reported for diatom ι-CAs. The best inhibitors were sulphamic acid, stannate, phenylarsonic acid, phenylboronic acid and sulfamide (KI values of 6.2–94 µM), whereas diethyldithiocarbamate, tellurate, selenate, bicarbonate and cyanate were submillimolar inhibitors (KI values of 0.71–0.94 mM). The halides (except iodide), thiocyanate, nitrite, nitrate, carbonate, bisulphite, sulphate, hydrogensulfide, peroxydisulfate, selenocyanate, fluorosulfonate and trithiocarbonate showed KI values in the range of 3.1–9.3 mM.

We here report a study on the activation of the ι-class bacterial CA from Burkholderia territorii (BteCAι). This protein was recently characterised as a zinc-dependent enzyme that shows a significant catalytic activity (kcat 3.0 × 105 s−1) for the physiological reaction of CO2 hydration to bicarbonate and protons. Some amino acids and amines, among which some proteinogenic derivatives as well as histamine, dopamine and serotonin, showed efficient activating properties towards BteCAι, with activation constants in the range 3.9–13.3 µM. L-Phe, L-Asn, L-Glu, and some pyridyl-alkylamines, showed a weaker activating effect towards BteCAι, with KA values ranging between 18.4 µM and 45.6 µM. Nowadays, no information is available on active site architecture, metal ion coordination and catalytic mechanism of members of the ι-group of CAs, and this study represents another contribution towards a better understanding of this still uncharacterised class of enzymes.

Primary sulfonamide derivatives with various heterocycles represent the most widespread group of potential human carbonic anhydrase (hCA) inhibitors with high affinity and selectivity towards specific isozymes from the hCA family. In this work, new 4-aminomethyl- and aminoethyl-benzenesulfonamide derivatives with 1,3,5-triazine disubstituted with a pair of identical amino acids, possessing a polar (Ser, Thr, Asn, Gln) and non-polar (Ala, Tyr, Trp) side chain, have been synthesized. The optimized synthetic, purification, and isolation procedures provided several pronounced benefits such as a short reaction time (in sodium bicarbonate aqueous medium), satisfactory yields for the majority of new products (20.6–91.8%, average 60.4%), an effective, well defined semi-preparative RP-C18 liquid chromatography (LC) isolation of desired products with a high purity (>97%), as well as preservation of green chemistry principles. These newly synthesized conjugates, plus their 4-aminobenzenesulfonamide analogues prepared previously, have been investigated in in vitro inhibition studies towards hCA I, II, IV and tumor-associated isozymes IX and XII. The experimental results revealed the strongest inhibition of hCA XII with low nanomolar inhibitory constants (Kis) for the derivatives with amino acids possessing non-polar side chains (7.5–9.6 nM). Various derivatives were also promising for some other isozymes.

Carbonic anhydrases (CAs) are essential metalloenzymes in nature, catalyzing the carbon dioxide reversible hydration into bicarbonate and proton. In humans, breathing and many other critical physiological processes depend on this enzymatic activity. The CA superfamily function and inhibition in pathogenic bacteria has recently been the object of significant advances, being demonstrated to affect microbial survival/virulence. Targeting bacterial CAs may thus be a valid alternative to expand the pharmacological arsenal against the emergence of widespread antibiotic resistance. Here, we report an extensive study on the inhibition profile of the recently discovered ι-CA class present in some bacteria, including Burkholderia territorii, namely BteCAι, using substituted benzene-sulfonamides and clinically licensed sulfonamide-, sulfamate- and sulfamide-type drugs. The BteCAι inhibition profile showed: (i) several benzene-sulfonamides with an inhibition constant lower than 100 nM; (ii) a different behavior with respect to other α, β and γ-CAs; (iii) clinically used drugs having a micromolar affinity. This prototype study contributes to the initial recognition of compounds which efficiently and selectively inhibit a bacterial member of the ι-CA class, for which such a selective inhibition with respect to other protein isoforms present in the host is highly desired and may contribute to the development of novel antimicrobials.

A 65-year-old man presented to our hospital with abdominal pain, dyspepsia and anorexia. Laboratory tests showed an altered liver function and abdomen ultrasonography revealed multiple liver nodules, suspected to be metastatic lesions. Serous tumor markers were elevated and a very high level of alpha-fetoprotein was found. Computer tomography confirmed the hepatic lesions and disclosed a thickening of the lesser curvature of the gastric wall. A subsequent endoscopy showed an ulcer on the lesser curvature. Biopsies taken from the gastric ulcer and the liver nodule revealed an adenocarcinoma, both of gastric origin. Shortly after the diagnosis, the patient's condition worsened and he died only 15 days later. This case report illustrates how alpha-fetoprotein-producing gastric adenocarcinomas have a high incidence of venous and lymphatic invasion and a rapid hepatic spread with a very poor prognosis.

Objectives EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed. Materials and methods All patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80 mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR). Results We report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method ( therascreen ® ) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy. Conclusion Although liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms. [ABSTRACT FROM AUTHOR]

Biliary tract cancers (BTCs) are a pool of diseases with poor prognosis and there is no orphan drug available. Currently, no molecular targets have been tested as druggable oncogenic drivers. C-ros oncogene 1 ( ROS1 ) rearrangements have been previously described in various tumors, including BTCs; however, data regarding their incidence and biological significance are controversial. Therefore, a retrospective multicenter study was performed to assess the incidence of ROS1 rearrangements in BTCs by means of immunohistochemistry and fluorescence in situ hybridization (FISH). The present study failed to demonstrate ROS1 expression in a multicenter series of 150 cases with BTCs and revealed that D4D6 was the most specific clone compared with other ROS1 primary antibodies, namely PA1-30318 and EPMGHR2. Notably, negative results obtained with D4D6 completely matched to data sorted out by FISH analysis, thus confirming a lack of ROS1 gene rearrangements in BTCs and false positive results when PA1-30318 and EPMGHR2 clones were used. These results suggest that ROS1 rearrangements may not be targets for molecular therapy of BTCs with specific inhibitors., (Copyright © 2020, Spandidos Publications.)

Somatostatine analogs (SSAs) are currently indicated in the treatment of acromegaly and neuroendocrine tumors (NETs). Actually, pregnancy in patients with acromegaly and NETs does not represent an exceptional event because reproductive behavior has changed in the last decades and patients with NETs show more frequently long-term survival. The safety profile of SSAs during pregnancy is still controversial. Concerning acromegaly, based on case reports and series, SSAs administration during pregnancy seems to be relatively well tolerated. Concerning patients with NETs, up to date only one patient with NET receiving SSA during pregnancy has been reported in literature. We report two cases of gastroenteropancreatic-NET patients receiving SSA lanreotide for the entire course of their pregnancy, with favorable outcomes for both mothers and babies. Our experience supports the possibility to continue safely SSA lanreotide during pregnancy in patients with NET.

Background: Aerobic and resistance exercises have been promoted recently to improve quality of life in cancer patients. Most cancer survivorship rehabilitation programs consist of supervised exercise programs; however, less data is available on the effects of unsupervised or home-based exercise interventions. The study aimed to compare the physical and physiologic changes in a group of cancer survivors (CS) and a control group of non-cancer, health controls (HC) who participated in individualized home-based aerobic and resistance exercises for 12 months., Methods: Thirty-three surviving cancer survivors (CS) aged 55.6±3 years were enrolled for 1 year of unsupervised exercise prescription programs. Anthropometric parameters hydration status, fitness, and echocardiographic examination were measured every six month and compared to10 HC (aged 52.6±7.7 years) individuals prior to starting the program (t0) and at 6 (t6) and 12 (t12) months., Results: Among the CS subjects, a significant reductions in waist circumference (t0: 97.5±15.2 cm, t6: 86.6±13.5 cm, t12: 85.8±13.9 cm; P<0.05), body cell mass (t0: 50.9±4.7%, t6: 52.3±4.4%, t12: 53.7±3.7%; P<0.05), and extracellular mass (t0: 49.1±4.7%, t6: 47.6±4.4%, t12: 46.2±3.7%; P<0.05) were observed, as well significant improvements in lower body muscle strength (chair test t0: 13.3±4.1, t6: 14.2±3.5, t12: 15.1±3.2; P<0.05). Changes in functionality and heart function were similar between CS and HC., Conclusions: Individually-prescribed home-based exercise programs were cost effective, safe and resulted in modest improvements in body composition, strength, and total body water distribution with little to no adverse effect on cardiac function.

Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is effective as first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC). We report 2 cases of EGFR-mutated locally advanced NSCLC treated in neoadjuvant setting with EGFR tyrosine kinase inhibitor at University of Florence/Careggi Hospital. In both cases, afatinib was used for up to 3 months, until 1 week before surgery. Both patients achieved significant reduction (downstaging) of the pulmonary mass and lymphadenopathies and after surgery, it was decided for both cases to restore afatinib treatment up to a further 4 months. Both patients experienced local and distant disease relapses after 9 and 10 months, respectively, and then we restored the afatinib treatment.

Background: We aimed to explore the use of platinum plus bevacizumab in a real world NSCLC population., Patients and Methods: We retrospectively collected data from patients affected by NS-NSCLC treated with platinum plus bevacizumab across Tuscany., Results: We evaluated 62 (median age: 63.5 [30-77] years) pts. All but one presented with adenocarcinoma and the majority had ECOG PS of 0/1. 17.7% presented with central lesion, 11.3% with brain metastasis, 38.7% with hypertension and 4.8% with mild haemoptysis. We observed a median time to progression (TTP) of 6.5 [2-37] and a median overall survival (OS) of 10.5 [2-39] months. Overall response rate (ORR) was 59.6% with a disease control rate (DCR) of 80.6%. Safety profile was acceptable. We observed five cardiovascular events and two major bleedings with no toxic deaths., Conclusion: Safety and efficacy real world data are consistent with those from clinical trials even in a less selected population.

Osteonecrosis of the jaw (ONJ) is a rare treatment related side effect that was firstly described in 2002 through a case report in metastatic bone cancer patient treated with bisphosphonates (BPs) therapy. ONJ is defined as an eight weeks or longer clinical finding of exposed bone in the oral cavity without response to appropriate therapy. The diagnosis is mainly clinical but often requires a radiological confirmation with an orthopantomography. So it must be made by a dental specialist with sufficient experience on ONJ and requires a detailed anamnestic exploration of comorbidities and treatments history. In particular, ONJ affects a wide number of oncologic patients treated with BPs for bone metastatic cancers and, more recently, with anti-angiogenic drugs. The aim of this this paper is to describe diagnosis and classification of this rare but serious side effect and its pathophysiology. In particular, we provide a detailed description of clinical evidences upon the relationship between anti-angiogenic drugs and ONJ. Considering the evolving of cancer epidemiology with a greater number of cancer surviving patients, this side effect always deserves more attention. We conclude that ONJ must be always carefully investigated and prevented with a multidisciplinary approach involving oncologist, radiation oncologist and skilled dental practitioner when a cancer patient must begin a BP or an antiangiogenic treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Colorectal cancer is the third leading cause of cancer-related deaths in the western world. Despite therapeutic advances, the prognosis of metastatic colorectal cancer patients remains poor due to intrinsic or acquired tumor drug resistance. The main mechanisms of tumor drug resistance are represented by genetic and epigenetic alterations. This leads to tumor refractoriness during treatment or disease progression following response to first-line therapy. Strategies to combat chemorefractory tumors involve the development of selective inhibitors of drug-resistant phenotypes, the epigenetic resensitization of drug-resistant cancer cells and new cytotoxic drugs devoid of cross resistance with first-line cytotoxics. The use of drug combination regimens may also increase treatment efficacy, and the exploitation of specific phenomena such as oncogenic and nononcogenic addiction or synthetic lethality represents another potential approach in combating tumor drug resistance. Clinical trials based on such strategies in mCRC patients whose tumors progressed following first-line chemotherapy are discussed herein.

Non-small-cell lung cancer is a term that encompasses a number of subtypes of lung cancer. In recent years, several intracellular pathways have been studied in order to discover a potential target for novel anticancer therapies such as anaplastic lymphoma kinase (ALK) and reactive oxygen species 1 (ROS1). Increased interest in oncologic treatment research has resulted from the observation that ALK- and ROS1-associated tyrosine kinases show molecular analogies in some of their domains. This discovery led to the hypothesis that target therapy against ALK translocation could have efficacy also in ROS1-positive tumors. Crizotinib is an oral tyrosine kinase inhibitor that binds the ALK tyrosine kinase domain, blocking its function. We report the case of a woman with heavily pretreated metastatic lung adenocarcinoma harboring ROS1 positivity who experienced a prolonged and dramatic clinical benefit from crizotinib therapy.

Gallbladder neuroendocrine neoplasms (GB-NENs) are rare. The majority of GB-NENs are poorly differentiated, with increased mitotic activity and clinically aggressive course. Surgery is the only curative approach and the optimal medical treatment is uncertain. In this report we describe the case of a woman affected by metastatic well differentiated GB-NEN with increased Ki 67. The patient underwent surgical removal of the gallbladder neoplasm and showed disease recurrence with pulmonary and liver metastases. After achieving a partial chemotherapy response, the patient rapidly died due to progressive disease. This case raises important issues. Well differentiated NENs with a high proliferative index are not included as a specific entity in any of the most widely used nomenclature systems. Moreover considering the proliferative index of the disease, it is reasonable to consider the patient a candidate for chemotherapy. Nevertheless, recently published papers raise the possibility that well differentiated NENs and specific proliferative index cutoff can predict low chemosensitivity in patients with highly proliferative neuroendocrine carcinoma.