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Abstract Background Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC. Methods We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice. Results Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway. Conclusion The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis.

Abstract Occurrence of resistance to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) approved in ovarian carcinoma, has already been shown in clinical settings. Identifying combination treatments to sensitize tumor cells and/or overcome resistance to olaparib is critical. Polo-like kinase 1 (PLK1), a master regulator of mitosis, is also involved in the DNA damage response promoting homologous recombination (HR)-mediated DNA repair and in the recovery from the G2/M checkpoint. We hypothesized that PLK1 inhibition could sensitize tumor cells to PARP inhibition. Onvansertib, a highly selective PLK1 inhibitor, and olaparib were tested in vitro and in vivo in BRCA1 mutated and wild-type (wt) ovarian cancer models, including patient-derived xenografts (PDXs) resistant to olaparib. The combination of onvansertib and olaparib was additive or synergic in different ovarian cancer cell lines, causing a G2/M block of the cell cycle, DNA damage, and apoptosis, much more pronounced in cells treated with the two drugs as compared to controls and single agents treated cells. The combined treatment was well tolerated in vivo and resulted in tumor growth inhibition and a statistically increased survival in olaparib-resistant-BRCA1 mutated models. The combination was also active, although to a lesser extent, in BRCA1 wt PDXs. Pharmacodynamic analyses showed an increase in mitotic, apoptotic, and DNA damage markers in tumor samples derived from mice treated with the combination versus vehicle. We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.

Asparagine and glutamine depletion operated by the drug Asparaginase (ASNase) has revolutionized therapy in pediatric patients affected by Acute Lymphoblastic Leukemia (ALL), bringing remissions to a remarkable 90 % of cases. However, the knowledge of the proproliferative role of asparagine in adult and solid tumors is still limited. We have here analyzed the effect of ASNase on three adenocarcinoma cell lines (A549, lung adenocarcinoma, MCF-7, breast cancer, and 786-O, kidney cancer). In contrast to MCF-7 cells, 786-O and A549 cells proved to be a relevant target for cell cycle perturbation by asparagine and glutamine shortage. Indeed, when the cell-cycle was analyzed by flow cytometry, A549 showed a canonical response to asparaginase, 786-O cells, instead, showed a reduction of the percentage of cells in the G1 phase and an increase of those in the S-phase. Despite an increased number of PCNA and RPA70 positive nuclear foci, BrdU and EdU incorporation was absent or strongly delayed in treated 786-O cells, thus indicating a readiness of replication forks unmatched by DNA synthesis. In 786-O asparagine synthetase was reduced following treatment and glutamine synthetase was totally absent. Interestingly, DNA synthesis could be recovered by adding Gln to the medium. MCF-7 cells showed no significant changes in the cell cycle phases, in DNA-bound PCNA and in total PCNA, but a significant increase in ASNS and GS mRNA and protein expression. The collected data suggest that the effect observed on 786-O cells following ASNase treatment could rely on mechanisms which differ from those well-known and described for leukemic blasts, consisting of a complete block in the G1/S transition in proliferating cells and on an increase on non-proliferative (G0) blasts.

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumor distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise and highly accurate for the measurement of the drug and the main metabolites. The lower limit of quantification resulted in 1 ng/mL. The curve range of 1–500 ng/mL and 50–2000 ng/mL, for plasma and tumor homogenate, respectively, was appropriate for the analysis, as demonstrated by the accuracy of between 96.8% and 102.4% for plasma and 96.6 to 102.3% for the tumor. The interdays precision and accuracy determined on quality controls at three different levels were in the ranges of 6.9 to 7.5% and 99.3 to 101.0%, and 0.96 to 1.91% and 102.3 to 105.8% for plasma and tumor, respectively. With the application of the novel assay in explorative pharmacokinetic studies, following acute and chronic oral administration of the nanoformulation, fenretinide was detected in plasma and tumor tissue at a concentration higher than the IC50 value necessary for in vitro inhibitory activity (i.e., 1–5 µM) in different cancer cells lines. We were also able to detect the presence in plasma and tumor of active and inactive metabolites of fenretinide.

The incidence of hypersensitivity reactions (HSRs) to PEG-asparaginase (PEG-ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP-BFM ALL 2009 study. Patients with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) were stratified as standard-risk/medium-risk (MR)/high-risk (HR) and those with T-ALL as non-High/HR. PEG-ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG-ASNase doses in induction; thereafter non-HR versus HR patients received 1 versus 6 PEG-ASNase doses, respectively. After the single regular dose of PEG-ASNase at the beginning of delayed intensification, BCP-ALL-MR patients were randomized to receive 9 additional PEG-ASNase doses every 2 weeks (experimental arm [EA]) versus none (standard arm [SA]); HR patients were randomized to receive, in consolidation, 4 weekly PEG-ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T-non- HR/BCP-Standard-Risk, BCP-MR-SA, BCP-MR-EA, HR-SA and HR-EA patients had 1-year-CI-HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG-ASNase did not significantly impact on HSR incidence in BCP-MR patients (1-y-CI-HSR 3.8% [0.8] versus 3.2% [0.6] in MR-EA versus MR-SA; P = 0.55), while impacted significantly in HR patients (1-y-CI-HSR 6.4% [1.3] versus 17.9% [1.8] in HR-EA and HR-SA, respectively; P < 0.001). The CI-HSR was comparable among non-HR groups and was not increased by a substantial intensification of PEG-ASNase in the BCP-MR-EA group whilst it was markedly higher in HR-SA than in HR-EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG-ASNase reduces the risk of developing an HSR.

We describe the development and validation of an HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory activity towards dimethylarginine dimethylaminohydrolase 1 (DDAH1) and vasculogenic mimicry, and its active metabolite L-257 in a xenograft model of triple-negative breast cancer (TNBC). The method proved to be reproducible, precise, and highly accurate for the measurement of both compounds in plasma and tumour tissue following acute and chronic (five days) intraperitoneal administration of ZST316 (30 mg/Kg daily) in six-week-old severe combined immunodeficiency disease (SCID) mice inoculated with MDA-MB-231 TNBC cells. ZST316 was detected in tumour tissue and plasma after 1 h (6.47 and 9.01 μM, respectively) and 24 h (0.13 and 0.16 μM, respectively) following acute administration, without accumulation during chronic treatment. Similarly, the metabolite L-257 was found in tumour tissue and plasma after 1 h (15.06 and 8.72 μM, respectively) and 24 h (0.17 and 0.17 μM, respectively) following acute administration of ZST316, without accumulation during chronic treatment. The half-life after acute and chronic treatment ranged between 4.4–7.1 h (plasma) and 4.5–5.0 h (tumour) for ZST316, and 4.2–5.3 h (plasma) and 3.6–4.9 h (tumour) for L-257. The results of our study demonstrate the (a) capacity to accurately measure ZST316 and L-257 concentrations in plasma and tumour tissue in mice using the newly developed HPLC-MS/MS method, (b) rapid conversion of ZST316 into L-257, (c) good intra-tumour penetration of both compounds, and (d) lack of accumulation of both ZST316 and L-257 in plasma and tumour tissue during chronic administration. Compared to a previous method developed by our group to investigate ZST316 in plasma, the main advantages of the new method include a wider range of linearity which reduces the need for dilutions and the combined assessment of ZST316 and L-257 in plasma and tumour tissue which limits the required amount of matrix. The new HPLC-MS/MS method is useful to investigate the in vivo effects of ZST316 and L-257 on vasculogenic mimicry, tumour mass, and metastatic burden in xenograft models of TNBC.

Abstract Background Scarce drug penetration in solid tumours is one of the possible causes of the limited efficacy of chemotherapy and is related to the altered tumour microenvironment. The abnormal tumour extracellular matrix (ECM) together with abnormal blood and lymphatic vessels, reactive stroma and inflammation all affect the uptake, distribution and efficacy of anticancer drugs. Methods We investigated the effect of PEGylated recombinant human hyaluronidase PH20 (PEGPH20) pre-treatment in degrading hyaluronan (hyaluronic acid; HA), one of the main components of the ECM, to improve the delivery of antitumor drugs and increase their therapeutic efficacy. The antitumor activity of paclitaxel (PTX) in HA synthase 3-overexpressing and wild-type SKOV3 ovarian cancer model and in the BxPC3 pancreas xenograft tumour model, was evaluated by monitoring tumour growth with or without PEGPH20 pre-treatment. Pharmacokinetics and tumour penetration of PTX were assessed by HPLC and mass spectrometry imaging analysis in the same tumour models. Tumour tissue architecture and HA deposition were analysed by histochemistry. Results Pre-treatment with PEGPH20 modified tumour tissue architecture and improved the antitumor activity of paclitaxel in the SKOV3/HAS3 tumour model, favouring its accumulation and more homogeneous intra-tumour distribution, as assessed by quantitative and qualitative analysis. PEGPH20 also reduced HA content influencing, though less markedly, PTX distribution and antitumor activity in the BxPC3 tumour model. Conclusion Remodelling the stroma of HA-rich tumours by depletion of HA with PEGPH20 pre-treatment, is a potentially successful strategy to improve the intra-tumour distribution of anticancer drugs, increasing their therapeutic efficacy, without increasing toxicity.

Purpose: Regorafenib monotherapy, a multikinase inhibitor of angiogenesis, tumor microenvironment, and tumorigenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in patients with advanced esophagogastric cancer (EGC) refractory to first-line treatment, and explore potential biomarkers. Methods: Patients received paclitaxel (80 mg/m 2 ) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on days 1–21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall survival (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second-/third-line systemic treatment. Paclitaxel pharmacokinetics were assessed using samples from day 1 (D1) and day 15 (D15). We performed enzyme-linked immunosorbent assay measurements of galectin-1, RNA sequencing, and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. Results: In the dose-escalation cohort ( n = 14), the MTD of regorafenib was 120 mg. In all, 34 patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade ⩾ 3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up: 7.8 months). OS ( p = 0.08) and PFS ( p = 0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p

Abstract Background An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.

Nifuroxazide (NAZ), a nitrofuran derivative used to treat diarrhea, has been recently shown to possess anticancer activity. However, its pharmacokinetic profile is poorly known. The pharmacokinetic profile of NAZ was thus investigated in mice using a newly developed method based on high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). We determined the concentrations of NAZ in the plasma and brain tissue of mice treated with the drug. The method proved to be specific, reproducible, precise, and accurate. It also demonstrated high sensitivity, reaching an LOQ in the order of ppb for both matrices, using samples of 100 µL or 0.2 g. The new HPLC–MS/MS assay was successfully applied to study the pharmacokinetics of NAZ after chronic intraperitoneal administration in mice at a dose of 30 mg/kg. One hour after treatment, plasma concentrations of NAZ were in the range of 336–2640 ng/mL. Moreover, unlike the brains of healthy mice or those with healed mechanical injuries, we found that NAZ was able to cross the injured blood–brain barrier of tumor-infiltrated brains. Thus, following i.p. administration, NAZ reaches systemic levels suitable for testing its efficacy in preclinical models of glioblastoma. Overall, these pharmacokinetic data provide robust evidence supporting the repositioning of NAZ as an antitumor drug.

Antibodies against polyethylene glycol (PEG) in healthy subjects raise concerns about the efficacy of pegylated drugs. We evaluated the prevalence of antibodies against PEG among patients with acute lymphoblastic leukemia (ALL) prior to and/or immediately after their first dose of pegylated E.coli asparaginase (PEG-ASNase). Serum samples of 701 children, 673 with primary ALL, 28 with relapsed ALL, and 188 adults with primary ALL were analyzed for anti-PEG IgG and IgM. Measurements in 58 healthy infants served as reference to define cut-points for antibody-positive and -negative samples. Anti-PEG antibodies were detected in ALL patients prior the first PEG-ASNase with a prevalence of 13.9% (anti-PEG IgG) and 29.1% (anti-PEG IgM). After administration of PEG-ASNase the prevalence of anti-PEG antibodies decreased to 4.2% for anti-PEG IgG and to 4.5% for anti-PEG IgM. Pre-existing anti-PEG antibodies did not inhibit PEG-ASNase activity but significantly reduced PEGASNase activity levels in a concentration dependent manner. Although pre-existing anti-PEG antibodies did not boost, pre-existing anti-PEG IgG were significantly associated with firstexposure hypersensitivity reactions (CTCAE grade 2) (p

The pharmacokinetic profile of ZST316 and ZST152, arginine analogues with inhibitory activity towards human dimethylarginine dimethylaminohydrolase-1 (DDAH1), was investigated in mice using a newly developed HPLC-MS/MS method. The method proved to be reproducible, precise, and accurate for the measurement of the compounds in plasma and urine. Four-week-old female FVB mice received a single dose of ZST316 and ZST152 by intravenous bolus (30 mg/Kg) and oral gavage (60 mg/Kg). ZST316 Cmax was 67.4 µg/mL (intravenous) and 1.02 µg/mL (oral), with a half-life of 6 h and bioavailability of 4.7%. ZST152 Cmax was 24.9 µg/mL (intravenous) and 1.65 µg/mL (oral), with a half-life of 1.2 h and bioavailability of 33.3%. Urinary excretion of ZST152 and ZST316 was 12.5%–22.2% and 2.3%–7.5%, respectively. At least eight urinary metabolites were identified. After chronic intraperitoneal treatment with the more potent DDAH1 inhibitor, ZST316 (30 mg/Kg/day for three weeks), the bioavailability was 59% and no accumulation was observed. Treatment was well tolerated with no changes in body weight vs. untreated animals and no clinical signs of toxicity or distress. The results of this study show that ZST316 has a favorable pharmacokinetic profile, following intraperitoneal administration, to investigate the effects of DDAH1 inhibition in mice.

BRAF is the most frequently mutated gene in melanoma. Constitutive activation of mutant BRAFV600E leads to aberrant Ras-independent MAPK signaling and cell transformation. Inhibition of mutant BRAF is a current frontline therapy for such cases, with improved survival compared with chemotherapy. Unfortunately, reactivation of MAPK signaling by several mechanisms has been shown to cause drug resistance and disease recurrence. In this work, we describe the co-occurrence of an in-frame deletion within an amplified BRAFV600E locus and a missense point mutation of the transcriptional repressor BCORL1 in vemurafenib-resistant A375 melanoma cells. Functional data confirmed that truncated p47BRAFV600E and mutant BCORL1Q1076H both contribute to resistance. Interestingly, either endogenous BCORL1 silencing or ectopic BCORL1Q1076H expression mimicked the effects of a CRISPR/Cas9-edited BCORL1Q1076H locus, suggesting a complex mixture of loss- and gain-of-function effects caused by the mutation. Transcriptomic data confirmed this hypothesis. Finally, we show that the pan-RAF inhibitor sorafenib is not affected by expression of BRAF deletion variant and effectively synergizes with vemurafenib to block resistant cells, suggesting a possible intervention for this class of mutants.

Liquid metal breeding blankets are extensively studied in nuclear fusion. In the main proposed systems, the Water Cooled Lithium Lead (WCLL) and the Dual Coolant Lithium Lead (DCLL), the liquid metal flows under an intense transverse magnetic field, for which a magnetohydrodynamic (MHD) effect is produced. The result is the alteration of all the flow features and the increase in the pressure drops. Although the latter issue can be evaluated with system models, 3D MHD codes are of extreme importance both in the design phase and for safety analyses. To test the reliability of COMSOL Multiphysics for the development of MHD models, a method for verification and validation of magnetohydrodynamic codes is followed. The benchmark problems solved regard steady state, fully developed flows in rectangular ducts, non-isothermal flows, flow in a spatially varying transverse magnetic field and two different unsteady turbulent problems, quasi-two-dimensional MHD turbulent flow and 3D turbulent MHD flow entering a magnetic obstacle. The computed results show good agreement with the reference solutions for all the addressed problems, suggesting that COMSOL can be used as software to study liquid metal MHD problems under the flow regimes typical of fusion power reactors.

We recently discovered that forebrain activation of the IL-1 receptor/Toll-like receptor (IL-1R1/TLR4) innate immunity signal plays a pivotal role in neuronal hyperexcitability underlying seizures in rodents. Since this pathway is activated in neurons and glia in human epileptogenic foci, it represents a potential target for developing drugs interfering with the mechanisms of epileptogenesis that lead to spontaneous seizures. The lack of such drugs represents a major unmet clinical need. We tested therefore novel therapies inhibiting the IL-1R1/TLR4 signaling in an established murine model of acquired epilepsy. We used an epigenetic approach by injecting a synthetic mimic of micro(mi)RNA-146a that impairs IL1R1/TLR4 signal transduction, or we blocked receptor activation with antiinflammatory drugs. Both interventions when transiently applied to mice after epilepsy onset, prevented disease progression and dramatically reduced chronic seizure recurrence, while the anticonvulsant drug carbamazepine was ineffective. We conclude that IL-1R1/TLR4 is a novel potential therapeutic target for attaining disease-modifications in patients with diagnosed epilepsy.

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels

The fibroblast growth factor receptor (FGFR) pathway has been implicated both as an escape mechanism from anti-angiogenic therapy and as a driver oncogene in different tumor types. Lucitanib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 1 to 3 (VEGFR1 to 3), platelet derived growth factor α/β (PDGFRα/β) and FGFR1–3 tyrosine kinases and has demonstrated activity in a phase I/II clinical study, with objective RECIST responses in breast cancer patients with FGFR1 or FGF3/4/19 gene amplification, as well as in patients anticipated to benefit from anti-angiogenic agents. We report here the in vitro and in vivo antitumor activity of lucitanib in experimental models with or without FGFR1/2 amplification or mutations. In cell assays, lucitanib potently inhibited the growth of tumor cell lines with amplified FGFR1 or mutated/amplified FGFR2. In all xenograft models studied, lucitanib demonstrated marked tumor growth inhibition due to potent inhibition of angiogenesis. Notably, in two lung cancer models with FGFR1 amplification, the antitumor efficacy was higher, suggesting that the simultaneous inhibition of VEGF and FGF receptors in FGFR1 dependent tumors can be therapeutically advantageous. Similar antitumor activity was observed in FGFR2 wild-type and amplified or mutated xenograft models. Pharmacokinetic studies showed lucitanib plasma concentrations in the micro/sub-micromolar range demonstrated drug accumulation following repeated lucitanib administration.

The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly present in the PDAC microenvironment and associated with disease progression. Here we have investigated the therapeutic value of the CCN2-targeting BLR100 and BLR200, two modified synthetic peptides derived from active regions of CCN3, an endogenous inhibitor of CCN2. In a murine orthotopic PDAC model, the two peptides, administered as monotherapy at low doses (approximating physiological levels of CCN3), had tumor inhibitory activity that increased with the dose. The peptides affected the tumor microenvironment, inhibiting fibrosis and vessel formation and reducing necrosis. Both peptides were active in preventing ascites formation. An increased activity was obtained in combination regimens, administering BLR100 or BLR200 with the chemotherapeutic drug gemcitabine. Pharmacokinetic analysis indicated that the improved activity of the combination was not mainly determined by the substantial increase in gemcitabine delivery to tumors, suggesting other effects on the tumor microenvironment. The beneficial remodeling of the tumor stroma supports the potential value of these CCN3-derived peptides for targeting pathways regulated by CCN2 in PDAC.

Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity. This suggests individual genetic variability, which might be used to glean the mechanistic insights into oxaliplatin neurotoxicity. We characterized the susceptibility of different mice strains to oxaliplatin neurotoxicity investigating the phenotypic features of neuropathy and gene expression profiles in dorsal root ganglia of six genetically different mice strains (Balb-c, C57BL6, DBA/2J, AJ, FVB and CD1) exposed to the same oxaliplatin schedule. Differential gene expression in dorsal root ganglia from each mice strain were assayed using a genome-wide expression analysis and selected genes were validated by RT-PCR analysis. The demonstration of consistent differences in the phenotypic response to oxaliplatin across different strains is interesting to allow the selection of the appropriate strain based on the pre-defined read-out parameters. Further investigation of the correlation between gene expression changes and oxaliplatin-induced neurotoxicity phenotype in each strain will be useful to deeper investigate the molecular mechanisms of oxaliplatin neurotoxicity.

A sensitive, simple and reproducible protocol for nanoparticle-assisted laser desorption/ionization mass spectrometry imaging technique is described. The use of commercially available TiO2 nanoparticles abolishes heterogeneous crystallization, matrix background interferences and enhances signal detection, especially in the low mass range. Molecular image normalization was based on internal standard deposition on tissues, allowing direct comparison of drug penetration and distribution between different organs and tissues. The method was applied to analyze the distribution of the anticancer drug paclitaxel, inside normal and neoplastic mouse tissue sections. Spatial resolution was good, with a linear response between different in vivo treatments and molecular imaging intensity using therapeutic drug doses. This technique distinguishes the different intensity of paclitaxel distribution in control organs of mice, such as liver and kidney, in relation to the dose. Animals treated with 30 mg/kg of paclitaxel had half of the concentration of those treated with 60 mg/kg. We investigated the spatial distribution of paclitaxel in human melanoma mouse xenografts, following different dosage schedules and found a more homogeneous drug distribution in tumors of mice given repeated doses (5×8 mg/kg) plus a 60 mg/kg dose than in those assigned only a single 60 mg/kg dose. The protocol can be readily applied to investigate anticancer drug distribution in neoplastic lesions and to develop strategies to optimize and enhance drug penetration through different tumor tissues.