Vaccine antibodies against a synthetic epidermal growth factor variant enhance the antitumor effects of inhibitors targeting the MAPK/ERK and PI3K/Akt pathways.

BACKGROUND: The EGFR pathway is involved in intrinsic and acquired resistance to a wide variety of targeted therapies in cancer. Vaccination represents an alternative to the administration of anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab. Here, we tested if anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) could potentiate the activity of drugs targeting the ERK/MAPK and PI3K/Akt pathways. METHODS: Non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and melanoma cell lines harboring KRAS, NRAS, BRAF and PIK3CA mutations were used. Anti-EGF VacAbs were obtained by immunizing rabbits with a fusion protein containing a synthetic, highly mutated variant of human EGF. Cell viability was determined by MTT, total and phosphorylated proteins by Western blotting, cell cycle distribution and cell death by flow cytometry and emergence of resistance by microscopic examination in low density cultures. RESULTS: Anti-EGF VacAbs potentiated the antiproliferative effects of MEK, KRAS G12C, BRAF, PI3K and Akt inhibitors in KRAS, NRAS, BRAF and PIK3CA mutant cells and delayed the appearance of resistant clones in vitro. The effects of anti-EGF VacAbs were comparable or superior to those of panitumumab and cetuximab. The combination of anti-EGF VacAbs with the targeted inhibitors effectively suppressed EGFR downstream pathways and sera from patients immunized with an anti-EGF vaccine also blocked activation of EGFR effectors. CONCLUSIONS: Anti-EGF VacAbs enhance the antiproliferative effects of drugs targeting the ERK/MAPK and PIK3CA/Akt pathways. Our data provide a rationale for clinical trials testing anti-EGF vaccination combined with inhibitors selected according to the patient's genetic profile.

Overcoming MET-mediated resistance in oncogene-driven NSCLC.

This study evaluates the efficacy of combining targeted therapies with MET or SHP2 inhibitors to overcome MET-mediated resistance in different NSCLC subtypes. A prevalence study was conducted for MET amplification and overexpression in samples from patients with NSCLC who relapsed on ALK, ROS1, or RET tyrosine kinase inhibitors. MET-mediated resistance was detected in 37.5% of tissue biopsies, which allow the detection of MET overexpression, compared to 7.4% of liquid biopsies. The development of drug resistance by MET overexpression was confirmed in EGFRex19del-, KRASG12C-, HER2ex20ins-, and TPM3-NTRK1-mutant cell lines. The combination of targeted therapy with MET or SHP2 inhibitors was found to overcome MET-mediated resistance in both in vitro and in vivo assays. This study highlights the importance of considering MET overexpression as a resistance driver to NSCLC targeted therapies to better identify patients who could potentially benefit from combination approaches with MET or SHP2 inhibitors.

Biomass Novel Adsorbents for Phenol and Mercury Removal.

This paper reports the use of activated carbons made from novel agriculture and industrial wastes, namely sunflower, vine shoots, and coffee endocarp, to remove two high-priority contaminants: phenol and mercury species (under different forms) from aqueous solutions. The activated carbons were used as prepared and also modified with nitric acid and triethylenediamine in order to explore additional adsorption mechanisms. The results showed an interesting potential of the materials to be used for water decontamination as indicated by the mercury uptake up to 1104 mg/g for Hg2+, 771 mg/g for [HgCl4]2-, 966 mg/g for HgCl2 and the maximum phenol adsorption capacity of 190 mg/g. The modification with triethylenediamine led to a significant increase in the phenol and mercury adsorption reaching an increment of 85% for phenol and 250% for Hg2+.

Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells.

Advanced NSCLC patients harboring EML4-ALK and CCDC6-RET rearrangements derive benefit from treatment with ALK and RET TKIs but not immune checkpoint inhibitors. New immunotherapeutic approaches, such as immunization against growth factors, can be of particular interest for combination treatment in these patients. Here, we investigated the effects of anti-EGF antibodies generated by vaccination (anti-EGF VacAbs), TKIs and combinations in EML4-ALK and CCDC6-RET NSCLC cell lines. We found that EGF and tumor growth factor alpha (TGFα) significantly decreased the antiproliferative activity of the RET inhibitor BLU-667 in CCDC6-RET cells and brigatinib, alectinib and crizotinib in EML4-ALK translocated cells. The addition of anti-EGF VacAbs reversed the effects of EGF and TGFα, potentiated the antitumor effects of the kinase inhibitors and delayed the appearance in vitro of resistant clones. Western blotting demonstrated that the combination of anti-EGF VacAbs with ALK or RET TKIs effectively suppressed EGFR downstream pathways in EML4-ALK translocated and CCDC6-RET cells, respectively. In conclusion, anti-EGF VacAbs significantly increased the antitumor activity of TKIs in ALK and RET-positive cell lines. Clinical trials of an EGF vaccine in combination with ALK and RET TKIs are warranted.

Surface Interactions during the Removal of Emerging Contaminants by Hydrochar-Based Adsorbents.

The aim of this work was to test activated carbons derived from hydrochars produced from sunflower stem, olive stone and walnut shells, as adsorbents for emerging contaminants in aqueous solution, namely fluoxetine and nicotinic acid. The adsorption capacity was determined by the chemical nature of the adsorbents, namely the presence of specific functional groups and their positive or negative ionization in aqueous solutions and also by steric factors. The activated carbons produced by air showed a higher adsorption capacity of fluoxetine, whilst the samples produced by carbon dioxide activation were more useful to remove nicotinic acid. In general, surface acidity was advantageous for fluoxetine adsorption and detrimental for nicotinic acid removal. The adsorption mechanisms involved in each case were discussed and related to the adsorbents characteristics. The maximum adsorption capacity, Q0, given by the Langmuir model was 44.1 and 91.9 mg g-1 for fluoxetine and nicotinic acid adsorption, respectively.

Magnetic Behavior of Carbon Materials Made from Biomass by Fe-Assisted Hydrothermal Carbonization.

Biomass magnetic materials were synthesized by several hydrothermal carbonization methods, by which iron was provided in different ways: as FeCl3 prior to or during hydrothermal carbonization, as pure Fe particles, or as magnetic ferrofluid, followed or not by pyrolysis processes. The materials were thoughtfully characterized in terms of elemental composition, thermal degradation, porosity (N2 adsorption, SEM micrography), surface chemistry (FTIR spectroscopy, XRD diffraction), and magnetization curves on a self-made installation. The results indicated that the process design can significantly improve the structure and chemistry of the material, as well as the magnetization effect induced on the adsorbent. Fe as FeCl3 was more interesting in regards to the development of porosity, mainly creating micropores, although it did not provide magnetism to the material unless a further pyrolysis was applied. Thermal treatment at 600 °C did not only increase the BET-specific surface (SBET) (262 m2 g-1) of the hydrochar, but also involved the transformation of Fe into magnetite, providing magnetic behavior of the hydrochar. Increasing pyrolyisis temperature to 800 °C even enhanced a better development of porosity (SBET of 424 m2 g-1) and also increased the specific magnetic susceptibility of the hydrochar as a result of the further transition of Fe into wustite and hydroxi-ferrite.

AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy.

Non-small cell lung cancer (NSCLC) tumors harboring mutations in EGFR ultimately relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Here, we show that resistant cells without the p.T790M or other acquired mutations are sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076. Phospho-histone H3 (pH3), a major product of AURKB, is increased in most resistant cells and treatment with AURKB inhibitors reduces the levels of pH3, triggering G1/S arrest and polyploidy. Senescence is subsequently induced in cells with acquired mutations while, in their absence, polyploidy is followed by cell death. Finally, in NSCLC patients, pH3 levels are increased after progression on EGFR TKIs and high pH3 baseline correlates with shorter survival. Our results reveal that AURKB activation is associated with acquired resistance to EGFR TKIs, and that AURKB constitutes a potential target in NSCLC progressing to anti-EGFR therapy and not carrying resistance mutations.

Prospective analysis of liquid biopsies of advanced non-small cell lung cancer patients after progression to targeted therapies using GeneReader NGS platform.

BACKGROUND: In a significant percentage of advanced non-small cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses at time to progression. We prospectively analyzed the appearance of genetic alterations associated with resistance in liquid biopsies of advanced NSCLC patients progressing to targeted therapies using the NGS platform. METHODS: A total of 24 NSCLC patients were included in the study, 22 progressing to tyrosine kinase inhibitors and two to other treatments. Liquid biopsies samples were obtained and analyzed using the GeneReadTM QIAact Lung DNA UMI Panel, designed to enrich specific target regions and containing 550 variant positions in 19 selected genes frequently altered in lung cancer tumors. Previously, a retrospective validation of the panel was performed in clinical samples. RESULTS: Of the 21 patients progressing to tyrosine kinase inhibitors with valid results in liquid biopsy, NGS analysis identified a potential mechanism of resistance in 12 (57%). The most common were acquired mutations in ALK and EGFR, which appeared in 8/21 patients (38%), followed by amplifications in 5/21 patients (24%), and KRAS mutations in one patient (5%). Loss of the p.T790M was also identified in two patients progressing to osimertinib. Three of the 21 (14%) patients presented two or more concomitant alterations associated with resistance. Finally, an EGFR amplification was found in the only patient progressing to immunotherapy included in the study. CONCLUSIONS: NGS analysis in liquid biopsies of patients progressing to targeted therapies using the GeneReader platform is feasible and can help the oncologist to make treatment decisions.

Anti-Epidermal Growth Factor Vaccine Antibodies Enhance the Efficacy of Tyrosine Kinase Inhibitors and Delay the Emergence of Resistance in EGFR Mutant Lung Cancer Cells.

INTRODUCTION: Mutations in EGFR correlate with impaired response to immune checkpoint inhibitors and the development of novel immunotherapeutic approaches for EGFR mutant NSCLC is of particular interest. Immunization against epidermal growth factor (EGF) has shown efficacy in a phase III trial including unselected NSCLC patients, but little was known about the mechanisms involved in the effects of the anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) or their activity in tumor cells with EGFR mutations. METHODS: The EGFR-mutant, NSCLC cell lines H1975, and PC9, together with several gefitinib and osimertinib-resistant cells derived from PC9, were treated with anti-EGF VacAbs and/or EGFR tyrosine kinase inhibitors (TKIs). Cell viability was analyzed by proliferation assays, cell cycle by fluorescence-activated cell sorting analysis, and levels of RNA and proteins by quantitative retro-transcription polymerase chain reaction and Western blotting. RESULTS: Anti-EGF VacAbs generated in rabbits suppressed EGF-induced cell proliferation and cycle progression and inhibited downstream EGFR signaling in EGFR-mutant cells. Sera from patients immunized with an EGF vaccine were also able to block activation of EGFR effectors. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of all TKIs tested, suppressed Erk1/2 phosphorylation, blocked the activation of signal transducer and activator of transcription 3 (STAT3) and downregulated the expression of AXL receptor tyrosine kinase (AXL). Finally, anti-EGF VacAbs significantly delayed the emergence in vitro of EGFR TKI resistant clones. CONCLUSIONS: EGFR-mutant patients can derive benefit from immunization against EGF, particularly if combined with EGFR TKIs. A phase I trial of an EGF vaccine in combination with afatinib has been initiated.

Pharmacogenomics in the treatment of lung cancer: an update.

Significant advances have been made in the analysis of the human genome in the first decades of the 21st century and understanding of tumor biology has matured greatly. The identification of tumor-associated mutations and the pathways involved has led to the development of targeted anticancer therapies. However, the challenge now in using chemotherapy to treat nonsmall-cell lung cancer is to identify more molecular markers predictive of drug sensitivity and determine the optimal drug sequences in order to tailor treatment to each patient. This approach could permit selection of patients who could benefit most from a specific type of chemotherapy by matching their tumor and individual genetic profile. Nevertheless, this potential has been limited so far by reliance on the single biomarker approach, though this is now on the way to being overcome through whole genome studies.

Immunotherapy meets targeted therapy: will this team end the war against cancer?

Cancer treatment as we know it today has dramatically changed over the last couple of decades. It has moved from non-specific treatment to personalized approaches. As oncologist, we now have further understanding of the processes leading to carcinogenesis; this has led to develop new therapeutic options. We have cytotoxic treatments, targeted therapy and in recent years, immunotherapy; the time to "mix and match" has begun.

Control of several emissions during olive pomace thermal degradation.

Biomass plays an important role as an energy source, being an interesting alternative to fossil fuels due to its environment-friendly and sustainable characteristics. However, due to the exposure of customers to emissions during biomass heating, evolved pollutants should be taken into account and controlled. Changing raw materials or mixing them with another less pollutant biomass could be a suitable step to reduce pollution. This work studied the thermal behaviour of olive pomace, pyrenean oak and their blends under combustion using thermogravimetric analysis. It was possible to monitor the emissions released during the process by coupling mass spectrometry analysis. The experiments were carried out under non-isothermal conditions at the temperature range 25-750 °C and a heating rate of 20 °C·min⁻¹. The following species were analysed: aromatic compounds (benzene and toluene), sulphur emissions (sulphur dioxide), 1,4-dioxin, hydrochloric acid, carbon dioxide and nitrogen oxides. The results indicated that pollutants were mainly evolved in two different stages, which are related to the thermal degradation steps. Thus, depending on the pollutant and raw material composition, different emission profiles were observed. Furthermore, intensity of the emission profiles was related, in some cases, to the composition of the precursor.

A critical question for cancer therapy: what new targets exist?

Designing molecular targeted therapy with high specificity based on novel tumor biomarkers is a high priority in lung cancer research. Several molecular aberrations have been already identified in non-small cell lung cancer (NSCLC), with subsequent development of drugs targeted to these aberrations. A more recent actionable target is MET, a multifaceted receptor tyrosine kinase which frequently interacts with other key oncogenic tyrosine kinases including epidermal growth factor receptor (EGFR) and ERBB3 leading to resistance to anti-EGFR therapies. However a phase III trial enrolling only patients with MET-positive tumors was stopped in early March due to futility since there was no evidence that the addition of onartuzumab to erlotinib has any positive effect. From the results of the MET lung phase III trial, we provide new pieces of information that can contribute to further preclinical validation and also be part of the armamentarium for clinical translational research.

Fundamental studies of methyl iodide adsorption in DABCO impregnated activated carbons.

Methyl iodide capture from a water vapor stream using 1,4-diazabicyclo[2.2.2]octane (DABCO)-impregnated activated carbons is, for the first time, fundamentally described here on the atomic level by means of both molecular dynamics and grand canonical Monte Carlo simulations. A molecular dynamics annealing strategy was adopted to mimic the DABCO experimental impregnation procedure in a selected slitlike carbon pore. Predictions, restricted to the micropore region, are made about the adsorption isotherms of methyl iodide, water, and nitrogen on both impregnated and bare activated carbon models. Experimental and simulated nitrogen adsorption isotherms are compared for the validation of the impregnation strategy. Selectivity analyses of the preferential adsorption toward methyl iodide over water are also reported. These simulated adsorption isotherms sum up to previous experimental studies to provide an enhanced picture for this adsorption system of widespread use at nuclear plant HVAC facilities for the capture of radioactive iodine compounds.

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Oxidation of MCPA and 2,4-D by UV radiation, ozone, and the combinations UV/H2O2 and O3/H2O2.

The phenoxyalkyl acid derivative herbicides MCPA (4-chloro 2-methylphenoxyacetic acid) and 2,4-D (2,4-dichlorophenoxyacetic acid) were oxidized in ultrapure water by means of a monochromatic UV irradiation and by ozone, as well as by the combinations UV/H2O2 and O3/H2O2. In the direct photolysis of MCPA, the quantum yield at 20 degrees C was directly evaluated and a value of 0.150 mol Eins(-1) was obtained in the pH range 5-9, while a lower value of 0.41 x 10(-2) mol Eins(-1) was determined at pH=3. Similarly, for 2,4-D a value of 0.81 x 10(-2) mol Eins(-1) was deduced, independent of the pH of work. The influence of the additional presence of hydrogen peroxide was established in the combined process UV/H2O2, and the specific contribution of the radical pathway to the global photo-degradation was evaluated. The oxidation by ozone and by the combination O3/H2O2 was also studied, with the determination of the rate constants for the reactions of both herbicides with ozone and hydroxyl radicals at 20 degrees C. These rate constants for the direct reactions with ozone were 47.7 and 21.9 M(-1) s(-1) for MCPA and 2,4-D respectively, while the found values for the rate constants corresponding to the radical reactions were 6.6 x 10(9) and 5.1 x 10(9) M(-1) s(-1).