bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantifying the impact of antiangiogenic therapy on hypoxia and implications for radiation therapy in glioblastoma multiforme with a biomathematical model.
Authors: Hawkins-Daarud Andrea , Rockne Russell , Kinahan Paul , Muzi Mark , Alessio Adam , Krohn Kenneth A. , Swanson Kristin 
Published: March 2020

e13028 Background: Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor. As angiogenesis is a major hallmark of GBM, it can be inferred that hypoxia plays a prominent role in the progression of the disease. However, due to difficulty in assessing hypoxia, the development and evolution of hypoxia has not been well studied for GBM. 18F-Fluoromisonidazole (FMISO) PET indirectly measures hypoxia. It is known that hypoxia reduces the efficacy of radiation therapy, and one current strategy being explored is to combine anti-angiogenic therapy and radiation therapy. However, it is unclear whether anti-angiogenic therapy is ultimately reducing or increasing hypoxia nor is it clear how long the effects last. Methods: We have developed a spatio-temporal biomathematical model for glioma proliferation and invasion that incorporates the angiogenic cascade. In this context, we can simulate the action of anti-angiogenic treatment, such as bevacizumab, by modifying the availability of angiogenic factors. By applying a pharmacokinetic model for the uptake of FMISO to the simulation results, we can generate the corresponding FMISO-PET images during and after anti-angiogenic therapy to compare with what would be seen in the clinic. Results: Simulation results for a wide range of tumor kinetics demonstrated that hypoxia in general decreased during anti-angiogenic therapy. However, the rates at which it decreased and the time for the hypoxia to return to pre-treatment levels were not uniform. Conclusions: Dynamic understanding of anti-angiogenic therapy effects on vascular normalization and hypoxia suggest that optimal timing of radiation therapy and anti-angiogenic therapies would vary by patient. This biomathematical model can be tuned to individual patients’ tumors and provide similar information as a FMISO-PET image and also give insight into the dynamics of the hypoxia over time. Such insight could be invaluable to patient-specific treatment planning for combining radiation with antiangiogenics.
Comparative dosimetric study of three-dimensional conformal (3DCRT), intensity modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT) for treatment in pituitary adenomas.
Authors: Gupta Subhash , Laviraj M. A , Kunhiparambath Haresh , Sharma Dayanand , M Rajendran , Julka Pramod Kumar , Rath Goura Kishor 
Published: March 2020

e13043 Background: Radiotherapy is usually delivered after surgery in pituitary adenomas. Usually stereotactic radiotherapy is used in their treatment. The studies evaluating the recent advances like IMRT, VMAT for pituitary adenomas are rare. Present study evaluates 3DCRT, IMRT, and VMAT for the treatment of pituitary adenomas. Methods: Ten patients of pituitary adenomas who were planned for post operative adjuvant radiotherapy were included. Planning CT was done with the patient supine with a customized thermoplastic cast of head on Philips wide bore CT (for 3 mm). The CT images were transferred online to the Pinnacle TPS V.8.0M. Tumor and the critical structures like brain stem and optic nerves were contoured on pinnacle. 3DCRT was planned on pinnacle. The CT images with the contoured structures were sent to Monaco TPS V.3.10.02. IMRT and VMAT were planned on Monaco. Dose: 50 Gy in 25 fractions. PTV indices analyzed: D mean, D2 (dose received by the hottest 2 percent volume), D98 (dose received by 98 percent), homogeneity index HI [(D2-D98)/D50)], and conformity index CI (PTV volume/volume of PTV covered by 95 percent isodose). Dmax and D2 (dose received by hottest 2cc) for the brain stem, right and left optic nerve PRV were evaluated. The average were calculated and compared. Statistical analysis was done by SPSS Version 14. Results: The Table shows that VMAT is better in terms of PTV indices. For the normal structures also VMAT provides the least dose. Conclusions: VMAT is superior to IMRT and both are better than 3DCRT for the radiotherapeutic treatment of pituitary adenoma. [Table: see text]
Linking kinases to adverse events through kinase inhibitors.
Authors: Iqbal Afsheen , Zhao Shan , Reichert Sonia Evelyn , Maki Robert G. 
Published: March 2020

e13524 Background: Small molecule oral kinase inhibitors (SMOKIs) are anticancer agents with unique activity and toxicity. We sought to determine if specific kinases blocked by SMOKIs could be linked to specific adverse events (AEs). Methods: We identified studies in which cancer indications for SMOKIs were compared to placebo or other therapy, and collected prevalence data of grade 3, 4, and 5 AEs for each study arm. Targets of each SMOKI were screened from existing data on kinase specificity, selecting Kd<500nM. Each SMOKI was mapped to its respective kinases. We compared the frequency of AEs from all studies when the kinase of interest was involved to AE frequency when the kinase was not involved, and computed the probabilities for attributed risk for each kinase and the significance of association between AE and drug of interest via t-test. We evaluated the significance in a pair-wise manner, computing the difference in probability for a single AE for each study independently, and then evaluating the significance of the average probability, assuming unequal variance across studies. Results: 67 trials fit our criteria, and led to the identification of AEs associated with varying number of kinases, e.g. diarrhea (45 kinases), asthenia (43), hypertension (30), rash (30), thrombocytopenia (plts, 29), and neutropenia (21). Most associations, while statistically significant, had low attributable risk (≤5%), except diarrhea (24 kinases), hand-foot syndrome (19), and plts (13). BRAF (5.4% attributable risk) and VEGFR1 (4.9%) inhibition were most strongly associated with hypertension; AXL (5.3%), FGFR3 (5.3%), MAP4K5 (5%), and YES1 (5%) were associated with neutropenia; and TNIK (5.4%), PLK4 (5.3%), STK16 (5.3%), RPS6KA1 (5.1%), and FGFR3 (5%) were associated with asthenia. Conclusions: Certain AEs are common to many SMOKIs and thus many kinases. Other AEs such as neutropenia and asthenia were more tightly linked to specific kinases. By developing SMOKIs that block the target of interest but not kinases identified from these data, it may be possible to decrease the toxicity burden of future generations of SMOKIs.
Effect of cilastatin on cisplatin-induced nephrotoxicity and on antitumoral activity.
Authors: Blanco-Codesido Montserrat , Humanes Blanca , Lazaro Alberto , Camaño Sonia , Jado Juan Carlos , Tejedor Alberto 
Published: March 2020

e13535 Background: Cisplatin (CDDP) is a very effective and common treatment in solid malignancies used mostly in breast, ovarian, bladder, esophageal, gastric, head and neck cancer and germ cell tumors. One of the most important side effects of CDDP is the nephrotoxicity, a limitating side effect, especially with high CDDP doses, affecting as much as 30% of the patients. Cilastatin (Cls) is a specific inhibitor of renal dedydrodipeptidase I which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. In this work we show that Cls acts as a nephroprotector against CDDP-induced damage without compromising its antitumor activity. Methods: Primary cultures of proximal tubular cells (PTCs) and cell lines of different malignancies (colon, breast, ovarian, bladder) were cultured with CDDP (1, 10 and 30 μM) in the presence or absence of Cls. Cell viability was assessed with MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. Wistar rats were treated with 5 mg/Kg of CDDP (single dose) and 75 mg/Kg/12 hours of Cls. We measured body weight, serum albumin, ALT, AST, creatinine, BUN, serum iones and GAP anion as well as urinary creatinine, osmolality, potassium, sodium and urea. Results: Concomitant treatment with Cls reduced CDDP-induced changes in PCTs. Several tumoral cell lines were tested with CDDP and Cls together. Cls did not increase or decreased tumor growth alone or in combination with CDDP. CDDP sensitivity was not affected by Cls. Wistar rats treated with CDDP alone showed loss of weight and significant worsening in renal function tests. Wistar rats experienced less loss of weight and a significant reduction in renal function worsening when treated simultaneously with CDDP and Cls. Liver function tests were not altered by the addition of Cls to the treatment. Conclusions: Our findings suggest that Cls administration might represent a novel strategy in the prevention of CDDP-induced acute renal injury without compromising its antitumor activity. Cls treatment could potentially increase the number of patients undergoing CDDP treatment or maintaining treatment. Further clinical trials for renal function preservation in cancer patients are on development.
Identification of pharmacogenetic target genes associated with chemotherapy-induced peripheral neuropathy.
Authors: Komatsu Masaaki , Wheeler Heather E. , Wing Claudia , Delaney Shannon , Dolan M. Eileen 
Published: March 2020

e13541 Background: Chemotherapy-induced Peripheral Neuropathy (CIPN) is a dose-limiting toxicity of many anticancer drugs, including taxanes, vinca alkaloids and platinating agents. There are no effective means to predict which patients are at risk for CIPN nor are there effective treatments. Therefore, we have used a whole genome approach in lymphoblastoid cell lines (LCLs) alone or combined with clinical study data to identify target genes associated with CIPN that we tested further in Neuroscreen-1 (NS-1: rat pheochromocytoma) cells and human neurons derived from induced pluripotent stem cells (iCell neurons). Methods: For selecting candidate target genes, we compared published genome-wide association studies (GWAS) results of sensory peripheral neuropathy in cancer patients receiving paclitaxel with GWAS results of pharmacologic phenotypes in LCLs after paclitaxel treatment. We evaluated neurotoxic drug-induced cell growth inhibition using Cell Titer Glo and neurite parameters of outgrowth, processes and branching through imaging following transient knockdown of target genes in NS-1 cells and iCell neurons. Results: After treatment of paclitaxel, vincristine and cisplatin, iCell neurons showed decrease of neurite outgrowth, processes and branching. Whereas, these parameters did not decrease for hydroxyurea, which is not reported to induce neuropathy. Through transient knockdown in NS-1 cells of RFX2, a gene identified through clinical and preclinical studies to be associated with paclitaxel-induced neuropathy, sensitivity to paclitaxel increased as measured by a decrease of neurite outgrowth. Conclusions: These findings imply our model system could identify pharmacogenetic target genes associated with CIPN. These genes have potential for biomarkers or therapeutic targets and enable future personalized treatments for cancer patients at risk for CIPN.
Preclinical characterization of a potent and selective inhibitor of the histone demethylase KDM1A for MLL leukemia.
Authors: Maes Tamara , Tirapu Iñigo , Mascaró Cristina , Ortega Alberto , Estiarte Angels , Valls Nuria , Castro-Palomino Julio , Buesa Arjol Carlos , Kurz Guido 
Published: March 2020

e13543 Background: The lysine-specific demethylase KDM1A catalyzes the removal of methyl groups from mono and dimethylated H3K4/K9, changes that have inductive or inhibitory effects on gene expression. KDM1A is a key regulator of leukemia stem cell (LSC) potential and is required for MLL-AF9 oncogenic transformation. Inhibition of KDM1A expression or activity overcomes the differentiation block in AML. Mixed lineage leukemia (MLL) is a form of AML that is especially sensitive to inhibition of KDM1A. Methods: Gene expression was analyzed using microarrays, cell differentiation was assessed by FACS, viability and apoptosis were assessed by MTT assay and PI staining, me2H3K4 levels were quantified by qPCR and ChIPseq. Results: We used computational models based on reported X-ray structures fine-tuned with the SAR of a first series of molecules to design and synthesize >800 KDM1A inhibitors. ORY-1001 is an enantiomerically pure KDM1A inhibitor (IC50 <20nM) with high selectivity against related FAD dependent aminoxidases (MAO-A/B, IL4I1, KDM1B >100uM, SMOX 7uM). ORY-1001 does not inhibit non-related histone modifiers, and is clean in a CEREP diversity panel. Treatment of THP-1 (MLL-AF9) cells with ORY-1001, results in a time/dose dependent me2H3K4 accumulation at KDM1A target genes and concomitant induction of differentiation markers (EC50 me2H3K4 and FACS CD11b <1nM). Microarray analysis of treated THP-1 cells reveals differentiation towards a monocyte-like phenotype. ORY-1001 induces apoptosis in THP-1 and inhibits proliferation and colony formation of MV(4;11) (MLL-AF4) cells (EC50 <1nM). Daily oral administration of doses <0.020mg/kg leads to significantly reduced tumor growth in rodent MV(4;11) xenografts. In vivo and in vitro IND/IMPD enabling studies have shown that ORY-1001 presents excellent oral bioavailability, target exposure and activity in vivo. The compound is stable in hepatocytes (Clint<0.6 mL/min/g liver, @1uM) and does not exhibit CYP (IC50>100uM) or hERG (%inhib.<2%, @10uM) inhibition. No off-target activity has been detected in 28d rat toxicology studies. Conclusions: A potent and selective KDM1A inhibitor is described with in vitro and vivo anti-leukemic efficacy.
Preclinical evaluation of genexol-PM, a nanoparticle formulation of paclitaxel, as a novel radiosensitizer for the treatment of non-small cell lung cancer.
Authors: Wang Andrew , Cummings Natalie Dawn , Sethi Manish , Wang Edina , Sukumar Rohit , Moore Dominic T. , Werner Michael Edward 
Published: March 2020

e13546 Background: A key research objective in radiation oncology is to identify agents that can improve chemoradiotherapy. Nanoparticle (NP) chemotherapeutics possess several properties, such as preferential accumulation in tumors, that are uniquely suited for chemoradiotherapy. To facilitate the clinical translation of NP chemotherapeutics in chemoradiotherapy, we conducted preclinical evaluation of Genexol-PM, the only clinically approved NP chemotherapeutic with a controlled drug release profile, as a radiosensitizer using non-small cell lung cancer as a model disease. Methods: The physical characteristics and drug release profile of Genexol-PM were characterized. Genexol-PM’s efficacy as a radiosensitizer was evaluated in vitro using NSCLC cell lines and in vivousing mouse xenograft models of NSCLC. Paclitaxel dose to normal lung and liver after Genexol-PM administration were quantified and compared to that of after Taxol administration. Results: Genexol-PM have a size of 23.91 ± 0.41 nm and surface charge of -8.1 ± 3.1 mV. It releases paclitaxel in a controlled release profile. In vitro evaluation of Genexol-PM as a radiosensitizer showed it is an excellent radiosensitizer and is more effective than Taxol, its small molecule counterpart at the half maximal inhibitory concentration (IC50). In vivostudy of Genexol-PM as a radiosensitizer demonstrated that it is more effective as a radiosensitizer than Taxol. We also found that Genexol-PM leads to lower paclitaxel exposure to normal lung and liver tissue than Taxol at 6 hours post administration. Conclusions: We have demonstrated that Genexol-PM is more effective than Taxol as a radiosensitizer in the preclinical setting and holds high potential for clinical translation. Our data support the clinical evaluation of Genexol-PM in chemoradiotherapy for NSCLC.
Targeting Y397 FAK scaffolding compared with FAK kinase inhibition: Efficacy and specificity for tumor cells.
Authors: Golubovskaya Vita , Ho Baotran , Stright Adam , Zajac-Kaye Maria , Hochwald Steven N. , Cance William G. 
Published: March 2020

e13547 Background: Focal Adhesion Kinase is a non-receptor kinase which is highly overexpressed and activated or autophosphorylated in many types of tumors and plays a major role in survival signaling and metastasis. Recently, our group developed a highly specific allosteric scaffolding FAK autophosphorylation inhibitor, Y15, that blocked FAK Y397 autophosphorylation, decreased cancer cell viability, and significantly decreased breast, neuroblastoma, pancreatic and glioblastoma tumor growth. In addition, Y15 was not toxic in mice. In this study, we compared side by side efficacy of Y15 with two other FAK inhibitors in clinical trials, Pfizer PF-04554878 and Glaxo GSK-2256098. Methods: MTT, clonogenicity and Western blotting assays were used to detect the effect of FAK inhibitors on different cancer and normal cells. Student’s t-test was used for statistical analysis and p<0.05 was considered significant. Results: We tested different cancer cell lines: kidney 293T, colon SW620 and LoVo; lung A549; glioblastoma U251 and U87; breast: BT474, MDA-231, MDA-361, MDA-453, MDA-468 and T47D and pancreatic PANC-1 cancer cells with different doses of Y15, PF and GSK inhibitors by MTT assay and found that Y15 was the most effective at decreasing cancer cell viability in most cancer cell lines, with higher efficacy than PF and much higher efficacy than GSK inhibitor. The same was observed for clonogenicity assay. In addition, we found that Y15 did not significantly affect viability of normal colon (CCD-112) cells, while viability of these cells with PF and GSK decreased to 54% and 57% at a 2 microM dose, respectively, from 100% in untreated cells. In addition, Y15 significantly decreased Y397-FAK, Y418-Src, phospho- Ser 473-AKT and phospho-ERK1/2, while PF had less effect and GSK only a minimal effect in four different cancer cell lines: U251, A549, 293T and Lovo at 10 microM and 100 microM doses, showing high potency of the FAK Y397 scaffolding inhibitor. Conclusions: These data show that Y15, which inhibits the Y397 site of FAK, is more potent against cancer cells and less toxic to normal cells than FAK inhibitors that target the conserved ATP-binding site in the kinase domain.
International collaboration in personalized medicine for the treatment of advanced and drug-refractory cancers: Clinical application of human tumor primary culture analyses.
Authors: Silva Fabricio Colacino , Maluf Fernando C. , Buzaid Antonio C. , Nagourney Robert Alan , Yamaguchi Nise Hitomi , D'Amora Paulo , Evans Steven , Bernard Paula J , Francisco Federico 
Published: March 2020

e13562 Background: Personalized oncology has advanced through genomic and proteomic platforms. BCR-abl; EGFr and ALK have provided drug-able targets and companion diagnostics in several diseases, yet many transforming events in humans are polygenic, complex and incompletely understood at a genomic level. Recognition that oncogenesis reflects changes in the cell and its micro environment has renewed interest in whole cell experimental models that capture native-state cell-cell, -stroma and -vascular signaling. Ex vivo analysis of programmed cell death (EVA/PCD) has been shown to correlate significantly with response, time to progression and survival (Nagourney, R. Curr. Treat Op Oncol, 2006).To explore EVA/PCD functional profiling in Brazil, hospital-based investigators, Centro de Genomas and Rational Therapeutics coordinated the transport of 67 surgical specimens for analyses. Methods: Dose-response curves using metabolic (ATP-content, mitochondrial) and morphologic endpoints, interpolated to LC50's and synergy by median-effect, were compared with databases to identify patient-specific profiles for cytotoxics, targeted agents and combinations. Reports provided day 7. Results: 62/67 (92%) provided adequate tumor for analysis; 39 male (58%); 28 (42%) female; 6 chemo-naive and 61 previously treated. Results provided for < 8 drugs in 14/62 (22%); 8-16 drugs in 34/62 (54%) and > 16 drugs in 14/62 (22%). Of 22 tumor types, breast (8); Melanoma (8); NSCLC (8); ovary (7); pancreas (7) and sarcoma (4) predominated. EVA/PCD was used to select the most active combinations. Agents selected, response rates and durations are being tabulated and will be reported. Conclusions: The transport, processing and reporting of human tumor primary culture analyses is feasible, providing results in 92% of specimens and median of 12 drugs evaluated (range 4-32). Preliminary outcomes in these drug-refractory patients reveal that novel, often unexpected drug combinations (Everolimus and Lapatinib in triple negative breast) were identified and provided objective tumor responses, supporting EVA/PCD in therapy selection (personalized therapy) and drug development.
Evaluation of GPER agonist G-1 combined with navitoclax in platinum-resistant and -sensitive ovarian cancer cells.
Authors: DeSimone Dennis C. , Nguyen Trung T. , Brailiou Eugen , Taylor John C. , Brailoiu Gabriela Cristina , Boyd Jeff , Ariazi Eric A. 
Published: March 2020

e13563 Background: Most ovarian cancer patients are treated with platinum-based chemotherapy but eventually relapse with incurable disease. The G protein-coupled estrogen receptor GPER (GPR30) mediates Ca2+ mobilization in response to estrogen and G-1, a synthetic agonist. Large and sustained Ca2+ responses can lead to mitochondrial Ca2+ overload and apoptosis. Hence, we evaluated whether G-1 could induce apoptosis in cisplatin-sensitive A2780 and isogenic cisplatin–resistant CP70 (14-fold resistant), C30 (70-fold resistant) and C200 (157-fold resistant) human ovarian cancer cells. Bcl-2 and Bcl-xL protect mitochondria from Ca2+overload, and were overexpressed in these cisplatin-resistant cells; thus we also examined combining the Bcl-2 family inhibitor navitoclax with G-1. Methods: Cytoplasmic [Ca2+]c and mitochondrial [Ca2+]m were monitored using microscopy and fluorescent Ca2+ probes. Cell cycle, apoptosis and mitochondrial membrane potential (MMP) were assessed by flow cytometry of propidium iodide, Annexin V and DiIC1(5) -stained cells. The intracellular Ca2+ chelator BAPTA was used to block Ca2+mobilization. Results: Expression of the 53kDa GPER but not the 38 kDa isoform progressively increased with increasing cisplatin resistance. G-1 elicited sustained [Ca2+]c rises that correlated with 53 kDa GPER expression, followed by rises in [Ca2+]m. In all cells, 2.5 μM G-1 blocked cell cycle progression at G2/M, inhibited proliferation, and induced apoptosis (A2780 > C30 > CP70 ≥ C200). G-1 induced p53, caspase-3 and PARP cleavage, and MMP loss. BAPTA prevented G-1’s cell cycle and apoptotic effects in cells showing large Ca2+ mobilization responses but did not in cells with small Ca2+responses. Combining navitoclax with G-1 superadditively decreased cell viability and increased apoptosis. Conclusions: G-1 blocked cell cycle progression and induced apoptosis via a Ca2+-dependent pathway in cells expressing high 53 kDa GPER levels, but via a Ca2+-independent pathway in cells with low 53 kDa GPER expression. G-1 also interacted cooperatively with naviticlax. Therefore, G-1 plus navitoclax shows potential for therapeutic use in platinum-sensitive and -resistant ovarian cancer.