bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor hypoxia as a mechanism of resistance to bevacizumab in a murine model.
Authors: Heijmen Linda , Boerman Otto C. , Punt Cornelis J. A. , Ter Voert E. , Oyen Wim J.G. , Bussink Jan , Sweep Fred C.G.J. , Laverman Peter , Span Paul , de Geus- Oei Lioe-Fee , Heerschap Arend , Van Laarhoven Hanneke W.M. 
Published: March 2020

e13111 Background: Despite the promise of preclinical and early phase clinical studies, the efficacy of bevacizumab in solid tumors is more limited than expected. One of the presumed reasons is the induction of tumor hypoxia by the anti-angiogenic effects of bevacizumab, leading to therapy resistance. The aim of this study was to assess the effect of bevacizumab on tumor hypoxia in vivo in a colorectal cancer model, using functional imaging techniques. Methods: Nude mice with s.c. LS174T colon carcinoma xenografts (0.05 - 0.3 cm3) were treated with bevacizumab (5 mg/kg; 2/wk, i.p.) or saline as a control. To assess tumor hypoxia in vivo 18F-MISO-PET microPET or T2*-MRI images were acquired of separate groups of mice (n=5) before treatment and at day 2, 6 and 10 days after start of treatment. Tumors were harvested directly after imaging to microscopically assess the hypoxic fraction (pimonidazole staining) and vascular density (9F1 staining). Results: Linear regression analyses showed that FMISO uptake increased significantly more over time in the control group than in the bevacizumab group (beta -0.44, p=0.02), indicating that bevacizumab reduced the inherent increase in tumor hypoxia over time. T2* time increased significantly less in the bevacizumab group (beta -0.45, p=0.01), indicating a higher deoxyhemoglobine concentration, which might indicate a higher perfusion of the tumor and thus less hypoxia. The hypoxic fraction did not change over time and no difference was observed between the tumors in the treated and the control group. Vessel density significantly decreased over time in the bevacizumab group (beta -0.25, p=0.05), while the hypoxic fraction remained unchanged in the control group. Conclusions: The bevacizumab-induced changes in the tumor were most prominent at 10 days after treatment initiation, implying a build-up effect of repeated bevacizumab administration. The treatment induced changes could be detected with both T2*-MRI as well as with FMISO microPET. Bevacizumab did not induce tumor hypoxia, despite the observed decrease in vascular density. Therefore, induction of tumor hypoxia as a resistance mechanism to bevacizumab treatment seems unlikely.
Intensified loading schedule of trastuzumab with concurrent taxane: Pilot study of cardiotoxicity and safety monitoring.
Authors: Zvirinska Lenka 
Published: March 2020

e13112 Background: Recent update of NCCGT trial (Perez et al. J Clin Oncol. 2011;29:4491-4497) has shown only minor trend toward improvement in DFS with concurrent administration of chemotherapy with Transtuzumab. However data on pharmacokinetics of trastuzumab (Leyland-Jones et al. J Clin Oncol. 2010;28:960-966) suggest that more intense loading schedule could achieve effective levels earlier which might be vital for optimal effect. Methods: Therefore we have analysed data of patient cohort treated in single institution (UHCW), in the first instance monitoring difference in cardiotoxicity in patients treated by standard concurrent trastuzumab + taxane regime (8mg/kg followed by 3 weekly 6mg/kg) compared to patients treated with slightly intensified trastuzumab regime (8 mg/kg followed by 6 mg/kg a week later and continue starting with standard 3 weekly 6 mg/kg dose). Results: Altogether 34 patients have been identified starting treatment with trastuzumab in UHCW between October 2008 and October 2010. Median follow up was 12 months (8- 48). 20 were treated by standard concurrent regime, 14 by intensified. 30 patients received 300 – 400mg/m2 of epirubicin prior to trastuzumab. EF was monitored by MUGA every 3 months as per NICE recommendations at the time.
Trial of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) in patients with EGFR-expressing recurrent/metastatic non-small cell lung cancer (NSCLC) and solid tumors.
Authors: Rathore Bharti , Davol Pam , Rathore Ritesh , Cummings Francis , Birnbaum Ariel E. , Maizel Abby , Lum Lawrence G 
Published: March 2020

e13124 Background: Patients (pts) with advanced NSCLC and solid tumors have a poor prognosis and novel approaches to improve targeting and cytotoxicity directed at these cancers are needed. Anti-CD3 activated T cells (ATC) can be expanded and armed with anti-CD3 x anti-EGFR bispecific antibody (EGFRBi). Methods: In a phase I trial using ATC armed with EGFRBi, 6 pts (NSCLC = 5 pts, pancreatic cancer =1 pt) were treated with 8 infusions (twice/week) for 4 weeks with 5, 10 billion armed ATC/dose to determine the maximum tolerated dose (3 pts each). T cells from leukopheresis were activated and expanded with anti-CD3/IL-2 for 14 days, harvested, armed with EGFRBi and cryopreserved. IL-2 (3 x 105 IU/m2/daily) and GM-CSF (250 µg/m2 twice/week) was given beginning 3 days prior to the 1st infusion and ending++ 3, performance status (PS 0= 2 pts, PS 1= 4 pts). Results: Restaging scans revealed stable disease in 2 pts and progression in 4 pts. One pt with NSCLC at each dose level had stable disease (23 mths, 11 mths). ATC infusions were well tolerated and noticeable toxicities included chills (grade 2= 1 pt, grade 3= 1 pt); headache (grade 1= 2 pts, grade 2= 2 pts), dizziness (grade 2= 1 pt), nausea (grade 1= 2 pts). Accrual continues for dose levels at 20, 40 billion armed ATC per dose. No major toxicities with IL-2 were observed; bone pain resulted in dose reductions for GM-CSF in 2 pts. Conclusions: Infusions of EGFRBi armed ATC can be safely accomplished in patients with advanced NSCLC and solid tumors; accrual continues.
New approach to adjuvant therapy in high-risk melanoma patients.
Authors: Elias E. George 
Published: March 2020

e13129 Background: Cutaneous melanoma is relatively chemoresistant, but it is an immunogenic tumor. However, it is very heterogenetic. As a result, the present adjuvant therapy has been met with limited success due to non-specifity of therapy. GM-CSF administration in cutaneous metastatic melanoma increases the number and activation of naive dendritic cells which are antigen presenting cells that can process tumor antigens, while IL-2 stimulates and activates mainly T cells. Hypothesis: The consequential administration of a single short course of both agents intradermally at the primary site, prior to its excision, can result in high tumor cell kill and forms a triad of autologous tumor cells, dendritic cells and and T lymphocytes. This triad can be capable of inducing cytotoxic cells that can be taken up by the lymphatics to regional lymph nodes (LN). Methods: Newly diagnosed high risk patients, each is to receive a single injection of GM-CSF: 500 microgram at the primary (biopsy) site on day # 1, followed by IL-2: 11 million IU/day injected at the same site on days 2 and 3, one week before the definitive surgery. Postoperatively, the patient is to receive low dose GM-CSF at 250 microgram twice/week, self-administered subcutaneously, to maintain the initial response. Results: In a pilot study, the pathological examination of rsected tissues from treated patient revealed complete tumor necrosis with massive histiocytosis at the primary site. Immunohistochemical studies showed overexpression of CD4+, CD8+, CD25+ and CD83+ both at the primary and LN. Conclusions: This non-toxic outpatient program is safe and well tolerated. It can initiate patient-specific and tumor-specific cytotoxic T cells that can overcome heterogeneity of the tumor and confers therapeutic specificity. It also establishes the lymphatic route of administration. Postoperative subcutaneous administration of GM-CSF is to systemically maintain the initial response. The beneficial effect of this approach on survival has to be evaluated in a prospective controlled randomized clinical trial.
Signaling pathway differences between EGFR TKI-sensitive and -resistant non-small cell lung cancer cells.
Authors: Fei Shi-Jiang , Zhang Xu-Chao , Dong Song , Cheng Hua , Zhang Yi-Fang , Chen Zhihong , Xie Zhi , Wu Yi Long 
Published: March 2020

e13510 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have showed dramatic clinical benefits in advanced non-small cell lung cancer (NSCLC), but the biggest problem is resistance. How to overcome resistance is still a serious problem to clinical practice. The aims of this studies was to analyse the signaling pathway differences between the EGFR TKI-sensitive and resistant NSCLC cell lines and to seek potential molecular targets for tumor treatment after resistance. Methods: We selected four types of NSCLC cell lines: PC-9(exon19 del), PC9GR (gefitinib-acquired resistant cell), H1650(exon19 del), H1975 (L858R+T790M), signaling pathway differences between PI3K/Akt/mTOR,MAPK and STAT3 were analysed through western blot, immunoprecipitation and confocal microscope. Results: Activation status of EGFR super signaling pathways: PI3K-Akt, Erk and STAT3 between EGFR TKI- sensitive and resistant NSCLC cells was different under basic state. The phosphorylation levels of Akt ser473, FOXO1 and Erk in EGFR TKI-resistant cells, especially in H1650 cell, were more higher than that in PC9 cell except for p-STAT3. p-STAT3 expression in PC9 was higher than that in resistant NSCLC cells. The further analysis showed that cellular localizations of p-STAT3 between sensitive and resistant cells were different through confocal microscope, p-STAT3 in PC9 and H1975 cells was almost in nucleus, while in PC9GR and H1650 cells was almost in cytoplasm. The assay of mTORC2 kinase activities in vitro showed that mTORC2 kinase activities in the resistant cells were obviously higher than that in sensitive cells. Conclusions: we found that EGFR TKI-sensitive and resistant NSCLC cells had different activation status of signaling pathways especially mTOR associated signaling pathways and different mTORC2 kinase activities. These results indicated that targeting mTOR with specific mTOR inhibitors would be a good strategy for NSCLC treatment after EGFR TKI resistance.
Rational for targeted polytherapy in sarcoma: Get the genie out of the bottle.
Authors: Dumont Sarah N. , Yang Dan , Dumont Amaury Gerard , Blay Jean-Yves , Trent Jonathan C. 
Published: March 2020

e13519 Background: While a change of paradigm occurred in the last decade from chemotherapy to targeted therapy for cancer treatment, this work investigates the optimal combination of targeted agents with doxorubicin in sarcoma. Methods: Three sarcoma cell lines were studied RD18 (rhabdomyosarcoma), A204 (undifferentiated sarcoma) and TC 71 (Ewing's sarcoma) and exposed to increasing concentrations of vorinostat (HDAC inhibitor), 17-DMAG (Hsp90 inhibitor), abacavir (anti-telomerase) and sorafenib (tyrosine kinase inhibitor) alone, combined 2 by 2, then with doxorubicin. Viability was assessed by MTS assay. The Chou and Talalay combination index (CI) was used to determine additive (CI=1), synergistic (CI<1) or antagonistic effect (CI>1). Cell cycle analysis, measure of apoptosis by Annexin V and caspase 3/7 activity were studied using flow cytometry analysis and luminescent assay. Results: In monotherapy, the agents showed 30% to 90% decrease in viability but abacavir, which remained less active. Combination therapies with vorinostat, sorafenib and 17-DMAG showed strong synergism. Abacavir was found antagonistic with each drug. Either vorinostat or 17DMAG synergized with doxorubicin, achieving 60% cell killing compared to doxorubicin alone 12% (p=0.007). However, no synergy was observed for sorafenib with doxorubicin. The triple therapy vorinostat, 17DMAG and Doxorubicin did not show synergism but transiently increased the subG1 population at 24H, 70% compared to 30% in monotherapy with an increase in early caspase-independent apoptosis (11% to 36%, p= 0.0008). Conclusions: This work provides evidence of synergism of dual combinations of vorinostat, 17DMAG and sorafenib. In adjunction to doxorubicin, these combinations enhance doxorubicin cytotoxicity at therapeutically relevant concentrations. [Table: see text]
Evaluation of dosimetric variance in whole breast forward intensity modulated radiotherapy based on 4D CT and 3D CT.
Authors: Wang Wei , Li Jianbin 
Published: March 2020

e13530 Background: To explore and compare the dosimetric variance in forward intensity modulated radiotherapy (IMRT) based on 4D CT and 3D CT after breast conserving surgery. Methods: Seventeen patients after breast conserving surgery underwent the 3D CT simulation scans followed by respiration-synchronized 4D CT simulation scans on the state of free breathing. The treatment plan constructed using the end inspiration (EI) scan was then copied and applied to the end expiration (EE) and 3D scans and the dose distribution was calculated separately. Dose–volume histograms (DVHs) parameters for the CTV, PTV, ipsilateral lung (IPSL) and heart were evaluated and compared. Results: The CTV volume amplitude was 11.93 ± 28.64 cm3, and volume of the CTV receiving 95%, 100%, and 103% prescription dose among different scans were all differed by < 0.4%. Mean PTV dose at EE was lower than EI (t = 2.87, p = 0.011), but there were no statistice significance between 3D CT scan and EI, EE scans (t = 1.06, -1.59; p = 0.304, 0.132). The homogeneity index (HI) at EI, EE, 3D plans were 0.156 ± 0.02, 0.162 ± 0.02, 0.161 ± 0.02, respectively, and difference only between EI and EE (t = -2.56, p = 0.021). The highest conformal index (CI) was at EI phase (t = 4.55, 2.70; p = 0.000, 0.016), and there was no significant difference between EE and 3D (t = 0.04, p = 0.967). The V20, V30, V40, V50 and Dmean of IPSL at EE phase were lower than EI (t = 2.39~5.54, p = 0.000~0.030). There were no significant differences in all the indexes for heart (t = -1.77~1.40, p = 0.128~0.693). Conclusions: The breast deformation during respiration may be disregarded in whole breast IMRT; PTV dose distribution was changed significantly between EI and EE phase, and the differentiation of the lung high dose area between EI and EE phase may induced by thorax expansion. 3D treatment planning is sufficient for whole breast forward IMRT, but 4D CT scans assist with respiratory gating ensure precise delivery of radiation dose.
Potential increase in androgen sensitivity following antisense oligonucleotide suppression of Bcl-2 in a prostate cancer model.
Authors: Guinan Patrick , Rubenstein Marvin , Hollowell Courtney M.P. 
Published: March 2020

e13532 Background: Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth stimulatory gene products. While most oligos have targeted growth factors or their receptors, others have been directed against inhibitors of apoptosis and mediators of androgen action. In LNCaP cells we evaluated a set of oligos which targeted and comparably suppressed the expression of the apoptosis inhibitor protein bcl-2. To evaluate the specificity of this type of gene therapy, targeted and non-targeted genes were evaluated for their expression. The purpose was to identify whether additional (non-targeted) genes altered their expression in a manner which could circumvent or compensate for the suppression of bcl-2, promoting growth through increased androgen sensitivity. Methods: LNCaP prostate cells were treated with mono- and bispecific oligos directed against bcl-2. Employing RT-PCR the expression of both targeted and non-targeted genes (androgen receptor [AR], coactivators p300 and creb binding protein [CREB]) was determined. Results: LNCaP cells adapted to the suppression of bcl-2 (an apoptosis inhibitor) with enhanced expression of both AR and p300. This suggests an increased sensitivity to androgens. Conclusions: In this model, oligo treatment directed against bcl-2, may be evaded through a compensatory increase in both AR and p300 expression. This promotion of tumor growth, and the altered expression of AR coactivators normally seen in advanced disease, suggests a tumor transition to a more aggressive phenotype following suppressive treatment directed against bcl-2.
An orthotopic xenograft model of metastatic nasopharyngeal carcinoma and its application in elucidating a therapeutic target that inhibits metastasis.
Authors: Smith Pamela Ann 
Published: March 2020

e13536 Background: Nasopharyngeal carcinoma (NPC) is a serious health problem in many parts of the world. Although rare in the United States and Western Europe, it is the leading form of cancer in men between the ages of 20-44 years in parts of southeast Asia, and is prevalent in Indonesia, North Africa, the Middle East, amongst Eskimo populations, and represents one of the most frequent epithelial tumors of children in geographically higher risk areas. Current treatment protocols have resulted in good clinical outcomes if the disease is diagnosed and treated at an early stage. Unfortunately, metastatic NPC is refractory to treatment and carries an extremely poor prognosis. Particularly concerning is, that among head and neck cancers of epithelial origin, it is associated with the highest rate of metastasis. This highlights the need for models that are amenable to the study of metastatic NPC and adequate to test new potential therapies. Methods: In order to define and therapeutically target mechanisms that mediate nasopharyngeal carcinoma (NPC) metastasis, we have developed a unique orthotopic xenograft mouse model that accurately recapitulates the invasive and metastatic behavior of human disease. Results: Based on published clinical data and gene array analysis we performed on biopsy samples, we concluded that the PI3K/Akt/mTOR axis is involved in aggressive NPC tumor behavior. We thus chose it as a therapeutic target to test the utility of our orthotopic system for evaluating the effectiveness of a targeted treatment for metastatic NPC. We have subsequently demonstrated that both the development and growth of metastatic lesions are markedly reduced by the mTOR inhibitor sirolimus. Conclusions: Thus, this orthotopic model provides a platform to study potential therapeutics for advanced NPC and demonstrates that targeting the PI3K/Akt/mTOR pathway is a promising intervention against disseminated disease.
The impact of novel compound 2'-hydroxyflavanone on proteomic networks of VHL-mutant renal cell carcinoma.
Authors: Dalasanur Nagaprashantha Lokesh Prasad Gowda , Talamantes Tatjana , Singhal Jyotsana , Awasthi Sanjay , Singhal Sharad S. , Prokai Laszlo 
Published: March 2020

e13557 Background: Von Hippel-Lindau (VHL) tumor suppressor is a major genetic factor that determines hypoxic acclimatization and response to therapy in renal cell carcinoma (RCC). Our initial studies revealed that 2'-Hydroxyflavanone (2HF) effectively inhibits the survival of VHL-mutant RCC. Hence, we performed proteomic analyses to study the signaling networks of clinical significance that are regulated by 2HF in VHL-mutant RCC. Methods: The 786-O cells, an established cell line from a male Caucasian patient, were provided by William Kaelin Jr., MD, Harvard Medical School, Boston, MA. The cells were cultured either in the presence or absence of 50 μM 2HF for 48 h in RPMI medium at 37°C in 5% CO2 and lysed in a buffer containing 6M urea. The lysate (200 µg of protein) was reduced, alkylated and digested with trypsin. Tryptic digests were desalted using a C-18 cartridge (Waters, USA) and subjected to liquid chromatography–tandem mass spectrometry (LC-MS/MS) analyses on linear ion trap–Fourier transform ion cyclotron resonance tandem mass spectrometer (LTQ-FT, Thermo) coupled to an Eksigent nano-LC system. MS/MS spectra were searched against human protein sequence database using Mascot (Matrix Science), and protein identifications were validated by Scaffold (version 3.0, Proteome Software). Quantifications were performed by extracted peptide intensities (Progenesis LC-MS, Nonlinear Dynamics). Results: 2HF treatment lead to up-regulation of 21 proteins including protein disulfide-isomerase A4 and macrophage migration inhibition factor. 2HF treatment lead to down-regulation of 23 proteins including vimentin, HSP90AB1, 14-3-3 gamma and glutaminase. The network analyses revealed that the identified proteins form critical nodes of regulation of vital tumor proteins like MAP3K14, ERK1/2, Myc and P53. Conclusions: Proteomic analyses of 2HF treated VHL-mutant RCC revealed a striking regulation of proteins of importance in RCC survival, invasion and metastases. The critical nodes of regulation as identified by the network analyses could facilitate further studies on the development of network targeting therapies using 2HF and other anti-cancer compounds for the effective management of VHL-mutant RCC.
Stromal and antitumor effects of BIBF 1120 (nintedanib) in a preclinical lung cancer model.
Authors: Gerber David E. , Kutluk Cenik Bercin , Ostapoff Katherine T , Brekken Rolf A. 
Published: March 2020

e13563 Background: BIBF 1120 is an angiogenic receptor tyrosine kinase inhibitor that potently inhibits VEGFR, PDGFR and FGFR kinase activity in in vitro enzymatic assays. This study investigated the effect and mechanism of BIBF 1120, in vitro and in vivo, as a single agent and in combination with chemotherapy in preclinical models of lung cancer. Methods: Anti-tumor effects of BIBF 1120 in vitro were assessed using cell proliferation assays on five lung cancer lines (A549, Calu-3, Calu-6, H1993, H1703) with BIBF 1120 as a single agent and in combination with gemcitabine and cisplatin. To demonstrate anti-tumor activity in vivo, NOD/SCID mice bearing subcutaneous A549 grafts were treated daily with BIBF 1120 or BIBF 1120 plus chemotherapy. Perfusion studies were conducted using labeled dextrans. Ex vivo tumor tissues were assessed for architecture, microvessel density, pericyte coverage, proliferation, and apoptosis. Results: In vitro, BIBF 1120 did not show anti-proliferative effects at pharmacologically achievable concentrations (IC50>20μM) as a single agent; nor did it sensitize tumor cells to chemotherapy. However, BIBF 1120 inhibited primary tumor growth as a single agent and in combination therapy in subcutaneous endpoint studies with A549 xenografts. There was no significant difference in tumor architecture between BIBF 1120 and control-treated animals. Microvessel density (CD31,endomucin) and pericyte-covered vessels (NG2) were significantly decreased in BIBF 1120-treated animals compared to the control and chemotherapy only groups. Proliferation (phospho-histone 3) was decreased and apoptosis (cleaved caspase 3) was increased in BIBF 1120-treated animals compared to the control and chemotherapy only groups. Finally, BIBF 1120 significantly decreased perfusion in A549 xenografts. Conclusions: BIBF 1120 demonstrated potent anti-tumor and anti-angiogenic activity in a preclinical model of lung cancer. Because A549 was previously demonstrated to be an anti-VEGFR therapy resistant cell line, this study highlights the importance of FGFR and PDGFR pathways in the treatment of lung cancer.