bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropilin-1 (Nrp-1) as a prognostic biomarker and potential drug target for pediatric medulloblastoma.
Authors: Riedemann Lars , Snuderl Matija , Batista Ana , Kirkpatrick Nathaniel David , Ruiz de Almodovar Carmen , Hasselblatt Martin , Rossig Claudia , Duda Gabriel Dan , Xu Lei , Fukumura Dai , Carmeliet Peter , Jain Rakesh K. 
Published: March 2020

2056 Background: Medulloblastoma survival rates have significantly improved over the last decades due to surgery and chemoradiation regimens. However, pediatric patients with high-risk disease and those with recurrence often succumb to their disease. The majority of children suffer from severe adverse effects of intense therapy regimens. We recently demonstrated the role of the Placental Growth Factor (PlGF)/Nrp-1 signaling pathway in medulloblastoma progression in preclinical models (Snuderl et al., Cell 2013). The aim of this study was to evaluate the role of Nrp-1 as a biomarker and therapeutic target in medulloblastoma patients. Methods: Thirty-two surgical samples of pediatric medulloblastoma were analyzed for expression of Nrp-1 and its ligand PlGF by immunohistochemistry, array-comparative genomic hybridization and deep gene sequencing. On an independent, clinically annotated cohort of 42 medulloblastoma samples, we evaluated the correlation between Nrp-1 expression and 5-year overall survival. The therapeutic relevance of Nrp-1 signaling was tested in a D283 orthotopic human xenograft mouse model using shRNA and a monoclonal antibody against Nrp-1. Results: Nrp-1 expression was detectable in 100% and PlGF in 90% of all medulloblastoma samples. No significant differences in expression could be detected between known histological or molecular medulloblastoma subtypes. Patients with high Nrp-1 expression had a significantly worse 5-year overall survival compared to patients with a low or moderate expression (40% vs. 86%, p = 0.0058). Treatment with an antibody against Nrp-1 or genetic silencing of Nrp-1 with shRNA significantly prolonged survival in a D283 orthotopic human xenograft mouse model (for both experiments: p < 0.01). Conclusions: Nrp-1 is widely expressed across all molecular subgroups of medulloblastoma and its expression levels are inversely associated with survival of patients. Targeting Nrp-1 leads to a significant survival benefit in an orthotopic human xenograft mouse model. This data support the hypothesis that targeting the PlGF/Nrp-1 signaling pathway may be a novel therapy approach for pediatric medulloblastoma.
Evaluation of invasion patterns and their correlation with integrin alphavbeta expression in brain metastases of solid cancers.
Authors: Berghoff Anna Sophie , Rajky Orsolya , Winkler Frank , Weller Michael , Zielinski Christoph , Schittenhelm Jens , Preusser Matthias 
Published: March 2020

2059 Background: Understanding the pathobiology of brain metastases (BM) could guide the establishment of new targeted therapies. Methods: We collected 57 autopsy specimens of BM (primary tumor: 27 lung cancer, 6 breast cancer, 8 melanoma, 1 kidney cancer, 2 colorectal cancer, 13 other) and histologically evaluated the patterns of invasion into the surrounding brain parenchyma. Expression of the following integrins was evaluated using immunohistochemistry: with novel antibodies for αv subunit, αvβ3, αvβ5, αvβ6 and αvβ8 integrin. Results: We observed three main invasion patterns: well-demarcated (29/57, 51%), vascular co-option (10/57, 18%) and diffuse infiltration (18/57, 32%). There was no association of invasion pattern with primary tumor type, although vascular co-option was most common in melanomas (4/10, 40%). αv subunit expression was lowest in the vascular co-option group (p = 0.05, t-test). αvβ6 levels were higher in the well-demarcated group than in the vascular co-option group (p = 0.025; t-test) and were higher in lung cancer BM than in melanoma BM (0.01, t-test). αvβ3 and αvβ5 were frequently expressed in tumoral (αvβ3: 30/57, 53%; αvβ5: 55/57, 97%) and peritumoral (αvβ3: 29/57, 51%, αvβ5: 54/57 (95%) vascular structures and 27/57 (47%) specimens showed avb5 and 6/57 (11%) αvβ3 expression on tumor cells. Prior radio- or chemotherapy did not correlate with invasion pattern or integrin expression. Conclusions: We delineate three distinct invasion patterns of BM into the brain parenchyma: well-demarcated growth, vascular co-option and diffuse infiltration. Integrin expression is frequent on tumor and vascular cells in BM and associated with distinct invasion patterns. Anti-integrin therapy could be a valid treatment option in patients with BM.
Validation of a gene expression-based diagnostic system for malignancy of glioma by multi-institute prospective-retrospective analysis.
Authors: Kato Kikuya , Shirahata Mitsuaki , Narita Yoshitaka , Muragaki Yoshihiro , Maruno Motohiko , Matoba Ryo 
Published: March 2020

2066 Background: Histopathological classification of gliomas is often clinically inadequate due to the diversity of tumors that fall within the same class. Based on the strong correlation between malignancy and gene expression profile in gliomas, we constructed a diagnostic system based on gene expression profiling of 152 glioma samples (Shirahata et al., Cancer Sci, 2009, 100, 165). The diagnostic system was converted to that based on expression value of 27 genes measured with real-time PCR (Kawarazaki et al., BMC Med Genomics, 2010, 3, 52). Methods: First, the diagnostic system was validated with 75 retrospective samples from the National Cancer Center Hospital, and threshold values of the diagnostic score (PC1-score) were determined. Second, the system was evaluated by prospective-retrospective analysis of 127 samples from the four institutions using the threshold. The analysis corresponded to the category C proposed by Simon et al. (JNCI, 2010, 101, 1446). Results: In general, the PC1-score gradually increased with the grade of the glioma from grade II to IV. The prognostic classification by the diagnostic system was compared with that by WHO grade classification using 66 grade IV and 39 grade 3 samples. Harrell’s C-index was 0.673 and 0.573 for the diagnostic system and grade classification, respectively. Hazard Ratio was 5.31 and 4.97, respectively. By the system the 66 grade 4 patients were confirmed to be classified into two prognostic groups (PFS, p = 0.013; OS, p = 0.098). The 39 grade III patients were classified into two prognostic groups (PFS, p = 0.112; OS, p = 0.022).Median observation time is 12 months for PFS and 15.5 months for OS, respectively. As for grade 3 patients, IDH1 mutation had better prognostic ability (PFS, p = 0.007; OS, p = 0.002). Conclusions: Based on two retrospective and one prospective-retrospective analysis, our diagnostic system was demonstrated to be an objective prognostic indicator complementing the grade classification. The prognostic ability within grade 3 or grade 4 may be useful in therapeutic decision making.
Racial disparities in survival of glioblastoma patients not treated with radiation.
Authors: Thakkar Jigisha P. , Dolecek Therese A. , Popa Andra M , Villano John L. 
Published: March 2020

2069 Background: Race-based outcomes have been documented for inpatient hospital care for glioblastoma (GBM), however, SEER-based population studies do not replicate the differences in race for outcomes in GBM. Moreover, most advanced cancers demonstrate differences in race based outcomes. We hypothesized that there is a difference in race based outcomes for GBM with advanced clinical involvement preventing an established standard of care such as radiation therapy (RT). Methods: We analyzed survival estimates and procedure frequencies by race for GBM patients (n=4931) 20 years and older, not treated with radiation in the initial round of therapy; from 2000-2008, using the Surveillance, Epidemiology, and End Results (SEER) 17 registries database and listed them by surgery type. Kaplan–Meier relative survival rates were calculated by surgery type and race group (blacks and whites) followed by evaluation of association between race and survival rate. Race comparisons were limited to 1 year because of small numbers in the subgroups. Results: We found no statistically significant support for a racial disparity in survival among GBM patients with different surgical interventions (tumor destruction/biopsy, partial or total resection). However, for those receiving no surgery (and no RT), blacks actually had better one-year survival than whites. By surgery, those receiving gross total resection had higher survival in both blacks and whites. In whites only, any type of surgery (tumor destruction/biopsy, partial or total resection) had better survival than none. Conclusions: Overall, there are no statistically significant differences between blacks and whites in terms of survival in GBM patients not receiving RT in the initial round of therapy. Differences in race based care for GBM have not been found outside of inpatient hospital based care, which is unusual for an aggressive cancer needing specialized multi-modality care. [Table: see text]
Use of axitinib, a new-generation tyrosine kinase inhibitor, to decrease glioblastoma growth despite primary resistance to the VEGF-antibody bevacizumab.
Authors: Kratzsch Tobias , Gruenwald Viktor , Vajkoczy Peter , Kuhn Susanne Antje 
Published: March 2020

2077 Background: Targeted therapies are increasingly important in oncology. Axitinib is a novel orally available tyrosine kinase inhibitor which is mainly directed against the VEGFR family. VEGF-antibody bevacizumab is the acting drug of running clinical trials in glioblastoma. Methods: In immunodeficient mice, cell line- and patient-derived glioblastoma xenografts were established and treated with axitinib. Temozolomide, bevacizumab, and phosphate buffered saline served as controls. Tumor size, vascularization (CD31), vascular pericyte coverage (NG-2), apoptosis in tumor and endothelial cells as well as expression of EGFR, VEGFR1, VEGFR2, PDGFRβ, VEGF, and PlGF were determined. Experiments were approved by local ethics committee. Results: Positive control temozolomide always caused growth inhibition whereas primary resistances to bevacizumab as primary drug were observed. As most delighting result, axitinib caused a delay of tumor growth in a glioblastoma xenograft with primary resistance to bevacizumab. Tumor cell proliferation (Ki67) was significantly lower than in controls (p<.05). The number of CD31 positive endothelial cells decreased (p<.001). Numbers of NG2 positive pericytes were reduced (p<.001) and triple immunofluorescence showed a significant reduction of NG2 positive pericyte coverage of CD31 positive endothelial cells (p<.001). Expression of EGFR, PDGFRβ, and VEGFR1 proteins showed no alterations under axitinib treatment, but RT-PCR revealed a significantly decreased mRNA expression of VEGF-A and PlGF. Conclusions: Axitinib had significant effects on glioblastoma xenografts even with primary resistance to bevacizumab in a so far untreated tumor. There are currently two recruiting phase II trials with axitinib in glioblastoma multiforme. Further comparative studies with bevacizumab should urgently define the potential of this substance in glioblastoma therapy.
A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors.
Authors: El-Khoueiry Anthony B. , Ning Yan , Yang Dongyun , Cole Sarah , Kahn Michael , Zoghbi Marwan , Berg Jennifer , Fujimori Masamoto , Inada Tetsuhi , Kouji Hiroyuki , Lenz Heinz-Josef 
Published: March 2020

2501 Background: PRI-724 is a first-in-class modulator of Wnt signaling that inhibits the CREB binding protein and β-catenin interaction. In pre-clinical models, PRI-724 (active metabolite C82) increases p300/β-catenin binding and promotes stem cell differentiation thereby eliminating tumor initiating cells and increasing sensitivity to cytotoxic or targeted drugs. Methods: PRI-724 was given as a continuous infusion X 7 days q 2 wks. There was an initial accelerated dose escalation with one pt per dose level and a plan to revert to a 3+3 escalation after 640 mg/m2 unless a dose limiting toxicity (DLT) or 2 moderate toxicities occurred earlier. Eligibility criteria: adequate bone marrow function, AST/ALT <5XULN, total bilirubin<1.5 mg/dL. Survivin/BIRC5 expression was measured by immunomagnetic RT-PCR on circulating tumor cells (CTC). Results: 18 pts treated; median age: 53 years (38-71); 12 (67%) males; median number of prior therapies: 3 (1-5). There was one DLT of grade 3 hyperbilirubinemia. Grade 3 AEs were limited to hyperbilirubinemia in 2 pts, one of which did not meet DLT criteria. Grade 2 AEs were: diarrhea (2pts; 11%), bilirubin elevation (2 pts; 11%), hypophosphatemia (2pts; 11%), nausea (1pt; 6%), fatigue (1pt; 6%), anorexia (1pt; 6%), thrombocytopenia (1 pt; 6%) and alkaline phosphatase elevation (1pt; 6%). There was no MTD at the doses tested. The recommended phase 2 dose was 905 mg/m2 based on the incidence of AEs at 1280 mg/m2 and the plateau in pK parameters. The median Cmax and AUC 0-t for C-82 at 905 mg/m2/day were 887 ng/mL and 262787 h*ng/mL. Median elimination T ½ was 7.35 h. 3 pts with colon cancer had stable disease for 8, 10 and 12 weeks. Survivin expression in CTCs decreased in 72% of pts on C1D8 and 61% on C2D8. There was an inverse relationship between C82 plasma concentration and survivin expression on C1D8 (Spearman correlation coefficient r = -0.72; p=0.001). Conclusions: PRI-724 had an acceptable toxicity profile. Downregulation of survivin expression in CTCs may serve as a pharmacodynamic marker of drug-on-target effect. Studies combining PRI-724 with chemotherapy are ongoing. Clinical trial information: NCT01302405. [Table: see text]
First-in-class, first-in-human phase I trial of KPT-330, a selective inhibitor of nuclear export (SINE) in patients (pts) with advanced solid tumors.
Authors: Razak Albiruni R A , Soerensen Morten Mau , Mahipal Amit , Shacham Sharon , Yau Cindy Y. F. , Lassen Ulrik Niels , McCauley Dilara , Cooksey Jennifer , Tan David Shao Peng , Saint-Martin Jean-Richard , Landesman Yossi , Pond Gregory , Oza Amit M. , Kauffman Michael , Siu Lillian L. , Mirza Mansoor Raza 
Published: March 2020

2505 Background: In cancers, the majority of tumor suppressor proteins (TSP) are transported out of the nucleus exclusively by Exportin 1 (XPO1/CRM1), rendering these TSPs non-functional. KPT-330 is a potent inhibitor of XPO1, and forces the nuclear retention and activation of > 10 TSPs resulting in tumor cell death in vitro, in murine preclinical models and in dogs with spontaneous lymphomas. Methods: KPT-330 was administered orally for 10 doses in a 28-day cycle. Detailed pharmacokinetic (PK) and pharmacodynamic (PDn) analyses and serial tumor biopsies were performed. Response evaluation was done every 2 cycles (RECIST 1.1). All pts entering the study had documented progressive disease. Results: 23 pts (10 males; median age 62 yrs; ECOG PS 0/1: 5/18) received KPT-330 across 6 dose levels (3 to 30 mg/m2). There has been no dose limiting toxicity. Nine drug related grade 3/4 adverse events (AEs) post cycle 1 were reported in 6 pts (neutropenia, thrombocytopenia, hyponatremia, increased ALT, fatigue, vomiting [n=2], nausea [n=2]). The most common grade 1/2 AEs were nausea (78%), fatigue (74%) and anorexia (74%). PK analysis demonstrated a fairly proportional increase in Cmax and AUC with increasing dose, with no accumulation and without affecting half-life or clearance of KPT-330. At 30 mg/m2, AUC0-last. (4375 ng*h/mL) was comparable to the anti tumor exposure observed in mice and dogs. Tmax (~3 hrs) and T1/2 (6-7 hrs) were consistent across doses. Significant increase (2-20x) in XPO1 mRNA levels (PDn marker) in circulating leukocytes was observed at all doses, with higher doses demonstrating higher levels of XPO1 mRNA induction. Analysis of tumor biopsies confirmed nuclear localization of TSPs (e.g. p53, FOXO3A, IκB) and apoptosis of cancer cells following KPT-330 administration. RECIST response was evaluable in 13 pts. Stable disease (SD) was noted in 9 pts, with 3 (colon, endocervical & endometrial stromal tumors) remaining with SD at 6+ months (dose levels 3 & 6 mg/m2), as well as one minor response (colon). Conclusions: KPT-330 treatment is generally well tolerated, with favorable PK and PDn properties. Preliminary signals of clinical antitumor activity were observed. Clinical trial information: NCT01607905.
First-in-human phase I study of the liposomal RNAi therapeutic Atu027 in patients with advanced cancer.
Authors: Schultheis Beate , Strumberg Dirk , Santel Ansgar , Gebhardt Frank , Khan Michael , Keil Oliver , Giese Klaus , Kaufmann Jörg 
Published: March 2020

2508 Background: Atu027 is a novel vascular stabilising, anti-metastatic, RNAi therapeutic, targeting systemic endothelial cell function and the tumor vasculature. Atu027 comprises a liposomal particle, containing an siRNA, which silences expression of the PKC pathway signalling molecule PKN3. Atu027 was previously shown to restrict tumor growth, local invasion and both, lymph node as well as pulmonary metastasis in mouse xenograft models. Methods: 34 patients with advanced cancer received 10 escalating doses of Atu027 without pre-medication as single and repeated i.v. infusions (qw2x4 per 28-d cycle) with a 3-wks dose intermission. Primary end points were safety, pharmacokinetics and -dynamics (biomarker identification). Response was monitored by CT/MR imaging at baseline, after treatment and at final follow-up (EoS) and was assessed according to RECIST. Results: Atu027 was well tolerated up to 0.336 mg/kg (around twice the predicted effective siRNA plasma levels). An MTD was not achieved. Around 50% of patients experienced disease stabilization according to RECIST. 8 patients had stable disease at EoS and 2 with neuroendocrine cancer had disease stabilization for 9 or 22 months. Partial regression of pulmonary metastasis and a regression of liver metastases were observed in subjects with neuroendocrine and breast cancer, respectively. An improved ECOG performance status was observed in patients of higher dose levels. Most AEs were low grade toxicities (1 or 2), including fatigue and increased lipase. Transient complement system activation was observed for certain factors. Area exposure levels of siRNA strands were dose-proportional and peaks were reached during 4 h-infusion. Of 102 plasma proteins assessed, sFLT1 (sVEGF-R1) was the most promising as a potential biomarker, with decreases from baseline in most pts from dose level 4-10 after treatment. Conclusions: Atu027 was well tolerated and there was suggestion of a clinically meaningful antitumor activity. In view of this further clinical trials can be initiated at a dose of up to 0.336 mg/kg and sFLT1 will be investigated as a potential biomarker. Clinical trial information: NCT00938574.
Phase I study of volasertib (BI 6727) combined with afatinib (BIBW 2992) in advanced solid tumors.
Authors: Peeters Marc , Machiels Jean-Pascal H. , Pilz Korinna , De Smet Marina , Strelkowa Natalja , Liu Dan , Rottey Sylvie 
Published: March 2020

2521 Background: Volasertib is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases (Plk). Volasertib and afatinib, an irreversible ErbB family blocker, have shown single agent anti-tumor activity and manageable safety profiles in patients (pts) with advanced solid tumors. This dose escalation study was designed to determine the maximum tolerated dose (MTD) of two combination schedules of volasertib and afatinib in pts with advanced solid tumors refractory to or not amenable to standard therapy. Methods: In a 3 + 3 design, cohorts of 3–6 pts received volasertib 150–300 mg IV d1 Q3W + afatinib 30–50 mg PO QD d2–21 Q3W (Schedule A) or afatinib 50–90 mg d2–6 Q3W (Schedule B). Up to 12 additional pts were enrolled at the MTD. Primary endpoint was the MTD per schedule. Secondary endpoints included pharmacokinetics (PK), safety and efficacy (RECIST). Results: 57 pts (median 58 yr; ECOG PS 0/1/2: 35%/60%/5%) were treated (n=29, Schedule A; n=28, Schedule B). MTD was volasertib 300 mg/afatinib 30 mg (Schedule A) and volasertib 300 mg/afatinib 70 mg (Schedule B). Cycle 1 dose limiting toxicities (DLTs) were experienced by 5 (Schedule A) and 7 (Schedule B) pts. Most common DLTs were diarrhea (n=5), neutropenia (n=3), fatigue (n=2) and decreased ejection fraction (n=2) in Schedule A, and thrombocytopenia (n=6), neutropenia (n=5), diarrhea (n=4) and febrile neutropenia (n=3) in Schedule B. Most common grade 3/4 adverse events were neutropenia (n=8), thrombocytopenia (n=6), diarrhea (n=3) and febrile neutropenia (n=3). Volasertib exhibited multi-exponential PK behavior with a long half-life (130 hr), moderate clearance (900 mL/min) and large volume of distribution (Vss >6000 L). Co-administration of volasertib and afatinib had no effect on the PK profile of either drug. Two pts in Schedule A (volasertib 300 mg/afatinib 30 mg) achieved partial responses (tumor types: NSCLC, head and neck). Conclusions: MTD of volasertib was 300 mg Q3W combined with afatinib 30 mg d2-21 (Schedule A) or afatinib 70 mg d2-6 (Schedule B). Both agents could be combined at previously shown active single agent doses. At the MTD, treatment was manageable and showed preliminary anti-tumor activity. Clinical trial information: NCT01206816.
Phase I study of everolimus (E, RAD001) and ganitumab (G, AMG 479) in patients (pts) with advanced solid tumors.
Authors: Jalal Shadia Ibrahim , Strother Robert Matthew , Sandusky George , Prasad Nagendra K , Berry William , Jones David R , Younger Anne , Funke Jennifer M. , Detty Tammi , Althouse Sandra , Perkins Susan M. , Chiorean E. Gabriela 
Published: March 2020

2529 Background: Synergism between IGF and mTOR inhibitors has been documented preclinically. We conducted a phase I study to determine the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor efficacy of E with G. Methods: Eligible pts had good organ function, ECOG PS 0-1. The study had a standard “3+3” design, using E 5 or 10 mg orally daily (QD), and G 12 mg/kg IV every 2 wks (Q2W) in 28 day cycles (C); an expansion cohort was added at MTD for further efficacy analysis. E was given as single agent during C1D1-7 with PKs on C1D1 and D7, and continuously after C1D16. G was started on C1D15 with single agent PK. PKs for both drugs at steady state were performed on C3D1. PDs (blood and serial tumor biopsies) for IGF and PI3K/Akt/mTOR pathways were performed at baseline, C1D7, C3D1 and time of progression. Results: 20 ptswere enrolled to date, M/F: 8/12, median age 55 yrs (24-70); PS: 0/1= 13/7. The table summarizes dose levels and DLTs. The most common toxicities were fatigue (5), diarrhea, mucositis, dysgeusia, anemia and thrombocytopenia (4 each), and rigors (3). Grade (Gr) 3 toxicities were: mucositis (3), anemia (2), thrombocytopenia (2), and diarrhea (1). Pts received a median of 3 cycles (0-9). One pt discontinued study on C1D9 due to intracerebral bleed and 1 pt withdrew consent on C1D15. Among 18 evaluable pts, none responded and 9 pts (50%) had SD with a median duration of 20 wks (range 11-35). Prolonged clinical benefit (SD ≥ 20 wks) was noted in refractory fibrolamellar HCC, neuroendocrine, GIST and urachal cancers. PKs showed no significant interaction between E and G. Baseline IGF-1R and PTEN expression, and IGF1 levels did not affect clinical benefit. pS6 downregulation and pAkt upregulation in paired tumor biopsies occurred in all (7/7) or most (6/7) samples evaluated, and did not correlate with efficacy. IGF1 and IGFBP3 levels increased on-treatment in 80-90% of pts. Conclusions: E+G is safe and the RP2D is E 10 mg QD + G 12 mg/kg Q2W. While on target pS6 reduction occured, the IGF1-R inhibition did not affect pAkt upregulation from mTOR blockade. Clinical trial information: NCT01122199. [Table: see text]