CTNI-43. CXCL12 INHIBITION IN MGMT UNMETHYLATED GLIOBLASTOMA – RESULTS OF AN EARLY PROOF-OF-CONCEPT ASSESSMENT IN THE MULTICENTRIC PHASE I/II GLORIA TRIAL (NCT04121455)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi69-vi69
Author(s):  
Frank Giordano ◽  
Julian Layer ◽  
Sonia Leonardelli ◽  
Lea Friker ◽  
Clemens Seidel ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Phase I ◽  
Cerebral Blood Volume ◽  
Promoter Hypermethylation ◽  
Tumor Burden ◽  
Proof Of Concept ◽  
Proliferation Zone ◽  
Maximum Increase ◽  
Maximum Reduction ◽  
Microvascular Proliferation

Abstract BACKGROUND Preclinical studies showed that CXCL12-mediated influx of highly angiogenic monocytes/macrophages is a key driver of tumor re-vascularization and re-growth after radiotherapy (RT) of glioblastoma (GBM). We report findings from a phase I/II proof-of concept (PoC) study on CXCL12 inhibition during and after RT of GBM. METHODS Patients ≥18years with incompletely or unresected GBM without MGMT promoter hypermethylation and ECOG≤2 were eligible to participate. Patients received continuous (24/7) i.v. infusions of 200mg/week (n=3), 400mg/week (n=3) or 600mg/week (n=3) of the CXCL12 inhibitor olaptesed pegol (OLA) for 26 weeks during and after normo- or hypofractionated RT (60Gy/40.05Gy). The primary endpoint was safety as per the incidence of treatment-related adverse events. The study was accompanied by PoC-research including multiparametric MRI biomarkers (relative cerebral blood volume, rCBV; fractional tumor burden with high perfusion, FTBhigh; apparent diffusion coefficient, ADC) and of multiplexed immunofluorescence imaging (CODEX®) of reference and patient samples. Initial results of these analyses are reported for the first six patients enrolled. RESULTS Five of six (83%) patients assessed with advanced MRI showed response under OLA in rCBV/FTBhigh and ADC. Maximum reduction in perfusion (rCBV) from baseline was 55%, maximum reduction of FTBhigh was 55% and maximum increase in ADC was 77%. Furthermore, five of six (83%) patients analyzed showed reduction of enhancing tissue volumes in at least one scan under OLA therapy. In both one patient and two reference samples CXCL12 co-localized with endothelial cells of the microvascular proliferation zone. In a paired sample (before/during OLA) of one patient, endothelial cells stained positive for CXCL12 before but not during treatment and almost all GBM cells were negative in Ki67 staining in the sample obtained under OLA therapy. CONCLUSIONS Advanced MRI and multiplexed immunofluorescence suggest efficacy of combined radiotherapy and CXCL12 inhibition in unmethylated GBM. Funded by NOXXON Pharma AG; ClinicalTrials.gov number, NCT04121455.

scholarly journals Delivering Minocycline into Brain Endothelial Cells with Liposome-Based Technology

2012 ◽  
Vol 32 (6) ◽  
pp. 983-988 ◽  
Author(s):  
Changhong Xing ◽  
Tatyana Levchenko ◽  
Shuzhen Guo ◽  
Monique Stins ◽  
Vladimir P Torchilin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis ◽  
Proof Of Concept ◽  
Brain Endothelial Cells ◽  
Cerebral Endothelium ◽  
Low Concentrations ◽  
Tnf Α ◽  
Factor Α ◽  
Very High ◽  
Necrosis Factor

Minocycline has been proposed as a way to blunt neurovascular injury from matrix metalloproteinases (MMPs) during stroke. However, recent clinical trials suggest that high levels of minocycline may have deleterious side-effects. Here, we showed that very high minocycline concentrations damage endothelial cells via calpain/caspase pathways. To alleviate this potential cytotoxicity, we encapsulated minocycline in liposomes. Low concentrations of minocycline could not reduce tumor necrosis factor α (TNF α)-induced MMP-9 release from endothelial cells. But low concentrations of minocycline-loaded liposomes significantly reduced TNF α-induced MMP-9 release. This study provides proof-of-concept that liposomes may be used to deliver lower levels of minocycline for targeting MMPs in cerebral endothelium.

Abstract LB-039: Translational research in a phase I proof-of-concept study supports that DCC-2618 is a pan-KIT inhibitor

2017 ◽  
Author(s):  
Filip Janku ◽  
Albi Razak ◽  
Michael Gordon ◽  
David Brooks ◽  
Daniel Flynn ◽  
...  
Keyword(s):  
Phase I ◽  
Translational Research ◽  
Proof Of Concept ◽  
Concept Study

Is metronomic vinorelbine (mVRL) able to inhibit both HUVEC and triple-negative breast cancer (TNBC) cells? The proof-of-concept VICTOR-0 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14014-e14014
Author(s):  
Maria Grazia Cerrito ◽  
Davide Pelizzoni ◽  
Marco De Giorgi ◽  
Nunzio Digiacomo ◽  
Marialuisa Lavitrano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Umbilical Vein ◽  
Metastatic Breast ◽  
Proof Of Concept ◽  
Proliferating Cells ◽  
Drug Concentrations

e14014 Background: TNBC represents an important clinical challenge because of poor prognosis. One of the emerging strategy to achieve disease control while reducing toxicity is metronomic chemotherapy (mCHT) which targets the endothelial cells (ECs) and inhibits the tumor growth. mVRL is a promising option in patients (pts) with metastatic breast cancer (MBC), resulting in a median PFS of 7.7 months and median OS of 15.9. To better explain the effect of mVRL we studied the effects of metronomic doses of VRL in in vitro models and compared them with standard doses of the same drug. Methods: Cell viability and cytotoxicity assays were performed on TNBC cancer cells (MDA-MB-231) and Human Umbilical Vein Endothelial Cells (HUVEC). Cell lines were exposed to different concentration (0,01nM-1mM) of VRL for 4 and 96 h. To simulate the metronomic dosing schedule, we replaced the drug-enriched medium every 24h, while to simulate the conventional administration protocol (sCHT) cells were exposed to VRL for 4h, then the medium was changed and replaced with fresh medium without drug every 24 h. The IC50was calculated by non-linear regression fit of the mean values of data obtained in triplicate experiments. Results: A significant anti-proliferative activity was observed on both HUVEC and MDA cells treated with VRL in mCHT as compared to sCHT protocol (see Table). These lower drug concentrations did not have remarkable effects on cell death. Conversely, the higher dose utilized in sCHT produced important cell death in MDA as well as in HUVEC, even if in vivo, the higher dose of drug inducing the largest apoptosis of cancer cells also affectd healthy proliferating cells causing toxicity. Our findings suggest that mCHT inhibited the proliferation of both endothelial and tumour cells and can block cancer progression with minor side effects. Conclusions: This study provides the proof-of-concept that metronomic doses of VRL, but not the standard ones, are able to inhibit, at the same concentration, both the ECs and the TNBC cells. The clinical trial TEMPO-BREAST, which compares metronomic vs standard VRL, is ongoing in MBC pts. [Table: see text]

Multi-institutional european single-arm phase II trial of pazopanib in advanced typical solitary fibrous tumors (SFT): A collaborative Spanish (GEIS), Italian (ISG), and French (FSG) sarcoma groups study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11038-11038
Author(s):  
Josefina Cruz Jurado ◽  
Sarah Naomie Dumont ◽  
Nicolas Penel ◽  
Pablo Luna Fra ◽  
Enrique Alava ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Response Assessment ◽  
Tumor Burden ◽  
Antiangiogenic Agents ◽  
Choi Criteria ◽  
Diagnostic Time ◽  
Central Pathology

11038 Background: SFT is a ubiquitous uncommon soft tissue sarcoma with a pronounced hemangiopericytoma-like vascular pattern, exhibiting rich VEGF (tumor and endothelial cells) and VEGFR1/2 (endothelial cells) expression. Pathologists distinguish typical SFT (T-SFT) and malignant SFT (M-SFT) based on mitosis (≤4 vs > 4), pleomorphism or necrosis. Yet, not clear boundaries are always seen between both subtypes. We have recently published a phase II trial exploring the activity of pazopanib (P) in M-SFT (Lancet Oncol Dec 2018). Here, we present the outcome of the T-SFT cohort of the same trial. Methods: Most relevant inclusion criteria were: unresectable or metastatic, T-SFT (tumor tissue from diagnostic time) confirmed by central pathology review before accrual, with evidence of STAT6 overexpression (IHC and FISH and/or NGS), ≥18 years, ECOG 0-2, progressive, measurable disease and no previous antiangiogenic agents. Main endpoint was response rate according to Choi criteria. Central radiological assessment was mandatory. P was administered at 800 mg/d continuously till progression or toxicity. Results: From June 2014 to December 2018, 34 patients were enrolled in this cohort. The median age was 64 y (31-81). At baseline, ECOG 0/1/2 was distributed as 16/15/3; whereas, locally advanced/metastatic distribution was 11 (32%) and 23 (68%) respectively. At the time of the present analysis, 24 patients were deemed eligible and evaluable for response. Response rates according to local and central assessment were PR 6 (25%), SD 15 (62%), PD 3 (12%) and PR 12 (50%), SD 11 (46%), PD 1 (4%). With a median follow-up of 21 months, the median PFS following local and central assessment were 18.4 (6.6-30.1) and 9.8 (7.5-12.2) months respectively, both were clearly superior to that previously published in M-SFT cohort (5.57 m). The median of OS was 49.8 months. High tumor burden at baseline > 116 mm, ECOG 1-2 vs 0, and PD by local or central response assessment showed significantly worse OS. Metastatic vs locally advanced patients had a similar outcome regarding OS. Conclusions: T-SFT cohort exhibited clearly longer PFS than previous reported M-SFT cohort to pazopanib treatment, and pazopanib showed to improve the historical outcome obtained with chemotherapy in advanced SFT. Clinical trial information: NCT02066285.

Direct evidence of endothelial injury during cardiopulmonary bypass by demonstration of circulating endothelial cells

Perfusion ◽  
2006 ◽  
Vol 21 (3) ◽  
pp. 133-137 ◽  
Author(s):  
Franz-Xaver Schmid ◽  
Bernhard Floerchinger ◽  
Nalini Kumar Vudattu ◽  
Günther Eissner ◽  
Marion Haubitz ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cardiopulmonary Bypass ◽  
Direct Evidence ◽  
Artery Bypass ◽  
Endothelial Activation ◽  
Endothelial Damage ◽  
Endothelial Injury ◽  
Circulating Endothelial Cells ◽  
Whole Body ◽  
Maximum Increase

Endothelial activation is considered a key process in the development of a whole body inflammatory response secondary to cardiopulmonary bypass (CPB). Increased levels of a multitude of soluble mediators have been described as being released during and after cardiac surgery. Circulating endothelial cells have recently been established as a novel marker of endothelial damage in a variety of vascular disorders. Blood samples from 20 patients undergoing elective coronary artery bypass surgery were obtained preoperatively and 1, 6, 12, 24, and 48 h after termination of CPB. Control samples were obtained from ten healthy volunteers. Circulating endothelial cells (CEC) were isolated with immunomagnetic anti-CD146-coated Dynabeads, and counted in a Nageotte chamber. Low numbers of CEC were observed in healthy control volunteers (12±6 cells/mL; median: 9 cells/mL). CEC numbers were already significantly elevated in all patients before CPB, and there was a further significant increase after weaning from CPB (maximum increase at 6 h after CPB: 73±30 cells/mL; range: 30-153 cells/mL, p < 0.001). The number of CEC provides further and direct evidence that CPB is associated with a pronounced endothelial injury and/or damage. CEC appear to be most useful markers for vascular endothelial activation because they are specific, stable, and circulating components of injured vessel wall.

Glomeruloid vascular structures in glioblastoma multiforme: an immunohistochemical and ultrastructural study

1996 ◽  
Vol 85 (6) ◽  
pp. 1078-1084 ◽  
Author(s):  
Amyn M. Rojiani ◽  
Katerina Dorovini-Zis
Keyword(s):  
Endothelial Cells ◽  
Glioblastoma Multiforme ◽  
Basal Lamina ◽  
Smooth Muscle Actin ◽  
Type I ◽  
Vascular Structure ◽  
Alpha Smooth Muscle Actin ◽  
Cytoplasmic Staining ◽  
Microvascular Proliferation ◽  
Vascular Structures

✓ Microvascular proliferation and glomeruloid vascular structures are important histopathological features of glioblastoma multiforme (GBM). The nature of cells participating in the formation of these structures remains unclear and is the subject of this study. To define these cells better, immunohistochemical markers directed against Factor VIII—related antigen (FVIIIR:Ag), alpha smooth-muscle actin (α-SMA), and the lectin Ulex europaeus agglutinin type I (UEA-I) were used. Cells lining the vascular channels and a large number of proliferating abluminal cells participating in glomeruloid vascular structure formation showed positive cytoplasmic staining for FVIIIR:Ag and UEA-I. Abluminal and luminal cells were variably labeled for α-SMA. Ultrastructurally, complex aggregates of focally anastomosing capillaries with narrow lumina composed the glomeruloid vascular structure. Endothelial cells were hyperplastic, varied in size and shape, overlapped focally, and contained numerous cytoplasmic filaments. Tight junctions bound together adjacent and overlapping endothelial cells. Weibel—Palade bodies, usually absent from brain microvessels, were present in increased numbers in the newly formed capillaries. Each capillary loop was surrounded by basal lamina encompassing a discontinuous layer of pericytes. This study indicates that glomeruloid vascular structures in GBM are complex aggregates of newly formed microchannels lined with hyperplastic endothelial cells that have an altered morphological phenotype and that these microchannels are supported by basal lamina and pericytes and are devoid of astrocytic end-feet.

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