scholarly journals INNV-26. IN VITRO CHEMO RESISTANCE PROFILES OF CIRCULATING GLIAL CELLS REPLICATE CHEMO CHARACTERISTICS OF TUMOR TISSUE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi135-vi135
Author(s):  
Dadasaheb Akolkar ◽  
Sanket Patil ◽  
Vishakha Mhase ◽  
Pradip Devhare ◽  
Pooja Fulmali ◽  
...  
Keyword(s):  
Glial Cells ◽  
Peripheral Blood ◽  
Drug Response ◽  
Tumor Tissue ◽  
High Grade Glioma ◽  
Cytotoxic Drugs ◽  
High Grade ◽  
Label Free ◽  
Chemotherapy Drugs

Abstract Survival of high-grade glioma patients remains dismal due to onset of resistance to even the limited systemic treatment option currently available. Except for indirect prediction of alkylating agent Temozolomide response through MGMT promotor methylation and NTRK fusions for larotrectinib, there are no biomarkers available for drug response prediction. Cell based, in vitro chemosensitivity assays can interrogate the efficacy of an array of cytotoxic drugs. However, the unavailability of live tumor cells for such assays pose challenges in clinical practice. Repeat biopsies are neither advisable nor feasible. Access to Circulating Glial Cells (CGCs) can provide real time insight into the chemo dynamics of the tumor. In this study, we show for the first time that CGCs can be harvested from peripheral blood of glioma patients for chemo response and resistance profiles (CRR) of cytotoxic drugs. CGCs were harvested from 15 ml of peripheral blood from high grade GBM patients (n=9) out of whom cells derived from surgically excised tumor tissue were also available for comparison in 2 patients. CellWizard™ process was adopted for enrichment of CGCs which is based upon epigenetically active media with paradoxical chemo-toxicity that selectively induces lethality in normal cells. This paradoxical cytotoxicity of the medium leads to selective elimination of most leukocytes thus facilitating a label free negative enrichment of CGCs. In vitro chemo sensitivity assay performed on live CGCs and cell death events were determined to evaluate response to different class of chemotherapy drugs. Evaluation of drug response showed very high concordance between tumor derived cells and CGCs in both patients where live tissue was available. In 7 patients where CGCs alone could be evaluated, the response showed replication between in vitro profile compared to treatment antecedents in 5 patients. 2 patients were treatment naïve and the response reflected high sensitivity to Temozolomide.

scholarly journals In Vitro Drug Response and Efflux Transporters Associated with Drug Resistance in Pediatric High Grade Glioma and Diffuse Intrinsic Pontine Glioma

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e61512 ◽  
Author(s):  
Susanna J. E. Veringa ◽  
Dennis Biesmans ◽  
Dannis G. van Vuurden ◽  
Marc H. A. Jansen ◽  
Laurine E. Wedekind ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Response ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Efflux Transporters ◽  
High Grade ◽  
Pontine Glioma ◽  
Pediatric High Grade Glioma

scholarly journals EXTH-48. BMP4 BINDING PEPTIDE AMPHIPHILE NANOFIBERS FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii97-ii97
Author(s):  
Cara Smith ◽  
Sonali Nayak ◽  
Ashorne Mahenthiran ◽  
Yufen Wang ◽  
Timmy Fyrner ◽  
...  
Keyword(s):  
Growth Factor ◽  
Clinical Application ◽  
Half Life ◽  
High Grade Glioma ◽  
Normal Brain ◽  
High Grade ◽  
Peptide Amphiphile ◽  
Chemotherapy Drugs

Abstract Pediatric high-grade glioma (pHGG) is among the most formidable cancers occurring in childhood. Bone morphogenetic protein 4 (BMP4) reduces the number of glioma stem-like cells and induces apoptosis. Treating tumors with exogenous BMP4 could prove effective in treating gliomas. However, a short half-life limits its clinical application. Glycosylated peptide amphiphile (GlycoPA), with a design inspired by heparin’s natural ability to bind growth factors including BMP4 through non-covalent interactions, was previously characterized and found to form high-aspect ratio supramolecular nanofibers that present growth-factor binding sulfated monosaccharides on their surface. These supramolecular nanofibers could carry excessive amounts of growth factor and markedly enhance their biological function. In this study, we verified that GlycoPA is able to bind BMP4 and dramatically increase its half-life with an ELISA assay. We also show that GlycoPA-BMP4, in comparison to free BMP4, significantly decreases pHGG cells’ proliferation in vitro. Initial in vivo intracranial distribution experimental results showed that GlycoPA has a superior normal brain distribution in comparison to a control PA (E2 PA) that has the same base structure as GlycoPA except with no glycosylated group. Preliminary results show that GlycoPA-BMP4 markedly decreases pediatric glioma tumor growth in comparison to free BMP4. Our combined in vitro and in vivo results demonstrate PA supramolecular nanofibers as an innovative and promising BMP4 delivery platform for clinical application in the treatment of brain tumors. Our future directions will investigate the therapeutic efficacy of GlycoPA-BMP4 in pediatric HGG through testing large numbers of animals and introducing first-line clinical chemotherapy drugs in combination and in various consequence.

scholarly journals Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma

2021 ◽  
Vol 22 (6) ◽  
pp. 2962
Author(s):  
Louise Orcheston-Findlay ◽  
Samuel Bax ◽  
Robert Utama ◽  
Martin Engel ◽  
Dinisha Govender ◽  
...  
Keyword(s):  
Life Expectancy ◽  
High Throughput Screening ◽  
High Grade Glioma ◽  
Tumour Microenvironment ◽  
In Vitro Models ◽  
Treatment Modalities ◽  
High Grade ◽  
Future Improvement ◽  
Complex Models

The life expectancy of patients with high-grade glioma (HGG) has not improved in decades. One of the crucial tools to enable future improvement is advanced models that faithfully recapitulate the tumour microenvironment; they can be used for high-throughput screening that in future may enable accurate personalised drug screens. Currently, advanced models are crucial for identifying and understanding potential new targets, assessing new chemotherapeutic compounds or other treatment modalities. Recently, various methodologies have come into use that have allowed the validation of complex models—namely, spheroids, tumouroids, hydrogel-embedded cultures (matrix-supported) and advanced bioengineered cultures assembled with bioprinting and microfluidics. This review is designed to present the state of advanced models of HGG, whilst focusing as much as is possible on the paediatric form of the disease. The reality remains, however, that paediatric HGG (pHGG) models are years behind those of adult HGG. Our goal is to bring this to light in the hope that pGBM models can be improved upon.

scholarly journals Dichotomy in Growth and Invasion From Low to High Grade Glioma Cellular Variants 

2021 ◽  
Author(s):  
Krishnendu Ghosh ◽  
Samarandranath Ghosh ◽  
Uttara Chatterjee ◽  
Pritha Bhattacharjee ◽  
Anirban Ghosh
Keyword(s):  
Tumor Tissue ◽  
High Grade Glioma ◽  
High Grade ◽  
General Increase ◽  
Grade Transition ◽  
Median Survival Period ◽  
Neoplastic Lesion ◽  
Tightly Coupled ◽  
Glial Dysfunction ◽  
Environmental Milieu

Abstract Glial dysfunction outraging CNS plasticity and integrity results into one of the most dangerous cancer, namely glioma, featuring little median survival period and high recurrence. The hallmark properties of proliferation, invasion and angiogenesis with the infiltrated macrophages in glioma are expected to be tightly coupled or cross-linked, but not definitely related so far. Present study is aimed to find a relationship between this featured quadrangle from lower to higher grades of post-operative glioma tissues and their invading subsets. Elevated Ki67 associated proliferation in lower grades was supported with VEGF dependent angiogenic maintenance which found decrease unlikely in higher grades. In contrast, MMP-2 and 9 associated invasions augmented high in higher grades with dominant presence of CD204+ M2 polarized macrophages and a general increase in global DNMT1 associated methylation. Marked differences found in ECM invading cellular subsets of higher grades showing high proliferative capacity indicating rationally for recurrence, contrasting the nature of gross tumor tissue of same grade. Thus in lower grades the neoplastic lesion is more inclined for its growth while in higher grade more disposed towards tissue wreckage in support with cellular environmental milieu whereas the cellular variants and subsets of invaded cells showed different trends. Therefore, some operational dichotomy or coupling among cellular variants in glioma is active in determining its low to high grade transition and aggressive progression.

CBIO-11. HISTONE H3.3 G34R/V MUTATIONS STIMULATE PEDIATRIC HIGH-GRADE GLIOMA FORMATION THROUGH THE INDUCTION OF CHROMOSOMAL INSTABILITY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi29-vi29
Author(s):  
Charles Day ◽  
Florina Grigore ◽  
Alyssa Langfald ◽  
Edward Hinchcliffe ◽  
James Robinson
Keyword(s):  
Gene Regulation ◽  
Chromosomal Instability ◽  
High Grade Glioma ◽  
Kinase Assay ◽  
High Grade ◽  
Newborn Mice ◽  
Cycle Arrest ◽  
Epigenetic Gene Regulation ◽  
Diploid Cells

Abstract H3.3 G34R/V mutations are drivers of high-grade pediatric glioma (pHGG). H3.3 G34R/V mutations are linked to altered H3.3 K36 trimethylation (H3K36me3); implicating epigenetic gene regulation as a possible contributor to pHGG formation. Here we show that H3.3 G34R/V also induces chromosomal instability (CIN); a hallmark of pHGG. If CIN promotes pHGG formation is unknown. We observed that H3.3 G34 mutant pHGG cells have reduced mitotic H3.3 S31 phosphorylation compare to WT H3.3 cell lines. And, H3.3 G34R reduced Chk1 phosphorylation at S31 by >90% in an in vitro kinase assay. Chk1 regulates chromosome segregation through phosphorylation of pericentromeric H3.3 S31 during early mitosis. Overexpression of H3.3 G34R or non-phosphorylatable S31A in H3.3 WT, diploid cells caused a significant increase in CIN. Likewise, H3.3 G34 mutant pHGG cells have significantly elevated rates of CIN as compare to H3.3 WT pHGG cells. During normal cell division, phospho-S31 is lost in anaphase. However, following chromosome missegregation, phospho-S31 spreads and stimulates p53-induced cell cycle arrest. Here we show that WT p53 cells expressing mutant G34 fail to arrest following chromosome mis-segregation. These studies demonstrate that H3.3 G34R/V mutations are sufficient to transform normal, diploid cells into proliferating CIN cells. To determine if this process contributes to tumorigenesis, we used RCAS Nestin-TVA mice to overexpress H3.3 WT, G34R, or S31A – P2A-linked to PDGFB expression in glial precursor cells of newborn mice. Over 100 days, S31A and G34R mice had drastically reduced survival (averaging 77, 81, and 100 days for S31A, G34R, and WT). Furthermore, most G34R and S31A mice developed HGG, while H3.3 WT mice remained tumor-free. Our work implicates CIN as a driver of H3.3 G34 mutant pHGG formation. Our ongoing studies utilize K36M and double mutants to further define the contributions of S31 phosphorylation (CIN) and H3K36me3 (epigenetic gene regulation) to tumorigenesis.

scholarly journals ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Lawrence Recht ◽  
Reena Thomas ◽  
Sophie Bertrand ◽  
Priya Yerballa ◽  
Gordon Li ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

β-arrestin 1 transfection induced cell death in high grade glioma in vitro

2020 ◽  
pp. 1-12
Author(s):  
Catalin Folcuti ◽  
Cristina Horescu ◽  
Edmond Barcan ◽  
Oana Alexandru ◽  
Cristian Tuta ◽  
...  
Keyword(s):  
Cell Death ◽  
High Grade Glioma ◽  
High Grade

scholarly journals OS12.2 Targeting epigenetic pathways in the treatment of recurrent high-grade glioma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii22-iii22
Author(s):  
A Hau ◽  
L Houben ◽  
E Klein ◽  
A Oudin ◽  
D Stieber ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Drug Response ◽  
High Grade Glioma ◽  
Differential Sensitivity ◽  
Targeted Sequencing ◽  
Patient Specific ◽  
Comparative Genomic ◽  
High Grade ◽  
Evolutionary Trajectory ◽  
Tumor Organoids

Abstract BACKGROUND High grade glioma (HGG) patients develop resistance to standard treatment leading to disease progression and limited life expectancy. Advances in the molecular characterisation of treatment-naïve HGGs based on next-generation sequencing and DNA methylation analyses have led to a better delineation of HGG subtypes and the identification of distinct genomic abnormalities. Furthermore, using large patient cohorts of longitudinal tumor samples, comprehensive genomic profiling studies emerged to investigate therapy-associated evolution of gliomas. All together, those studies point out the need for personalised treatment strategies, where applied drugs will be adapted to the unique patient-specific genetic abnormalities. MATERIAL AND METHODS We collected fresh samples of more than 800 brain tumors containing almost 300 glioma specimen with approximately 100 longitudinal samples of initial and recurrent tumors from 43 matched patients. By now, we have successfully established 34 patient-derived orthotopic xenografts (PDOXs) in mice. We performed comprehensive molecular profiling using array comparative genomic hybridisation, DNA methylation analysis and targeted DNA sequencing on patient specimen and their derivatives such as 3D tumor organoids and PDOXs. The custom-design sequencing panel comprises 234 genes that reflect both established genetic identifiers for individual glioma subtype classification and novel genes encoding mainly epigenetic effector genes. Based on patient-derived material we carried out drug response screening on 3D tumor organoids using a compound library matching the majority of genes that were assessed by targeted sequencing. RESULTS We succeeded in generating a live biobank of HGG patient-derived xenografts and 3D organoids that neatly recapitulates the mutational spectrum including structural DNA variation and methylation-based subtypes of gliomas. A highlight is the generation of 19 PDOXs of paired initial and relapse HGGs from a total of 9 glioma patients. A detailed analysis of the paired longitudinal samples indicated that PDOX models closely recapitulate the evolutionary trajectory of the parental tumors. Targeted sequencing of longitudinal HGG PDOXs suggests that relapse tumors accumulate somatic mutations in epigenetic effectors compared with the Initial. Differential drug responses between initial and relapse tumors were observed after screening of in vitro 3D tumor organoids. CONCLUSION Response assessment of naïve initial gliomas and recurrences provides crucial information on the differential sensitivity between initial and relapsed HGGs and offers novel personalised therapeutic options in the relapse setting. Furthermore, in depth correlation of the profiled somatic molecular landscape with drug response will enable pharmacogenomic predictions of potential inhibitors in the clinical setting.

Tolerability and preliminary efficacy of BXQ-350 for refractory solid tumors and high-grade gliomas: First-in-human, first-in-class phase I trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3505-3505
Author(s):  
Olivier Rixe ◽  
John Charles Morris ◽  
Robert Wesolowski ◽  
Emrullah Yilmaz ◽  
Richard Curry ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Human Study ◽  
Treatment Protocol ◽  
High Grade Glioma ◽  
Maximum Tolerated Dose ◽  
High Grade ◽  
Serious Adverse Events

3505 Background: BXQ-350 is a first-in-class agent comprised of Saposin C (SapC) and dioleoyl phosphatidylserine (DOPS). SapC, a multifunctional lysosomal-activator glycoprotein that preferentially interacts with tumor cell phospholipids, has demonstrated anti-tumor effects in both in vitro and in vivo preclinical models. The tolerability and preliminary efficacy of BXQ-350 in the first-in-human study are summarized here. Methods: Eighty-six refractory solid tumor (ST) or high-grade glioma (HGG) patients age ≥18 (36F:50M, age 24-81) were enrolled in a 3-part first-in-human trial (NCT02859857) from 2016-2019 and received at least one dose of BXQ-350. Doses were administered via intravenous infusion during 28-day cycles until disease progression occurred. The previously reported part 1 dose escalation portion of the study (9 HGG, 9 ST patients) established the highest planned dose of 2.4mg/kg as safe but did not identify a maximum tolerated dose. The part 2 expansion cohort treated 37 patients (18 HGG and 19 ST) and an additional part 3 cohort treated 31 ST gastrointestinal (GI) patients, both at the 2.4 mg/kg dose level. Preliminary antitumor activity was evaluated (RECISTv1.1 or RANO). Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals with the exception of 1 allergic type reaction. Three patients (Glioblastoma, Ependymoma, Appendiceal) demonstrated a partial response per RECIST/RANO. Two HGG patients with progressive radiologic enhancement were seen to have treatment effect at surgery, and hence considered to have stable disease. Seven patients (2 HGG, 3 GI, 2 other ST) remain on study and have received treatment for 9+ to 41+ months, with 5 patients treated for > 1 year. A continuing treatment protocol is planned in order to allow these patients to remain on BXQ-350 treatment. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. Preliminary results indicate this novel agent demonstrated possible anti-tumor activity in refractory solid tumors and HGG. Clinical trial information: NCT03967093) .

scholarly journals INNV-16. CLINICAL APPLICABILITY OF INDIVIDUALIZED DRUG RESPONSE PROFILING UTILIZING EX-VIVO TISSUE-DERIVED 3D CELL CULTURE ASSAYS IN HIGH-GRADE GLIOMA: A SINGLE INSTITUTION CASE SERIES USING 3D-PREDICT RESULTS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii119-ii120
Author(s):  
Lindsay Lipinski ◽  
Ajay Abad ◽  
Laszlo Mechtler ◽  
Andrew Fabiano ◽  
Ashley Smith ◽  
...  
Keyword(s):  
Cell Culture ◽  
Drug Response ◽  
Ex Vivo ◽  
Performance Status ◽  
Case Series ◽  
3D Cell Culture ◽  
High Grade Glioma ◽  
Patient Specific ◽  
High Grade ◽  
Ex Vivo Tissue

Abstract Recurrent high-grade glioma is a challenging disease process, without consensus on effective second-line therapy options. Individualized, patient-specific, biologically-based data is desirable in driving therapeutic decision-making. Patients with recurrent high-grade glioma and planned surgical re-resection at our institution were prospectively enrolled into the 3D-PREDICT study. Tissue was collected at the time of surgery for ex vivo 3D cell culture assays comprising a panel of agents commonly used for high-grade glioma, including chemotherapies and targeted therapies used in other solid cancers. In all cases, therapeutic agent selection was guided by the neuro-oncologist’s clinical judgement, factoring the patient’s age, performance status, comorbidities, toxicities/side effect profile of potential agents, and drug accessibility, plus ex-vivo drug response RESULTS: We present 3 cases in which the selection of agents was influenced by the tissue-derived 3D cell culture results; treatment led to clinical response observed in terms of progression free survival, quality of life, and pharmacologic tolerability. In Case 1, a patient with recurrent anaplastic astrocytoma was treated with a BRAF inhibitor for 12 months with excellent tolerability and no radiographic progression. Case 2 demonstrates the use of combination bevacizumab and irinotecan after disease progression subsequent to standard treatment. This patient had local radiographic control for 7 months, tolerating the regimen well. In Case 3, an individual with recurrent glioblastoma was treated with combination carboplatin and etoposide based on assay response prediction to both agents; treatment has been tolerated well with radiographic stability at 6 months while maintaining good performance status. This case series represents our institutional experience of utilizing patient-specific, ex-vivo tissue-derived cell drug response profiling to guide choice of therapy for recurrent high-grade glioma patients. Using individualized, tumor-specific drug sensitivity data to guide these decisions is representative of the ongoing paradigm shift into the realm of individualized medicine to improve outcomes in cancer patients.

Sign in / Sign up

Export Citation Format

Share Document