bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDEL-04. BIOMATERIAL SCAFFOLDS FOR THE DELIVERY OF NEURAL STEM CELL THERAPIES INTO THE GLIOBLASTOMA RESECTION CAVITY
Authors: Bomba Hunter , Kass Lauren , Carey-Ewend Abigail , Sheets Kevin , Valdivia Alain , Goetz Morgan , Findlay Ingrid , Mercer-Smith Alison , Khagi Simon , Hingtgen Shawn 
Published: November 2022

Abstract
Therapeutic neural stem cells (tNSCs) are a promising new platform for the treatment of glioblastoma (GBM). tNSCs exhibit a characteristic known as tumor tropism, in which they can migrate towards distant GBM foci via cytokine signaling. Complementarily, genetic engineering of NSCs may be performed to turn the cells into drug-producing therapeutics. Together, this results in NSCs that act as targeted drug delivery vehicles that can seek out and kill invasive GBM lesions post-resection. However, one limitation of this cell therapy platform is that tNSCs delivered directly into the GBM resection cavity are rapidly cleared. We hypothesized that the commercially available, FDA-approved hemostat FLOSEAL® may be used as a drug delivery system for improving cell persistence in the brain, thus resulting in improved therapeutic efficacy. It was found that tNSCs encapsulated in FLOSEAL® were detectable in the brain for over 95 days in mice, a drastic improvement compared to directly injected cells and cells encapsulated in other existing hemostat systems, which persisted 2 weeks or less. However, two in vivo efficacy studies of tNSCs encapsulated in FLOSEAL® yielded contrasting results. While the FLOSEAL®-tNSC system was significantly more efficacious against a GBM8 tumor model in mice compared to directly injected tNSCs, it was not significantly more effective against a U87 tumor model. This could be due to a variety of factors, including the tumor type (diffuse vs. solid for GBM8 and U87, respectively) and negative impacts of FLOSEAL® on tNSC markers of proliferation, migration, drug production, and anti-apoptosis. While FLOSEAL® is a promising material for the delivery of tNSCs in the treatment of post-operative GBM, alternative systems that allow for improved persistence while maintaining the therapeutic activity of the cells would be optimal for long-term treatment with tNSCs.
DDEL-05. PHARMACOKINETICS AND CNS DISTRIBUTION OF A NOVEL ATM INHIBITOR, WSD0628, FOR THE TREATMENT OF BRAIN TUMORS
Authors: Rathi Sneha , Oh Ju-Hee , Sarkaria Jann , Elmquist William F 
Published: November 2022

Abstract
The treatment of brain tumors using chemo- and radio-sensitizers may be limited by a lack of effective drug delivery. Radiation and some cytotoxic therapies induce DNA damage, and DNA damage response (DDR) pathways modulate resistance to effective chemo-radiation therapy. Inhibiting DDR pathways by targeting ATM leads to sensitization and enhances cytotoxicity. The purpose of this study is to determine the key pre-clinical pharmacokinetic parameters and mechanisms that influence the CNS delivery of WSD0628, a novel ATM inhibitor. Pharmacokinetics and CNS distribution studies were conducted in FVB wild-type mice following intravenous (IV) and oral (PO) dosing (5 mg/kg). Plasma, brain, and spinal cord samples were harvested after dosing and drug concentrations were measured using LC-MS/MS. The free fraction of WSD0628 was measured in plasma, brain, and spinal cord using rapid equilibrium dialysis. Our results indicate that WSD0628 has a half-life of 4.11 hrs and a high oral bioavailability (0.95). The brain partition coefficient (AUCbrain/AUCplasma, i.e., Kp, brain) is 0.05 and 0.11 after IV and PO dosing, respectively. The free fraction in plasma is 2.01 ± 0.02 % and in brain it is 1.22 ± 0.40 %. The unbound brain partition coefficient (Kpuu brain) is 0.03 and 0.06 after IV and PO dosing, respectively. The differential binding to plasma and brain tissues results in a relatively low Kpuu, a key parameter describing brain penetrability. These data show that WSD0628, a highly potent inhibitor of ATM, reached sufficient concentrations in brain after a single dose of 5 mg/kg to engage ATM over the desired time frame and elicit a response after DNA damage by chemo-radiotherapy. WSD0628 shows promising potential and further evaluations are underway to determine if efflux transporters at the BBB limit its brain distribution.
DDEL-11. DETERMINING THE DOSE OF REGADENOSON MOST LIKELY TO TRANSIENTLY ALTER THE INTEGRITY OF THE BLOOD-BRAIN BARRIER IN PATIENTS WITH GLIOMAS
Authors: Romo Carlos , Ellingson Benjamin , Strowd Roy , Lesser Glenn , Raymond Catalina , Kral Brian , Ye Xiaobu , Desideri Serena , Fisher Joy , Grossman Stuart 
Published: November 2022

Abstract

BACKGROUND
The blood brain barrier (BBB) is a major obstacle to the delivery of chemotherapy to the CNS. Regadenoson is an FDA approved adenosine A2 agonist used for cardiac stress tests. In murine models, it transiently increases BBB permeability to a 70KD dextran. This multi-institutional, NIH funded, Adult Brain Tumor Consortium trial was designed to discover a dose of regadenoson that substantially increases vascular permeability in normal appearing white matter (NAWM) where drug delivery is particularly challenging.

METHODS
Adults ages 18-45 with supratentorial gliomas at low-risk for regadenoson complications were recruited (n = 7). One patient was treated at each of seven dose levels (from 0.05 to 1.4 mg) that are known to be safe in humans. The primary outcome measure is change in vascular permeability via dynamic contrast enhanced (DCE) perfusion MRI estimates of Ktrans. The primary outcome measure was a 10-fold higher Ktrans in NAWM than reported in literature (Ktrans &gt; 0.04 min-1). Contrast-enhanced T1 subtraction map estimates of change in contrast enhancement and other measurements in normal brain and non-enhancing tumor were quantified.

RESULTS
Ktrans measures in NAWM averaged 1.13x10-3 ± 0.44x10-3 (SEM) min-1, lower than the target of 0.04 min-1. Normalized, contrast enhanced T1-weighted MR signal intensity in NAWM increased an average of 74.0 ± 22.4% min-1 (SEM) min-1, which was significantly higher than zero (P = 0.0163). Data available from this limited sample failed to meet the target goal in Ktrans increase or change in contrast enhancing signal intensity.

CONCLUSION
Administration of regadenoson at seven different doses did not significantly elevate Ktrans for gadolinium in NAWM. This data suggests that single doses of regadenoson are unlikely to substantially increase the delivery of therapeutic agents in non-enhancing brain tissue. This trial design is appropriate for further human testing of other regadenoson schedules and other novel approaches aimed at transiently modifying BBB permeability.
DDEL-13. ULTRASOUND-ENHANCED DELIVERY OF LIPOSOMAL DOXORUBICIN ACROSS THE BLOOD BRAIN BARRIER INDUCES AN IFN-GPHENOTYPE IN MICROGLIA, MACROPHAGES, AND T CELLS AND IMPROVES RESPONSE TO PD-1 BLOCKADE IN GLIOMAS
Authors: Arrieta Victor , Gould Andrew , Kim Kwang Soo , Dmello Crismita , Zhang Daniel , Castro Brandyn , Chen Li , Pandey Surya , Kai Li , Duffy Joseph , McCord Matthew , Ward Rachel , Muzzio Miguel , Canney Michael , Balyasnikova Irina , Zhang Bin , Horbinski Craig , Miska Jason , Stupp Roger , Lee-Chang Catalina , Sonabend Adam M 
Published: November 2022

Abstract

INTRODUCTION
Given the limited drug penetration across the blood-brain barrier (BBB), the therapeutic potential of new and existing therapies has not been fully exploited for the benefit of glioblastoma (GBM) patients.

METHODS
Here we employed a novel drug delivery technology based on low-intensity pulsed ultrasound combined with intravenous microbubbles (LIPU/MB) that temporarily opens the BBB to deliver liposomal doxorubicin (DOX) and anti-PD-1 therapy (aPD-1) in mouse glioma models and 3 recurrent GBM patients. Immunological variables were evaluated in tumor and immune cells as well as efficacy in glioma-bearing mice treated with DOX delivered by LIPU. These included measurement of HLA ABC and HLA DR protein expression by tumor cells, microglia, and macrophages and IFN-g production by glioma-associated microglia and macrophages in mouse and human tumors. We also assessed efficacy of LIPU/MB enhanced combination therapy in glioma-bearing mice.

RESULTS
Upregulation of HLA ABC and HLA DR was observed in GBM cell lines at low concentrations of DOX. Tumor cells from GBM patients treated with DOX, aPD-1 and LIPU/MB showed increased expression of HLA ABC and HLA DR compared to paired pretreatment samples. In both mice and humans, LIPU/MB liposomal DOX increased absolute brain drug concentrations and elicited a specific IFN-g phenotype and MHC I expression in glioma-associated microglia and macrophages in mice and humans. Furthermore, LIPU/MB-mediated BBB opening increased brain concentrations of aPD-1 in mice and in peritumoral regions of GBM patients. Combined treatment with liposomal DOX and aPD-1 delivered with LIPU/MB resulted in long-term survival of glioma-bearing mice that relied on the activity of CD8+ T cells for its efficacy.

CONCLUSIONS
Overall, this translational study demonstrates the utility of LIPU/MB to stimulate intracranial immune responses in the context of treatment with DOX and aPD-1 for gliomas.
DDEL-16. DELIVERY OF OT-101 - TGF-Β ANTISENSE- FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Trieu Vuong 
Published: November 2022

Abstract
OT-101 - a TGF-beta antisense- is active against recurrent glioblastoma in G004- a phase 2 clinical trial [Uckun FM, Qazi S, Hwang L, Trieu VN. Recurrent or refractory high grade gliomas treated by convection enhanced delivery of a TGF-beta2 targeting RNA therapeutic: a post-hoc analysis with long-term follow up. Cancers. 2019, 11:1892]. OT-101 was delivered intratumorally by Convection Enhanced Delivery (CED). To further expand the application of OT-101, we explored the intrathecal delivery of tritiated OT-101 into Sprague-Dawley CD (albino) rats. Throughout the studies, there were no sex differences. After 1 hr intracerebral infusion in rats, OT-101 was limited to the infusion site. Whereas for the 1 hr itravesicular infusion, OT-101 was more widespread with 35X, 19X, 12X higher concentration found in cerebellum, remaining cerebrum, cerebrospinal fluid (CSF), respectively. OT-101 concentration was stable for the first 4 hours post infusion and decayed biexponentially with a slow terminal half life for tissue but not for CSF, suggestive of rapid penetration of the underlying tissue away from the CSF compartment. Minimum amount of OT-101 was detected in the plasma compartment. Intrathecal bolus administration of 0.1mL of OT-101 at 14, 30, 200, 300, and 500 uM into cynomolgus monkies did not result in any single dose toxicity. Histopathology examination revealed no substance-related histomorphological lesions in the cavum subarachnoideale of the lumbar region. No changes were noted in the grey and white matter of the spinal cord, the nerve trunk, and nerve cells did not show any abnormalities. These data suggest that intrathecal administration of OT-101 is a potentially effective delivery route for antisense therapeutics such as OT-101 to the midline ie. for Diffuse Midline Glioma (DMG). A phase 1b/2 clinical trial evaluating OT-101 against DMG is proposed and the trial design will be presented
DDEL-17. POOLED CANCER CELL SCREENING IDENTIFIES GENOMIC DETERMINANTS OF NANOPARTICLE DELIVERY TO CANCER CELLS: SUB ANALYSIS OF CENTRAL NERVOUS SYSTEM TUMOR CELL LINES
Authors: Straehla Joelle , Boehnke Natalie , Safford Hannah , Kocak Mustafa , Rees Matthew , Ronan Melissa , Rosenberg Danny , Cheah Jaime , Roth Jennifer , Koehler Angela , Hammond Paula 
Published: November 2022

Abstract

Background
There is great interest in utilizing nanoparticles to improve drug delivery to central nervous system (CNS) tumors, but the biologic features underlying successful delivery at the tumor site are not known.

METHODS
We developed a pooled screening assay to investigate cellular features predictive of nanoparticle delivery and screened 35 fluorescent nanoparticle formulations against 488 pooled cancer cell lines with DNA barcodes. The nanoparticle library was comprised of nonlethal liposomal or polymeric cores with varied surface functionality, including natural and synthetic polymers. Cells were profiled using fluorescence-activated cell sorting and barcodes sequenced and deconvolved to generate an association score for each nanoparticle-cell line pair.

RESULTS
Of 488 cancer cell lines, 22 cancer cell lineages (tissues of origin) were included. There were 35 cell lines derived from CNS tumors; of these 22 were classified as astrocytoma or glioblastoma, one as oligodendroglioma, and 2 as medulloblastoma. Of CNS tumor cell lines, 40% were from female patients and average age at cell line derivation was 52 years; TP53 hotspot mutations were detected in 25/35 lines, PTEN hotspot mutations in 15/25 lines. Using unsupervised hierarchical clustering by nanoparticle association profiles, CNS tumor lines did not cluster together by lineage, subtype, or mutation status but rather by baseline expression of genes involved in nanocarrier trafficking. Nanoparticle association profiles were heterogeneous among the CNS tumor lines for most formulations, though CNS tumor lines had high association with polystyrene formulations with respect to other lineages. Select CNS tumor lines had high uptake of liposomes coated with the natural polymers fucoidan, alginate, hyaluronic acid and chondroitin sulfate; these trends were further probed in a non-pooled screen of 5 additional cell lines.

Conclusions
Uptake of liposomal and polymeric nanoparticles is heterogeneous across CNS tumor lines, but can be predicted using baseline gene expression.
DDEL-18. PEG-AU-BP NANOCARRIERS FOR DBTRG HUMAN GLIOMA CELLS
Authors: Liu Szu-Yuan , Liu Szu-Yuan 
Published: November 2022

Abstract
n-butylidenephthalide (BP) has been verified to have the superior ability of cancer cell toxicity. Furthermore, gold nanoparticles (Au) are biocompatible materials as well as the effective carrier to deliver bio-active molecular for cancer therapeutics. In present research, Au nanoparticles were firstly conjugated with polyethylene glycol (PEG), and cross-linked with BP to obtain PEG-Au-BP nanocarriers. The physicochemical properties were characterized through Ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR) and Dynamic light scattering (DLS) to confirm the combination of PEG,Au,and BP. Through iv vitro, normal BAEC cells and DBTRG human glioma cells were treated with PEG-Au-BP nanocarriers to investigate the cytotoxicity, cell uptake efficiency, and mechanism of endocytic routes. According to the results of MTT assay, PEG-Au-BP could significantly inhibit DBTRG cells proliferation. Cell uptake efficiency and potential cellular transportation in both BAEC and DBTRG cell lines were observed to be significantly higher at the time point of 2hr and 24 hr. Moreover, the mechanisms of endocytosis, clathrin-mediated endocytosis and cell autophagy, were explored to routes for BAEC and DBTRG cells to absorb PEG-Au-BP nanocarriers. Next, the cell progression and apoptosis of DBTRG cells after PEG-Au-BP treatment was investigated by flow cytometry. The results figured out that PEG-Au-BP could remarkably regulate DBTRG cell cycle at Sub-G1 phase as well as induced more apoptotic cells. The expression of apoptotic-related proteins in DBTRG cells was determined. After the treatment of PEG-Au-BP, the apoptotic cascade proteins, p21, BAX, Act-caspase-3 were significantly expressed in DBTRG cells. Through in vivo, the tissue morphology and particle distribution in mice were examined by retro-orbital sinus injection with PEG-Au-BP nanocarriers. The results demonstrated the tissue integrity in brain (forebrain, midbrain, cerebellum), and other organs did not show significant destruction. The above finding elucidated PEG-Au-BP to be a potential nanodrug for brain tumor therapies.
DDDR-01. AZD9574 IS A NOVEL, BRAIN PENETRANT PARP-1 SELECTIVE INHIBITOR WITH ACTIVITY IN AN INTRACRANIAL XENOGRAFT MODEL OF TRIPLE NEGATIVE BREAST CARCINOMA WITH HOMOLOGOUS RECOMBINATION REPAIR DEFICIENCY
Authors: Jamal Kunzah , Staniszewska Anna , Gordon Jacob , Pilger Domenic , Illuzzi Giuditta , Wilson Joanne , Smith Aaron , Gosselin Eric , McWilliams Lisa , Wen Shenghua , McGrath Frank , Dowdell Gregory , Kabbabe Dominic , Griffin Matthew , Davies Barry , Hamerlik Petra , Schou Magnus , Pike Andy , Johannes Jeffrey 
Published: November 2022

Abstract
The Poly (ADP-ribose) polymerase (PARP) family has numerous essential functions in cellular processes such as transcription, chromatin remodelling, DNA damage response and repair as well as apoptosis. PARP inhibition blocks base excision repair and results in conversion of SSBs to DNA double-strand break (DSBs), the most deleterious form of DNA damage. DSBs can be repaired by homologous recombination repair (HRR) or non-homologous end joining (NHEJ). The physiological importance of HRR is underscored by the observation of genomic instability in HRR-deficient (HRD+) cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HRR genes. PARP1 and PARP2 are required for SSB repair, while PARP1 is also involved in the repair of DNA double-strand breaks (DSBs) and replication fork damage. AZD9574 is a novel brain penetrant PARP1 inhibitor that acts by selectively inhibiting and trapping PARP1 at the sites of SSBs. While AZD9574 inhibited PARP1 enzymatic activity in all tested cell lines irrespective of the HRR status (IC50 range between 0.3 – 2 nM), colony formation assay in isogenic cell lines pairs confirmed higher potency and selectivity towards HRD+ models. In vivo, AZD9574 demonstrated dose-dependent efficacy in a BRCA1 mutant MDA-MB-436 subcutaneous xenograft model. Anti-tumour effects of AZD9574 were manifested by significant growth regressions that were durable after treatment withdrawal. An intracranial xenograft model of breast cancer brain metastases was developed to assess the efficacy of AZD9574 in the context of blood-brain barrier penetrance. Treatment of animals with established intracranial lesions showed sustained tumour growth suppression resulting in a significantly extended survival of tumour-bearing mice. Collectively, we believe that our data support the development of AZD9574 as a potential therapy for patients with HRD+ breast cancer whose disease has spread to the brain.This abstract was previously presented at AACR 2022 (Hamerlik et al, AACR 2022, Abs #3880)
DDDR-05. ERK INHIBITION INCREASES SENSITIVITY TO ANTI-PD-1 THERAPY IN A MOUSE MODEL OF BRAF MUTANT MELANOMA BRAIN METASTASIS
Authors: de Sauvage Magali , Nayyar Naema , Torrini Consuelo , Nieblas-Bedolla Edwin , Brastianos Priscilla 
Published: November 2022

Abstract

BACKGROUND
Immune checkpoint inhibitors (ICI) have revolutionized the landscape of cancer treatment, including brain metastases. However, only a subset of patients with brain metastases respond to ICI. Activating mutations in the mitogen-activated protein kinase (MAPK) signaling pathway, a key regulator of cell processes, are frequently found in brain metastases. LY3214996 (LY321) is a selective ERK 1/2 inhibitor that inhibits MAPK signaling and leads to regression of extracranial disease in preclinical models. Our objective was to evaluate whether with ERK inhibition (ERKi) can improve the efficacy of ICI in preclinical models of brain metastases.

METHODS
We tested sensitivity to LY321 in a BRAFV600E mutant, ICI resistant murine melanoma cell line (D4M) both in vitro and in vivo. To model brain metastases in vivo, we implanted D4M cells subcutaneously with subsequent intracranial implantation three days later. The treatment arms included LY321 and anti-PD-1 combination therapy, single agent therapies, and respective controls. We tested the efficacies of 2-week versus 4-week LY321 treatments, as well as 3-week treatment in an independent experiment.

RESULTS
D4M demonstrates in vitro sensitivity to LY321 (IC50 value of 4.75 µM). Our model demonstrated that LY321 in combination with anti-PD-1 improves both intracranial and extracranial disease control. Increased survival with combination therapy was observed with 3-week and 4-week LY321 administration. While individually, LY321 and anti-PD-1 produced better survival outcomes than control groups, combination therapy significantly outperformed both monotherapies.

CONCLUSION
Previous studies demonstrated that LY321 has minimal intracranial activity. However, we found that ERKi reduces intracranial tumor burden, with improved efficacy in combination with ICI in immunocompetent mice. Together, these data suggest that ERKi increases sensitivity to ICI therapy in pre-clinical brain metastasis models. Further investigation is needed to elucidate the mechanisms of this therapeutic approach, and to ultimately determine whether this combination will improve patient outcomes.
DDDR-07. EVALUATING THE ROLE OF THE PIK3CB PATHWAY IN TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA USING THE GENOMICS OF DRUG SENSITIVITY IN CANCER (GDSC) AND CANCER CELL LINE ENCYCLOPEDIA (CCLE) DATABASES
Authors: Huang Leah , Sheng Zhi , Tegge Allison 
Published: November 2022

Abstract
Glioblastoma multiforme (GBM) is a lethal primary brain cancer with a median survival of 14.6 months despite standard treatment of maximal surgical resection, radiotherapy, and temozolomide (TMZ). Recent research has identified PIK3CB/p110β as the most important regulator of AKT activation and GBM cell survival. Utilizing the pharmacogenomic databases Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE), we sought to elucidate the relationship between PIK3CB mRNA expression or AKT phosphorylation and GBM treatment resistance. We first identified cell lines with matched PI3K isoform mRNA expression, protein expression (AKT phosphorylation at S473 and T308; reverse phase protein array) and drug sensitivity (defined by the area under the curve; AUC) from the GDSC1 and CCLE databases. Associations between PI3K isoforms, AKT phosphorylation, and drug sensitivities were reported by fitting univariable and multivariable linear regression models with and without interaction terms to communicate the effects of AKT phosphorylation conditional on PIK3CB levels. We found that AKT phosphorylation and PIK3CB mRNA data together performed better as a biomarker in predicting therapeutic response to p110β-selective inhibitors than each variable alone, specifically we found that AKT phosphorylation at T308 was negatively related to p110β-selective inhibitor AZD6482 sensitivity at low PIK3CB expression levels (B = -0.069, p = 0.0513) and this relationship disappeared at higher expression levels (B = 0.04, p = 0.176) with an interaction at near statistical significance (p = 0.0674). We found that PIK3CB mRNA levels were significantly positively associated with TMZ resistance in GBM (B=0.019, p=0.0211) while other PI3K isoforms were not. While AKT phosphorylation is currently used as a biomarker for PI3K pathway inhibitors, in this study, we demonstrate that both PIK3CB mRNA and AKT phosphorylation together was a significant biomarker in sensitivity to p110β inhibitors as compared to assessing each independently. Furthermore, PIK3CB was implicated in TMZ resistance in GBM as compared to other catalytic isoforms.