Biology subjects

Kornblum, H.

Publications and source records attributed to Kornblum, H..

16 recordsLinked to original sources

bioRxiv2026

Temporal Mapping of Radiation-Induced Neural Injury and Mitigation in Human Cortical Organoids

BackgroundRadiation therapy is a standard-of-care oncological treatment for central nervous system (CNS) malignancies. However, as survival outcomes improve, radiation-induced injury to normal brain tissue has increased in clinical significance. CNS radiation injury is a delayed, multifactorial process characterized by impaired neurogenesis, reactive gliosis, and persistent functional deficits. Mechanistic exploration and development of effective radiation mitigators have been limited by the lack of scalable, human-relevant models. MethodsMature human iPSC-derived cortical organoids were exposed to single-dose or clinically relevant fractionated radiation (5 x 2 Gy). DNA damage, apoptosis, and growth dynamics were assessed longitudinally. Structural organization, synaptic integrity, and neuroinflammatory responses were evaluated by immunofluorescence and real-time PCR. Transcriptomic profiling was performed at 72 hours and 2 weeks after fractionated radiation to capture acute and delayed effects. Two candidate radiation mitigators, NSPP and amisulpride, were tested for their therapeutic effects within the organoid system. ResultsCortical organoids exhibited partial recovery following single doses up to 4 Gy or fractioned irradiation. Transcriptomic analyses revealed that radiation not only reduced overall cell viability but also reshaped lineage trajectories, characterized by depletion of neural stem/progenitor populations, loss of neuronal identity, enhanced gliogenesis, increased inflammatory cytokines, and disrupted cortical layering and synaptic integrity. Treatment with NSPP or amisulpride attenuated injury-associated transcriptional and structural alterations. ConclusionHuman cortical organoids recapitulate key features of radiation-induced neural injury, recovery, and therapeutic modulation, providing a robust, scalable, and human-relevant platform for studying CNS radiation biology and preclinical screening of candidate radiation mitigators. Key pointsO_LIHuman iPSC-derived cortical organoids enable study of human CNS radiation responses. C_LIO_LIOrganoids recover after single-dose and fractionated radiation relevant to clinical exposure. C_LIO_LIThe platform supports scalable, human-relevant testing of radiation mitigation strategies. C_LI

cell biology↗

bioRxiv2025

Design and Biological Activity of a Novel Brain Penetrant Urea Compound Against Glioblastoma

Glioblastoma (GBM) remains the most lethal primary brain tumor, largely due to therapy-resistant glioma stem cells (GSCs) and the ability of non-stem cells to dedifferentiate under therapeutic pressure. We developed MXC-017, a novel urea-based compound that crosses the blood-brain-barrier, directly targets GSCs, and prevents radiation-induced GSC formation. Using click chemistry pull-down and mass spectrometry, we identified vimentin as the target of MXC-017, further validated by in silico docking. Global transcriptomic profiling (bulk RNA-seq) and single-cell RNA-seq analyses revealed MXC-017s efficacy with minimal off-target effects, supported by metabolic and kinome assays. Normal cell toxicity was negligible in fibroblasts, microglia, astrocytes, and murine neural progenitors. Maximum tolerated dose was identified and we observed significantly extended median survival in 17 PDOX GBM models when treated with MXC-017 plus radiation, benchmarked against standard-of-care temozolomide. These findings underscore the therapeutic potential of vimentin-targeting agents to overcome radiation resistance and improve outcomes for GBM patients. Statement of SignificanceGlioblastomas distinctive nature and the blood-brain barrier hamper therapies targeting therapy-resistant GSCs. We developed a novel urea-based agent that crosses the barrier, targets GSCs, and prevents radiation-induced GSC formation. With minimal off-target effects, reduced toxicity, and superior survival in PDOX models, it offers potential to improve outcome in GBM.

neuroscience↗

bioRxiv2023

De novo lipogenesis pathway is a vulnerability in IDH1 mutant glioma

Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-epileptic and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild type tumors. Surprisingly, genes upregulated by VPA showed no change in chromatin accessibility at the promoter, but there was a correlation between VPA downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decrease in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA targeted a key lipogenic gene, fatty acid synthase (FASN), via inhibition of the mTOR pathway and both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find HDACs are involved in the regulation of lipogenic genes and in particular HDAC6 is important for regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in a IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic option in IDH1 mutant gliomas.

cancer biology↗

bioRxiv2022

Single-cell analysis characterizes non-enhancing region of recurrent high-grade glioma

BackgroundNon-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. MethodsWe leveraged single-nucleus RNA-sequencing on 15 specimens from 5 high grade gliomas to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining for Ki67 to identify proliferative cell burden. ResultsTumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched for mesenchymal-like states. These NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and presence of cell-mediated immune response, but increased glioma-to-non-pathological cellular interactions. ConclusionsThis comprehensive analysis illustrates differing tumor and non-tumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. Key PointsSignificant proliferating tumor burden exist in non-enhancing regions of glioma; non-enhancing regions have unique tumor and non-tumor expression properties Importance of StudyStandard of care treatment for glioblastoma relies on visualization of tumor via contrast-enhanced magnetic resonance imaging. However, non-enhancing regions harbor tumor cells that should be targets for adjuvant therapy given these regions are not resected in surgery. To begin addressing these infiltrating non-enhancing tumor cells, we thoroughly characterize the tumor and non-tumor microenvironment of non-enhancing regions in high grade gliomas. Understanding the total tumor burden, proliferating tumor ratio, and presence of putative glioma stem cells may help design adjuvant therapies for these unique population of tumor cells. Understanding the non-tumor immune and vascular microenvironment may help target these areas in regards to drug delivery and immunotherapy. Overall, in a disease marked by significant intratumoral heterogeneity, we focus identifying therapeutic strategies for areas not addressed at surgery.

neuroscience↗

bioRxiv2022

NADPH oxidase promotes glioblastoma radiation resistance in a PTEN-dependent manner

AimsThe goal of this study was to determine whether NADPH oxidase (NOX)-produced reactive oxygen species enhances brain tumor growth of glioblastoma (GBM) under hypoxic conditions and during radiation treatment. ResultsExogenous ROS promoted brain tumor growth in gliomasphere cultures that expressed functional PTEN, but not in tumors that were PTEN deficient. Hypoxia induced the production of endogenous cytoplasmic ROS and tumor cell growth via activation of NOX. NOX activation resulted in oxidation of PTEN and downstream Akt activation. Radiation also promoted ROS production via NOX which, in turn, resulted in cellular protection that could be abrogated by knockdown of the key NOX component, p22. Knockdown of p22 also inhibited tumor growth and enhanced the efficacy of radiation in PTEN-expressing GBM cells. InnovationWhile other studies have implicated NOX function in GBM models, these studies demonstrate NOX activation and function under physiological hypoxia and following radiation in GBM, two conditions that are seen in patients. NOX plays an important role in a PTEN-expressing GBM model system, but not in PTEN-non-functional systems and provide a potential, patient-specific therapeutic opportunity. ConclusionsThis study provides a strong basis for pursuing NOX inhibition in PTEN-expressing GBM cells as a possible adjunct to radiation therapy.

cancer biology↗

bioRxiv2022

Canonical BMP2/4 signaling degrades SOX2 in glioblastoma propagating cells.

The effect of Bone Morphogenetic Proteins (BMPs) on glioblastoma propagation cells (GPCs) is being debated [1-5]. We observed that exposure of GPCs to BMP2/4 initiates a rapid proteasomal degradation of the pluripotency factor SOX2 followed by the differentiation of GPCs into glial cells using 5 primary human glioblastoma lines tested. Enforced expression of SOX2 in GPCs antagonized BMP2/4-induced gliogenesis and reduction of proliferation. Both outcomes are consistent with the role of SOX2 in normal neurogenesis [6-8]. Using gene expression analysis, we observed that level of SOX2 in different glioblastoma lines tracks with the levels of oncogenes H/K/N-RAS and OLIG2. Our work provides support for BMP2/4-SOX2 axis in GPCs and points to the proteasome-regulated degradation of SOX2 that initiates glycogenic differentiation similar to that observed during normal development [6, 7]. Our work supports a potential for developing novel therapeutic strategies aimed at differentiation of GPC into non-tumorigenic glia.

cancer biology↗

bioRxiv2021

Generation of a molecular interactome of the glioblastoma perivascular niche reveals Integrin Binding Sialoprotein as a key mediator of tumor cell migration

Glioblastoma (GBM) is characterized by extensive microvascular hyperproliferation. In addition to supplying blood to the tumor, GBM vessels also provide trophic support to glioma cells and serve as conduits for migration into the surrounding brain promoting recurrence. Here, we enriched CD31-expressing glioma vascular cells (GVC) and A2B5-expressing glioma tumor cells (GTC) from primary GBM and utilized RNA sequencing to create a comprehensive interaction map of the secreted and extracellular factors elaborated by GVC that can interact with receptors and membrane molecules on GTC. To validate our findings, we utilized functional assays, including a novel hydrogel-based migration assay and in vivo mouse models to demonstrate that one identified factor, the little-studied integrin binding sialoprotein (IBSP) enhances tumor growth and promotes the migration of GTC along the vasculature. This perivascular niche interactome will serve a resource to the research community in defining the potential functions of the GBM vasculature.

cancer biology↗

bioRxiv2020

Spatial heterogeneity of glioblastoma cells reveals sensitivity to NAD+ depletion at tumor edge

Even after total resection of glioblastoma core lesions by surgery and aggressive post-surgical treatments, life-threatening tumors inevitably recur. A characteristic obstacle in effective treatment is high intratumoral heterogeneity, both longitudinally and spatially. Recurrence occurs predominantly at the brain parenchyma-tumor core interface, a region termed tumor edge. Given the difficulty of accessing it surgically, the composition of the tumor edge, harboring both cancerous and non-cancerous cells, remains largely unknown. Here, to identify phenotypic diversity among heterogeneous glioblastoma core and edge lesions, we uncovered the existence of three phenotypically-distinct clonal subpopulations within individual tumors from glioblastoma patients. Clones from the tumor core shared the same phenotype, exclusively generating tumor-core cells. In contrast, two distinct clonal subtypes were identified at the tumor edge: one generated only edge-lesion cells and the other expanded more broadly to establish both edge- and core-lesions. Using multiple xenograft experimental models in mouse brains, tumor edge development was found to require that both somatic and tumor cells express the NADase CD38, combinedly elevating glioblastoma malignancy. In vitro data suggested that intracellular NADase activity at the edge was provoked through intercellular communication between edge clones and normal astrocytes. Systemic treatment of tumor-bearing mice with 78c, a small-molecule CD38 inhibitor, attenuated the formation of glioblastoma edge lesions, suggesting its clinical potential to pharmacologically eliminate tumor-edge lesions. Collectively, these findings provide novel phenotypic and mechanistic insights into clonal heterogeneity within glioblastoma, particularly in the surgically unresectable, currently understudied tumor edge.

cancer biology↗

bioRxiv2020

Tumor edge architecture in glioblastoma is constructed by inter-cellular signals from vascular endothelial cells

One of the hallmarks of glioblastoma (GBM) is extensive neovascularization. In addition to supplying blood and nutrients, vascular endothelial (VE) cells provide trophic support to GBM cells via paracrine signaling, the precise mechanisms of which are being unraveled. Here, using patient-derived GBM and VE cells as well as orthotopic GBM mouse models, we report that Endocan (ESM1), an endothelial-secreted proteoglycan, confers enhanced proliferative, migratory, and angiogenic properties to GBM cells and regulates their spatial identity. Mechanistically, Endocan exerts at least part of its functions via direct binding and activation of the PDGFRA receptor. Subsequent downstream signaling enhances chromatin accessibility of the Myc promoter and upregulates Myc expression inducing highly stable phenotypic changes in GBM cells. Furthermore, Endocan confers a radioprotection phenotype in GBM cells, both in vitro and in vivo. Inhibition of Endocan-PDGFRA signaling with ponatinib increases survival in the Esm1 wild-type but not in the Esm1 knock-out mouse GBM model. Our findings identify Endocan and its downstream signaling axis as a potential target to subdue the recurrence of GBM and further highlight the importance of vascular to tumor cell signaling for GBM biology. Significance statementIdentification of the Endocan/PDGFRA/Myc axis demonstrates an important role of VE cells in GBM malignancy. The contribution of Endocan to the development of GBM cell populations with different phenotypes reveal an additional pathway underlying the origin of GBM intratumoral heterogeneity. Targeting Endocan-mediated crosstalk may enhance the efficacy of GBM treatment.

cancer biology↗

bioRxiv2020

Brain aging-dependent glioma traits reversible by NAD+/BDNF-mediated neuronal reactivation

The rise in aging population worldwide is increasing death from cancer, including glioblastoma. Here, we explore the impact of brain aging on glioma tumorigenesis. We find that glioblastoma in older patients and older mice displayed reduced neuronal signaling, including a decline of NTRK-like family member 6 (SLITRK6), a receptor for neurotrophic factor BDNF. This reduction was linked to the systemic decline of nicotinamide adenine dinucleotide (NAD+) with aging, as old mice exposed to young blood via parabiosis or supplemented with the NAD+ precursor NMN (nicotinamide mononucleotide) reverted phenotypically to young-brain responses to glioma, with reactivated neuronal signaling and reduced death from tumor burden. Interestingly, the phenotypic reversal by NMN was largely absent in old mice undergoing parabiosis with BDNF+/- young mice and in BDNF+/- mice undergoing tumor challenge, supporting the notion that the lower NAD+-BDNF signaling in the aging brain aggravated glioma tumorigenesis. We propose that the aging-associated decline in brain NAD+ worsens glioma outcomes at least in part by decreasing neuronal/synaptic activity and increasing neuroinflammation.

cancer biology↗

bioRxiv2020

Docosahexaenoic acid has stem cell-specific effects in the SVZ and restores olfactory neurogenesis and function in the aging brain

Fatty acids are well known as important constituents for the synthesis of membrane lipids and as sources of cellular energy in the CNS. However, fatty acids can also act as vital second messenger molecules in the nervous system and regulate the activity of many proteins affecting cell growth and survival. Here, we show that an essential dietary fatty acid, Decosahexaenoic acid, (DHA), can enhance stem cell function in vitro and in vivo. We found that this effect is not due to an increase in the overall proliferation rate of all neural progenitors, but is due to an increase in the number of multipotent stem cells that leads to greater levels of subventricular zone (SVZ) neurogenesis with restoration of olfactory function in aged mice. These effects were likely mediated through increased EGF-receptor sensitivity, a conversion of EGRFR+ progenitors back into an EGRFR+/GFAP+ stem cell state, and the activation of the PI3K/AKT signaling pathway, which is a critical pathway in many NSC cell functions including cell growth and survival. Together these data demonstrate that neural stem cells in the aged and quiescent neurogenic niche of the mouse SVZ retain their ability to self-renew and contribute to neurogenesis when apparently rejuvenated by DHA and PI3K/AKT pathway activation. DHA stimulation of this signaling enhances the number of multipotent stem cells and neurogenesis in young and aged rodent and human stem cells and hence may have implications for the manipulation of neural stem cells for brain repair. Significance StatementWe have identified potentially important effects of DHA on the stem cell population which may be unique to the SVZ stem cell niche. Our studies demonstrate that DHA can promote the production of neural stem cells, possibly via a non-proliferative mechanism stimulated by EGF receptor activation, and prolongs their viability. Aging animals undergo an apparent loss in SVZ stem cells and an associated decline in olfactory bulb function. We find that dietary DHA supplementation at least partially restores stem cell numbers, olfactory bulb neurogenesis and olfactory discrimination and memory in aged mice, demonstrating a capacity for rejuvenation is retained despite age-related changes to the niche, which has significant implications for ameliorating cognitive decline in aging and for endogenous brain repair.

neuroscience↗

bioRxiv2020

Combined Treatment with Dopamine Receptor Antagonists and Radiation Creates a Metabolic Vulnerability in Mouse Models of Glioblastoma

BackgroundGlioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. MethodsUsing patient-derived glioblastoma lines and mouse models of glioblastoma we test the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing. ResultsTreatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals. ConclusionsOur results indicate high efficacy of a triple combination of quetiapine, atorvastatin and radiation against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

neuroscience↗

bioRxiv2020

Quantitative single cell heterogeneity profiling of patient derived tumor initiating gliomaspheres reveals unique signatures of malignancy and response

BackgroundGlioblastoma is a deadly brain tumor with median patient survival of 14.6 months. At the core of this malignancy are rare, highly heterogenous malignant stem-like tumor initiating cells. Aberrant signaling across the EGFR-PTEN-AKT-mTOR signal transduction pathways are common oncogenic drivers in these cells. Though gene-level clustering has determined the importance of the EGFR signaling pathway as a treatment indicator, multiparameter protein-level analyses are necessary to discern functional attributes of signal propagation. Multiparameter single cell analyses is emerging as particularly useful in identifying such attributes. MethodsSingle cell targeted proteomic analysis of EGFR-PTEN-AKT-mTOR proteins profiled heterogeneity in a panel of fifteen patient derived gliomaspheres. A microfluidic cell array chip tool served as a low cost methodology to derive high quality quantitative single cell analytical outputs. Chip design specifications produced extremely high signal-to-noise ratios and brought experimental efficiencies of cell control and minimal cell use to accommodate experimentation with these rare and often slow-growing cell populations. Quantitative imaging software generated datasets to observe similarities and differences within and between cells and patients. Bioinformatic self-organizing maps (SOMs) and hierarchical clustering stratified patients into malignancy and responder groups which were validated by phenotypic and statistical analyses. ResultsFifteen patient dissociated gliomaspheres produced 59,464 data points from 14,866 cells. Forty-nine molecularly defined signaling phenotypes were identified across samples. Bioinformatics resolved two clusters diverging on EGFR expression (p = 0.0003) and AKT/TORC1 activation (p = 0.08 and p = 0.09 respectively). TCGA status of a subset showed genetic heterogeneity with proneural, classical and mesenchymal subtypes represented in both clusters. Phenotypic validation measures indicated drug responsive phenotypes to EGFR blocking were found in the EGFR expressing cluster. EGFR expression in the subset of drug-treated lines was statistically significant (p<.05). The EGFR expressing cluster was of lower tumor initiating potential in comparison to the AKT/TORC1 activated cluster. Though not statistically significant, EGFR expression trended with improved patient prognosis while AKT/TORC1 activated samples trended with poorer outcomes. ConclusionsQuantitative single cell heterogeneity profiling resolves signaling diversity into meaningful non-obvious phenotypic groups suggesting EGFR is decoupled from AKT/TORC1 signalling while identifying potentially valuable targets for personalized therapeutic approaches for deadly tumor-initiating cell populations.

cancer biology↗

bioRxiv2020

1--4-phenylpiperazine Treatment After Brain Irradiation Preserves Cognitive Function in Mice

BackgroundNormal tissue toxicity to the CNS is an inevitable consequence of a successful radiotherapy of brain tumors or cancer metastases to the CNS. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuro-inflammation and de-myelinization are contributing factors that lead to progressive cognitive decline. MethodsThe effects of Compound #5 on irradiated murine neurospheres, microglia cells and patients-derived gliomaspheres were assessed in sphere-formation assays, flow cytometry and IL-6 ELISAs, Activation of the Hedgehog pathway was studied by qRT-PCR. The in vivo effects of Compound #5 were analyzed using flow cytometry, sphere-formation assays, immune-histochemistry, behavioral testing and an intracranial mouse model of glioblastoma. ResultsWe report that 1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine (Compound #5) mitigates radiation-induced normal tissue toxicity in the brains of mice. Compound #5 treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine interleukin-6. Behavioral testing revealed that treatment with Compound #5 after radiotherapy successfully mitigates radiation-induced decline in motor, sensory and memory function of the brain. In mouse models of glioblastoma, Compound #5 showed no toxicity and did not interfere with the growth-delaying effects of radiation. ConclusionsWe conclude that Compound #5 has the potential to mitigate cognitive decline in patients undergoing partial or whole brain irradiation without promoting tumor growth and that the use of this compound as a radiation mitigator of radiation late effects on the CNS warrants further investigation. Importance of the StudySuccessful radiotherapy of CNS malignancies inevitably lead to cognitive decline in cancer survivors and treatment options to mitigate this side effect are limited. We present evidence that a piperazine compound can prevent cognitive decline in mice after total brain irradiation without compromising the antitumor effect of radiation, suggesting that this compound could be used to mitigate radiation side effects in brain tumor patients undergoing radiotherapy.

neuroscience↗

bioRxiv2019

The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma

Glioblastoma (GBM) is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2 and {beta}-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs. SignificanceGBM is the most common and most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 months. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood-brain-barrier. Ultimately, all patients succumb to the disease. Our study describes radiation-induced cellular plasticity as a novel resistance mechanism in GBM. We identified a dopamine receptor antagonist as a readily available, FDA-approved drug known to penetrate the blood-brain-barrier which prevents phenotype conversion of glioma cells into glioma-initiating cells and prologs survival in mouse models of GBM, thus suggesting that it will improve the efficacy of RT without increasing toxicity.

neuroscience↗

bioRxiv2019

Injectable diblock copolypeptide hydrogel provides platform to maintain high local concentrations of taxol and local tumor control.

IntroductionSurgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy.\n\nMethodsThe development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells.\n\nResultsThe DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model, of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to a high local concentration of paclitaxel and led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment.\n\nConclusionsThese findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

bioengineering↗