Publications by authors named "Peter Canoll"

158 Publications

Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and accelerate functional maturation of human stem cell-derived interneurons.

Elife 2021 Apr 27;10. Epub 2021 Apr 27.

Department of Pathology and Cell Biology, Columbia University, New York, United States.

Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex - a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures. Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.
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http://dx.doi.org/10.7554/eLife.56063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099424PMC
April 2021

COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.

Brain 2021 Apr 15. Epub 2021 Apr 15.

Department of Pathology and Cell Biology, Division of Neuropathology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, and the New York Presbyterian Hospital, New York, NY, 10032, USA.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms, though, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological, and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical center. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit (ICU). Hospital-associated complications were common, including 8 (20%) with deep vein thrombosis/pulmonary embolism (DVT/PE), 7 (17%) patients with acute kidney injury requiring dialysis, and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 hours of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischemic changes in all brains, both global and focal; large and small infarcts, many of which appeared hemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, though none had evidence of vasculitis. Eighteen (44%) contained pathologies of neurodegenerative diseases, not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR (qRT-PCR), RNAscope, and immunocytochemistry with primers, probes, and antibodies directed against the spike and nucleocapsid regions. qRT-PCR revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in nasal epithelia. RNAscope and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in COVID-19 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but rather likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischemia. Further studies are needed to define whether these pathologies, if present in patients who survive COVID-19, might contribute to chronic neurological problems.
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http://dx.doi.org/10.1093/brain/awab148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083258PMC
April 2021

How COVID-19 Affects the Brain.

JAMA Psychiatry 2021 Mar 26. Epub 2021 Mar 26.

Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri.

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http://dx.doi.org/10.1001/jamapsychiatry.2021.0500DOI Listing
March 2021

Focused ultrasound mediated blood-brain barrier opening is safe and feasible in a murine pontine glioma model.

Sci Rep 2021 Mar 22;11(1):6521. Epub 2021 Mar 22.

Department of Radiation Oncology, Columbia University Irving Medical Center, 622 W. 168th Street, New York, NY, 10032, USA.

Drug delivery in diffuse intrinsic pontine glioma is significantly limited by the blood-brain barrier (BBB). Focused ultrasound (FUS), when combined with the administration of microbubbles can effectively open the BBB permitting the entry of drugs across the cerebrovasculature into the brainstem. Given that the utility of FUS in brainstem malignancies remains unknown, the purpose of our study was to determine the safety and feasibility of this technique in a murine pontine glioma model. A syngeneic orthotopic model was developed by stereotactic injection of PDGF-BPTENp53 murine glioma cells into the pons of B6 mice. A single-element, spherical-segment 1.5 MHz ultrasound transducer driven by a function generator through a power amplifier was used with concurrent intravenous microbubble injection for tumor sonication. Mice were randomly assigned to control, FUS and double-FUS groups. Pulse and respiratory rates were continuously monitored during treatment. BBB opening was confirmed with gadolinium-enhanced MRI and Evans blue. Kondziela inverted screen testing and sequential weight lifting measured motor function before and after sonication. A subset of animals were treated with etoposide following ultrasound. Mice were either sacrificed for tissue analysis or serially monitored for survival with daily weights. FUS successfully caused BBB opening while preserving normal cardiorespiratory and motor function. Furthermore, the degree of intra-tumoral hemorrhage and inflammation on H&E in control and treated mice was similar. There was also no difference in weight loss and survival between the groups (p > 0.05). Lastly, FUS increased intra-tumoral etoposide concentration by more than fivefold. FUS is a safe and feasible technique for repeated BBB opening and etoposide delivery in a preclinical pontine glioma model.
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http://dx.doi.org/10.1038/s41598-021-85180-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985134PMC
March 2021

Disruption of nuclear architecture as a cause of COVID-19 induced anosmia.

bioRxiv 2021 Feb 9. Epub 2021 Feb 9.

Olfaction relies on a coordinated partnership between odorant flow and neuronal communication. Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, yet the mechanism behind this abrupt sensory deficit remains elusive. Here, using molecular evaluation of human olfactory epithelium (OE) from subjects succumbing to COVID-19 and a hamster model of SARS-CoV-2 infection, we discovered widespread downregulation of olfactory receptors (ORs) as well as key components of their signaling pathway. OR downregulation likely represents a non-cell autonomous effect, since SARS-CoV-2 detection in OSNs is extremely rare both in human and hamster OEs. A likely explanation for the reduction of OR transcription is the striking reorganization of nuclear architecture observed in the OSN lineage, which disrupts multi-chromosomal compartments regulating OR expression in humans and hamsters. Our experiments uncover a novel molecular mechanism by which a virus with a very selective tropism can elicit persistent transcriptional changes in cells that evade it, contributing to the severity of COVID-19.
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http://dx.doi.org/10.1101/2021.02.09.430314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885920PMC
February 2021

Convection Enhanced Delivery of Topotecan for Gliomas: A Single-Center Experience.

Pharmaceutics 2020 Dec 30;13(1). Epub 2020 Dec 30.

Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA.

A key limitation to glioma treatment involves the blood brain barrier (BBB). Convection enhanced delivery (CED) is a technique that uses a catheter placed directly into the brain parenchyma to infuse treatments using a pressure gradient. In this manuscript, we describe the physical principles behind CED along with the common pitfalls and methods for optimizing convection. Finally, we highlight our institutional experience using topotecan CED for the treatment of malignant glioma.
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http://dx.doi.org/10.3390/pharmaceutics13010039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823846PMC
December 2020

Focused Ultrasound-Mediated Blood-Brain Barrier Opening Increases Delivery and Efficacy of Etoposide for Glioblastoma Treatment.

Int J Radiat Oncol Biol Phys 2020 Dec 17. Epub 2020 Dec 17.

Department of Radiation Oncology, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, New York, New York. Electronic address:

Purpose: Glioblastoma (GBM) is a devastating disease. With the current treatment of surgery followed by chemoradiation, outcomes remain poor, with median survival of only 15 months and a 5-year survival rate of 6.8%. A challenge in treating GBM is the heterogeneous integrity of the blood-brain barrier (BBB), which limits the bioavailability of systemic therapies to the brain. There is a growing interest in enhancing drug delivery by opening the BBB with the use of focused ultrasound (FUS). We hypothesize that an FUS-mediated BBB opening can enhance the delivery of etoposide for a therapeutic benefit in GBM.

Methods And Materials: A murine glioma cell line (Pdgf, Pten, P53) was orthotopically injected into B6(Cg)-Tyrc-2J/J mice to establish the syngeneic GBM model for this study. Animals were treated with FUS and microbubbles to open the BBB to enhance the delivery of systemic etoposide. Magnetic resonance (MR) imaging was used to evaluate the BBB opening and tumor progression. Liquid chromatography tandem mass spectrometry was used to measure etoposide concentrations in the intracranial tumors.

Results: The murine glioma cell line is sensitive to etoposide in vitro. MR imaging and passive cavitation detection demonstrate the safe and successful BBB opening with FUS. The combined treatment of an FUS-mediated BBB opening and etoposide decreased tumor growth by 45% and prolonged median overall survival by 6 days: an approximately 30% increase. The FUS-mediated BBB opening increased the brain tumor-to-serum ratio of etoposide by 3.5-fold and increased the etoposide concentration in brain tumor tissue by 8-fold compared with treatment without ultrasound.

Conclusions: The current study demonstrates that BBB opening with FUS increases intratumoral delivery of etoposide in the brain, resulting in local control and overall survival benefits.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.019DOI Listing
December 2020

Myosin 10 Regulates Invasion, Mitosis, and Metabolic Signaling in Glioblastoma.

iScience 2020 Dec 13;23(12):101802. Epub 2020 Nov 13.

Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

Invasion and proliferation are defining phenotypes of cancer, and in glioblastoma blocking one stimulates the other, implying that effective therapy must inhibit both, ideally through a single target that is also dispensable for normal tissue function. The molecular motor myosin 10 meets these criteria. Myosin 10 knockout mice can survive to adulthood, implying that normal cells can compensate for its loss; its deletion impairs invasion, slows proliferation, and prolongs survival in murine models of glioblastoma. Myosin 10 deletion also enhances tumor dependency on the DNA damage and the metabolic stress responses and induces synthetic lethality when combined with inhibitors of these processes. Our results thus demonstrate that targeting myosin 10 is active against glioblastoma by itself, synergizes with other clinically available therapeutics, may have acceptable side effects in normal tissues, and has potential as a heretofore unexplored therapeutic approach for this disease.
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http://dx.doi.org/10.1016/j.isci.2020.101802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702012PMC
December 2020

Assessment of Prognostic Value of Cystic Features in Glioblastoma Relative to Sex and Treatment With Standard-of-Care.

Front Oncol 2020 16;10:580750. Epub 2020 Nov 16.

Department of Radiology, Mayo Clinic, Arizona, AZ, United States.

Glioblastoma (GBM) is the most aggressive primary brain tumor and can have cystic components, identifiable through magnetic resonance imaging (MRI). Previous studies suggest that cysts occur in 7-23% of GBMs and report mixed results regarding their prognostic impact. Using our retrospective cohort of 493 patients with first-diagnosis GBM, we carried out an exploratory analysis on this potential link between cystic GBM and survival. Using pretreatment MRIs, we manually identified 88 patients with GBM that had a significant cystic component at presentation and 405 patients that did not. Patients with cystic GBM had significantly longer overall survival and were significantly younger at presentation. Within patients who received the current standard of care (SOC) ( = 184, 40 cystic), we did not observe a survival benefit of cystic GBM. Unexpectedly, we did not observe a significant survival benefit between this SOC cystic cohort and patients with cystic GBM diagnosed before the standard was established ( = 40 with SOC, = 19 without SOC); this significant SOC benefit was clearly observed in patients with noncystic GBM ( = 144 with SOC, = 111 without SOC). When stratified by sex, the survival benefit of cystic GBM was only preserved in male patients ( = 303, 47 cystic). We report differences in the absolute and relative sizes of imaging abnormalities on MRI and the prognostic implication of cysts based on sex. We discuss hypotheses for these differences, including the possibility that the presence of a cyst could indicate a less aggressive tumor.
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http://dx.doi.org/10.3389/fonc.2020.580750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705378PMC
November 2020

Integrating single-cell RNA-seq and imaging with SCOPE-seq2.

Sci Rep 2020 11 10;10(1):19482. Epub 2020 Nov 10.

Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA.

Live cell imaging allows direct observation and monitoring of phenotypes that are difficult to infer from transcriptomics. However, existing methods for linking microscopy and single-cell RNA-seq (scRNA-seq) have limited scalability. Here, we describe an upgraded version of Single Cell Optical Phenotyping and Expression (SCOPE-seq2) for combining single-cell imaging and expression profiling, with substantial improvements in throughput, molecular capture efficiency, linking accuracy, and compatibility with standard microscopy instrumentation. We introduce improved optically decodable mRNA capture beads and implement a more scalable and simplified optical decoding process. We demonstrate the utility of SCOPE-seq2 for fluorescence, morphological, and expression profiling of individual primary cells from a human glioblastoma (GBM) surgical sample, revealing relationships between simple imaging features and cellular identity, particularly among malignantly transformed tumor cells.
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http://dx.doi.org/10.1038/s41598-020-76599-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655825PMC
November 2020

Sex differences in health and disease: A review of biological sex differences relevant to cancer with a spotlight on glioma.

Cancer Lett 2021 02 29;498:178-187. Epub 2020 Oct 29.

Mathematical NeuroOncology Laboratory, Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, USA; Department of Neurological Surgery, Mayo Clinic, Phoenix, AZ, USA; School of Mathematical and Statistical Sciences, Arizona State University, Tempe, AZ, USA. Electronic address:

The influence of biological sex differences on human health and disease, while being increasingly recognized, has long been underappreciated and underexplored. While humans of all sexes are more alike than different, there is evidence for sex differences in the most basic aspects of human biology and these differences have consequences for the etiology and pathophysiology of many diseases. In a disease like cancer, these consequences manifest in the sex biases in incidence and outcome of many cancer types. The ability to deliver precise, targeted therapies to complex cancer cases is limited by our current understanding of the underlying sex differences. Gaining a better understanding of the implications and interplay of sex differences in diseases like cancer will thus be informative for clinical practice and biological research. Here we review the evidence for a broad array of biological sex differences in humans and discuss how these differences may relate to observed sex differences in various diseases, including many cancers and specifically glioblastoma. We focus on areas of human biology that play vital roles in healthy and disease states, including metabolism, development, hormones, and the immune system, and emphasize that the intersection of sex differences in these areas should not go overlooked. We further propose that mathematical approaches can be useful for exploring the extent to which sex differences affect disease outcomes and accounting for those in the development of therapeutic strategies.
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http://dx.doi.org/10.1016/j.canlet.2020.07.030DOI Listing
February 2021

Neuronophagia and microglial nodules in a SARS-CoV-2 patient with cerebellar hemorrhage.

Acta Neuropathol Commun 2020 08 26;8(1):147. Epub 2020 Aug 26.

Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY, USA.

We document the neuropathologic findings of a 73-year old man who died from acute cerebellar hemorrhage in the context of relatively mild SARS-CoV2 infection. The patient developed sudden onset of headache, nausea, and vomiting, immediately followed by loss of consciousness on the day of admission. Emergency medical services found him severely hypoxemic at home, and the patient suffered a cardiac arrest during transport to the emergency department. The emergency team achieved return of spontaneous circulation after over 17 min of resuscitation. A chest radiograph revealed hazy bilateral opacities; and real-time-PCR for SARS-CoV-2 on the nasopharyngeal swab was positive. Computed tomography of the head showed a large right cerebellar hemorrhage, with tonsillar herniation and intraventricular hemorrhage. One day after presentation, he was transitioned to comfort care and died shortly after palliative extubation. Autopsy performed 3 h after death showed cerebellar hemorrhage and acute infarcts in the dorsal pons and medulla. Remarkably, there were microglial nodules and neuronophagia bilaterally in the inferior olives and multifocally in the cerebellar dentate nuclei. This constellation of findings has not been reported thus far in the context of SARS-CoV-2 infection.
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http://dx.doi.org/10.1186/s40478-020-01024-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447601PMC
August 2020

Rapid, label-free detection of diffuse glioma recurrence using intraoperative stimulated Raman histology and deep neural networks.

Neuro Oncol 2020 Jul 16. Epub 2020 Jul 16.

Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan.

Background: Detection of glioma recurrence remains a challenge in modern neuro-oncology. Noninvasive radiographic imaging is unable to definitively differentiate true recurrence versus pseudoprogression. Even in biopsied tissue, it can be challenging to differentiate recurrent tumor and treatment effect. We hypothesized that intraoperative stimulated Raman histology (SRH) and deep neural networks can be used to improve the intraoperative detection of glioma recurrence.

Methods: We used fiber-laser-based SRH, a label-free, non-consumptive, high-resolution microscopy method (<60 secs per 1 x 1 mm2) to image a cohort of patients (n = 35) with suspected recurrent gliomas who underwent biopsy or resection. The SRH images were then used to train a convolutional neural network (CNN) and develop an inference algorithm to detect viable recurrent glioma. Following network training, the performance of the CNN was tested for diagnostic accuracy in a retrospective cohort (n = 48).

Results: Using patch-level CNN predictions, the inference algorithm returned a single Bernoulli distribution for the probability of tumor recurrence for each surgical specimen or patient. The external SRH validation dataset consisted of 48 patients (recurrent, 30; pseudoprogression, 18), and we achieved a diagnostic accuracy of 95.8%.

Conclusion: SRH with CNN-based diagnosis can be used to improve the intraoperative detection of glioma recurrence in near-real time. Our results provide insight into how optical imaging and computer vision can be combined to augment conventional diagnostic methods and improve the quality of specimen sampling at glioma recurrence.
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http://dx.doi.org/10.1093/neuonc/noaa162DOI Listing
July 2020

CD8 T-cell-Mediated Immunoediting Influences Genomic Evolution and Immune Evasion in Murine Gliomas.

Clin Cancer Res 2020 08 19;26(16):4390-4401. Epub 2020 May 19.

Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: Cancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intratumor heterogeneity characteristic of gliomas, we hypothesized that CD8 T cells mediate immunoediting in these tumors.

Experimental Design: We developed retrovirus-induced PDGF murine gliomas and evaluated glioma progression and tumor immunogenicity in the absence of CD8 T cells by depleting this immune cell population. Furthermore, we characterized the genomic alterations present in gliomas that developed in the presence and absence of CD8 T cells.

Results: Upon transplantation, gliomas that developed in the absence of CD8 T cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8 T-cell depletion. In contrast, gliomas that developed under pressure from CD8 T cells were able to fully engraft in both CD8 T-cell-depleted mice and immunocompetent mice. Remarkably, gliomas developed in the absence of CD8 T cells exhibited increased aneuploidy, MAPK pathway signaling, gene fusions, and macrophage/microglial infiltration, and showed a proinflammatory phenotype. MAPK activation correlated with macrophage/microglia recruitment in this model and in the human disease.

Conclusions: Our studies indicate that, in these tumor models, CD8 T cells influence glioma oncogenic pathways, tumor genotype, and immunogenicity. This suggests immunoediting of immunogenic tumor clones through their negative selection by CD8 T cells during glioma formation.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442699PMC
August 2020

Sex-specific impact of patterns of imageable tumor growth on survival of primary glioblastoma patients.

BMC Cancer 2020 May 19;20(1):447. Epub 2020 May 19.

Precision Neurotherapeutics Innovation Program, Mayo Clinic, 5777 East Mayo Blvd , SSB 02-700, Phoenix, AZ, 85054, USA.

Background: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences.

Methods: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females).

Results: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR = 1.027, p = 0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR = 1.011, p < 0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p = 0.010 t-test), but tumor size was not correlated with female overall survival (p = 0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p = 0.004, F p = 0.001, t-test).

Conclusion: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.
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http://dx.doi.org/10.1186/s12885-020-06816-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238585PMC
May 2020

Extent of resection, molecular signature, and survival in 1p19q-codeleted gliomas.

J Neurosurg 2020 May 8:1-11. Epub 2020 May 8.

2Department of Radiation Oncology, Vagelos College of Physicians and Surgeons, NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York.

Objective: Genomic analysis in neurooncology has underscored the importance of understanding the patterns of survival in different molecular subtypes within gliomas and their responses to treatment. In particular, diffuse gliomas are now principally characterized by their mutation status (IDH1 and 1p/19q codeletion), yet there remains a paucity of information regarding the prognostic value of molecular markers and extent of resection (EOR) on survival. Furthermore, given the modern emphasis on molecular rather than histological diagnosis, it is important to examine the effect of maximal resection on survival in all gliomas with 1p/q19 codeletions, as these will now be classified as oligodendrogliomas under the new WHO guidelines.The objectives of the present study were twofold: 1) to assess the association between EOR and survival for patients with oligodendrogliomas in the National Cancer Database (NCDB), which includes information on mutation status, and 2) to demonstrate the same effect for all patients with 1p/19q codeleted gliomas in the NCDB.

Methods: The NCDB was queried for all cases of oligodendroglioma between 2004 and 2014, with follow-up dates through 2016. The authors found 2514 cases of histologically confirmed oligodendrogliomas for the final analysis of the effect of EOR on survival. Upon further query, 1067 1p/19q-codeleted tumors were identified in the NCDB. Patients who received subtotal resection (STR) or gross-total resection (GTR) were compared to those who received no tumor debulking surgery. Univariable and multivariable analyses of both overall survival and cause-specific survival were performed.

Results: EOR was associated with increased overall survival for both histologically confirmed oligodendrogliomas and all 1p/19q-codeleted-defined tumors (p < 0.001 and p = 0.002, respectively). Tumor grade, location, and size covaried predictably with EOR. When evaluating tumors by each classification system for predictors of overall survival, facility setting, age, comorbidity index, grade, location, chemotherapy, and radiation therapy were all shown to be significantly associated with overall survival. STR and GTR were independent predictors of improved survival in historically classified oligodendrogliomas (HR 0.83, p = 0.18; HR 0.69, p = 0.01, respectively) and in 1p/19q-codeleted tumors (HR 0.49, p < 0.01; HR 0.43, p < 0.01, respectively).

Conclusions: By using the NCDB, the authors have demonstrated a side-by-side comparison of the survival benefits of greater EOR in 1p/19q-codeleted gliomas.
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http://dx.doi.org/10.3171/2020.2.JNS192767DOI Listing
May 2020

HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models.

J Clin Invest 2020 07;130(7):3699-3716

Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.

The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect-related super-enhancers. Extracellular flux and carbon-tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc-dependent manner and lowered ATP levels. This resulted in the engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/-2 elicited a suppression of c-Myc protein levels and a concomitant increase in 2 transcriptional drivers of oxidative metabolism, PGC1α and PPARD, suggesting an inverse relationship. Rescue and ChIP experiments indicated that c-Myc bound to the promoter regions of PGC1α and PPARD to counteract their upregulation driven by HDAC1/-2 inhibition. Finally, we demonstrated that combination treatment with HDAC and FAO inhibitors extended animal survival in patient-derived xenograft model systems in vivo more potently than single treatments in the absence of toxicity.
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http://dx.doi.org/10.1172/JCI129049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324177PMC
July 2020

Glioma-Induced Alterations in Neuronal Activity and Neurovascular Coupling during Disease Progression.

Cell Rep 2020 04;31(2):107500

Laboratory for Functional Optical Imaging, Zuckerman Mind Brain Behavior Institute, Departments of Biomedical Engineering and Radiology, Columbia University, New York, NY 10027, USA. Electronic address:

Diffusely infiltrating gliomas are known to cause alterations in cortical function, vascular disruption, and seizures. These neurological complications present major clinical challenges, yet their underlying mechanisms and causal relationships to disease progression are poorly characterized. Here, we follow glioma progression in awake Thy1-GCaMP6f mice using in vivo wide-field optical mapping to monitor alterations in both neuronal activity and functional hemodynamics. The bilateral synchrony of spontaneous neuronal activity gradually decreases in glioma-infiltrated cortical regions, while neurovascular coupling becomes progressively disrupted compared to uninvolved cortex. Over time, mice develop diverse patterns of high amplitude discharges and eventually generalized seizures that appear to originate at the tumors' infiltrative margins. Interictal and seizure events exhibit positive neurovascular coupling in uninfiltrated cortex; however, glioma-infiltrated regions exhibit disrupted hemodynamic responses driving seizure-evoked hypoxia. These results reveal a landscape of complex physiological interactions occurring during glioma progression and present new opportunities for exploring novel biomarkers and therapeutic targets.
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http://dx.doi.org/10.1016/j.celrep.2020.03.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443283PMC
April 2020

Lentiviral Vector Induced Modeling of High-Grade Spinal Cord Glioma in Minipigs.

Sci Rep 2020 03 24;10(1):5291. Epub 2020 Mar 24.

Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA.

Background: Prior studies have applied driver mutations targeting the RTK/RAS/PI3K and p53 pathways to induce the formation of high-grade gliomas in rodent models. In the present study, we report the production of a high-grade spinal cord glioma model in pigs using lentiviral gene transfer.

Methods: Six Gottingen Minipigs received thoracolumbar (T14-L1) lateral white matter injections of a combination of lentiviral vectors, expressing platelet-derived growth factor beta (PDGF-B), constitutive HRAS, and shRNA-p53 respectively. All animals received injection of control vectors into the contralateral cord. Animals underwent baseline and endpoint magnetic resonance imaging (MRI) and were evaluated daily for clinical deficits. Hematoxylin and eosin (H&E) and immunohistochemical analysis was conducted. Data are presented using descriptive statistics including relative frequencies, mean, standard deviation, and range.

Results: 100% of animals (n = 6/6) developed clinical motor deficits ipsilateral to the oncogenic lentiviral injections by a three-week endpoint. MRI scans at endpoint demonstrated contrast enhancing mass lesions at the site of oncogenic lentiviral injection and not at the site of control injections. Immunohistochemistry demonstrated positive staining for GFAP, Olig2, and a high Ki-67 proliferative index. Histopathologic features demonstrate consistent and reproducible growth of a high-grade glioma in all animals.

Conclusions: Lentiviral gene transfer represents a feasible pathway to glioma modeling in higher order species. The present model is the first lentiviral vector induced pig model of high-grade spinal cord glioma and may potentially be used in preclinical therapeutic development programs.
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http://dx.doi.org/10.1038/s41598-020-62167-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093438PMC
March 2020

Transferrin Receptor Is a Specific Ferroptosis Marker.

Cell Rep 2020 03;30(10):3411-3423.e7

Department of Biological Sciences, Columbia University, Northwest Corner Building, 12th Floor, MC 4846, 550 West 120(th) Street, New York, NY 10027, USA; Department of Chemistry, Columbia University, Northwest Corner Building, 12th Floor, MC 4846, 550 West 120(th) Street, New York, NY 10027, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address:

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models or patient samples. We address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin and screening ∼4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We find that one antibody, 3F3 ferroptotic membrane antibody (3F3-FMA), is effective as a selective ferroptosis-staining reagent. The antigen of 3F3-FMA is identified as the human transferrin receptor 1 protein (TfR1). We validate this finding with several additional anti-TfR1 antibodies and compare them to other potential ferroptosis-detecting reagents. We find that anti-TfR1 and anti-malondialdehyde adduct antibodies are effective at staining ferroptotic tumor cells in multiple cell culture and tissue contexts.
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http://dx.doi.org/10.1016/j.celrep.2020.02.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172030PMC
March 2020

Misclassification of Diffuse Gliomas-Letter.

Clin Cancer Res 2020 03;26(5):1198

Department of Radiation Oncology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.

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http://dx.doi.org/10.1158/1078-0432.CCR-19-3257DOI Listing
March 2020

From cells to tissue: How cell scale heterogeneity impacts glioblastoma growth and treatment response.

PLoS Comput Biol 2020 02 26;16(2):e1007672. Epub 2020 Feb 26.

Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida, United States of America.

Glioblastomas are aggressive primary brain tumors known for their inter- and intratumor heterogeneity. This disease is uniformly fatal, with intratumor heterogeneity the major reason for treatment failure and recurrence. Just like the nature vs nurture debate, heterogeneity can arise from intrinsic or environmental influences. Whilst it is impossible to clinically separate observed behavior of cells from their environmental context, using a mathematical framework combined with multiscale data gives us insight into the relative roles of variation from different sources. To better understand the implications of intratumor heterogeneity on therapeutic outcomes, we created a hybrid agent-based mathematical model that captures both the overall tumor kinetics and the individual cellular behavior. We track single cells as agents, cell density on a coarser scale, and growth factor diffusion and dynamics on a finer scale over time and space. Our model parameters were fit utilizing serial MRI imaging and cell tracking data from ex vivo tissue slices acquired from a growth-factor driven glioblastoma murine model. When fitting our model to serial imaging only, there was a spectrum of equally-good parameter fits corresponding to a wide range of phenotypic behaviors. When fitting our model using imaging and cell scale data, we determined that environmental heterogeneity alone is insufficient to match the single cell data, and intrinsic heterogeneity is required to fully capture the migration behavior. The wide spectrum of in silico tumors also had a wide variety of responses to an application of an anti-proliferative treatment. Recurrent tumors were generally less proliferative than pre-treatment tumors as measured via the model simulations and validated from human GBM patient histology. Further, we found that all tumors continued to grow with an anti-migratory treatment alone, but the anti-proliferative/anti-migratory combination generally showed improvement over an anti-proliferative treatment alone. Together our results emphasize the need to better understand the underlying phenotypes and tumor heterogeneity present in a tumor when designing therapeutic regimens.
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http://dx.doi.org/10.1371/journal.pcbi.1007672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062288PMC
February 2020

Fluorescein-guided resection of gliomas.

J Neurosurg Sci 2019 Dec;63(6):648-655

Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY, USA.

Standard of care in the management of high-grade gliomas includes gross total resection (GTR) followed by treatment with radiation and temozolomide. GTR remains one of the few independent prognostic factors for improved survival in this disease. Sodium fluorescein is an organic fluorophore that has been studied as a surgical adjunct to improve the likelihood of achieving GTR in gliomas. Though sodium fluorescein does not selectively accumulate in glioma cells, it allows for real-time identification of regions of blood brain barrier breakdown, corresponding to the contrast-enhancing cores of high-grade gliomas. In addition to its high predictive value for identifying pathologic tissue, use of fluorescein has been shown to improve rates of GTR. In stereotactic needle biopsies, it helps reduce procedure time by rapidly confirming the presence of diagnostic tissue. Furthermore, in non-enhancing, low-grade gliomas, it labels focal regions of vascular dysregulation that have been correlated with high-grade features. Fluorescein has also been shown to be significantly less expensive than other contemporary surgical adjuncts such as intraoperative ultrasound, intraoperative MRI, and the recently FDA approved fluorophore, 5-aminolevulinic acid (5-ALA). Here, we review the current literature on the effectiveness of fluorescein as a surgical tool in the resection of gliomas.
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http://dx.doi.org/10.23736/S0390-5616.19.04738-6DOI Listing
December 2019

Near real-time intraoperative brain tumor diagnosis using stimulated Raman histology and deep neural networks.

Nat Med 2020 01 6;26(1):52-58. Epub 2020 Jan 6.

Department of Neurological Surgery, Columbia University, New York, NY, USA.

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH), a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min). In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.
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http://dx.doi.org/10.1038/s41591-019-0715-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960329PMC
January 2020

Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers.

ACS Chem Biol 2020 02 14;15(2):469-484. Epub 2020 Jan 14.

Department of Biological Sciences , Columbia University , New York , New York 10027 , United States.

Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through system x inhibition or GPX4 inhibition synergize with radiation to induce ferroptosis in several cancer types by enhancing cytoplasmic lipid peroxidation but not increasing DNA damage or caspase activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the antitumor effect of radiation in a murine xenograft model and in human patient-derived models of lung adenocarcinoma and glioma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.
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http://dx.doi.org/10.1021/acschembio.9b00939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180072PMC
February 2020

Toward a standard pathological and molecular characterization of recurrent glioma in adults: a Response Assessment in Neuro-Oncology effort.

Neuro Oncol 2020 04;22(4):450-456

Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Regardless of subtype, diffuse gliomas of adulthood are characterized by inexorable progression through treatment. Cancer recurrence in the context of therapy is by no means unique to gliomas. For many tumors residing outside the central nervous system (CNS), tissue-based analyses are routinely employed to document the molecular and cellular features of disease recurrence. Such interventions are inconsistently applied for gliomas, however, and lack rigorous standardization when they are. While many of the reasons underlying these discrepancies reflect pragmatic realities inherent to CNS disease, the suboptimal employment of histological and molecular assessment at recurrence nevertheless represents a missed opportunity to proactively guide patient management and increase knowledge. Herein, we address this quandary by pairing a succinct description of the histological, biological, and molecular characteristics of recurrent glioma with recommendations for how to better standardize and implement quality pathological assessment into patient management. We hope this review will prompt thoughtful revision of standard operating procedures to maximize the utility of glioma re-biopsy.
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http://dx.doi.org/10.1093/neuonc/noz233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158649PMC
April 2020

Ex vivo multi-electrode analysis reveals spatiotemporal dynamics of ictal behavior at the infiltrated margin of glioma.

Neurobiol Dis 2020 02 12;134:104676. Epub 2019 Nov 12.

Department of Neurology, Columbia University Medical Center, New York, NY, USA.

The purpose of this study is to develop a platform in which the cellular and molecular underpinnings of chronic focal neocortical lesional epilepsy can be explored and use it to characterize seizure-like events (SLEs) in an ex vivo model of infiltrating high-grade glioma. Microelectrode arrays were used to study electrophysiologic changes in ex vivo acute brain slices from a PTEN/p53 deleted, PDGF-B driven mouse model of high-grade glioma. Electrode locations were co-registered to the underlying histology to ascertain the influence of the varying histologic landscape on the observed electrophysiologic changes. Peritumoral, infiltrated, and tumor sites were sampled in tumor-bearing slices. Following the addition of zero Mg solution, all three histologic regions in tumor-bearing slices showed significantly greater increases in firing rates when compared to the control sites. Tumor-bearing slices demonstrated increased proclivity for SLEs, with 40 events in tumor-bearing slices and 5 events in control slices (p-value = .0105). Observed SLEs were characterized by either low voltage fast (LVF) onset patterns or short bursts of repetitive widespread, high amplitude low frequency discharges. Seizure foci comprised areas from all three histologic regions. The onset electrode was found to be at the infiltrated margin in 50% of cases and in the peritumoral region in 36.9% of cases. These findings reveal a landscape of histopathologic and electrophysiologic alterations associated with ictogenesis and spread of tumor-associated seizures.
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http://dx.doi.org/10.1016/j.nbd.2019.104676DOI Listing
February 2020

SETD2 Mutation in an Aggressive Optic Nerve Glioma.

JAMA Ophthalmol 2020 Jan;138(1):102-104

Ophthalmic Plastic and Reconstructive Surgery, Orbital Surgery Division, Department of Ophthalmology, New York Presbyterian Hospital, Columbia University Irving Medical Center, New York.

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http://dx.doi.org/10.1001/jamaophthalmol.2019.4511DOI Listing
January 2020

MET Inhibition Elicits PGC1α-Dependent Metabolic Reprogramming in Glioblastoma.

Cancer Res 2020 01 6;80(1):30-43. Epub 2019 Nov 6.

Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.

The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-C-glucose, U-C-glutamine, and U-C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and β-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy. SIGNIFICANCE: c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942623PMC
January 2020

Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl-xL inhibition.

EMBO Mol Med 2019 10 29;11(10):e10769. Epub 2019 Aug 29.

Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY, USA.

Liver-X-receptor (LXR) agonists are known to bear anti-tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti-proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U- C-glucose and U- C-glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing their stability. In turn, energy starvation drives an integrated stress response (ISR) that up-regulates pro-apoptotic Noxa in an ATF4-dependent manner. Cholesterol and nucleotides rescue from the ISR elicited by LXR agonists and from cell death induced by LXR agonists and BH3 mimetics. In conventional and patient-derived xenograft models of colon carcinoma, melanoma, and glioblastoma, the combination treatment of ABT263 and LXR agonists reduces tumor sizes significantly stronger than single treatments. Therefore, the combination treatment of LXR agonists and BH3 mimetics might be a viable efficacious treatment approach for solid malignancies.
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http://dx.doi.org/10.15252/emmm.201910769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783693PMC
October 2019