H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, ...and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments.
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•H3.3K27M mutations enhance glucose, glutamine, and TCA cycle metabolism•TCA cycle intermediate α-KG enables maintenance of H3K27 hypomethylation•Targeting enzymes related to α-KG synthesis including WT-IDH1 and/or GDH is therapeutic•H3.3K27M and mutant-IDH1 in gliomas are mutually exclusive and are synthetic lethal
Chung et al. show that H3.3K27M mutation in DIPGs enhances glycolysis and TCA cycle metabolism to produce α-KG that is required to maintain a preferred epigenetic state of low H3K27me3. Inhibiting enzymes related to α-KG production increases H3K27me3 and results in anti-tumor activity in mouse models of DIPG.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose: The presence of disseminated tumor cells (DTC) in the bone marrow of breast cancer patients is an acknowledged independent
prognostic factor. The biological metastatic potential of these ...cells has not yet been shown. The presence of putative breast
cancer stem cells is shown both in primary tumors and distant metastases. These cells with a CD44 + CD24 −/low phenotype represent a minor population in primary breast cancer and are associated with self-renewal and tumorigenic potential.
Recognizing the potential effect of prevalence of putative stem cells among DTC, we evaluated the bone marrow DTC.
Experimental Design: We employed the double/triple-staining immunohistochemistry protocol and modified the established bone marrow cytokeratin
(CK) staining protocol by adding steps for additional antigens, CD44 and/or CD24. We evaluated 50 bone marrow specimens, previously
categorized as CK + from early breast cancer patients. CK + cells were examined for CD44 and CD24 expression by light microscopy, fluorescence microscopy, and spectral imaging.
Results: We detected the putative stem cell–like phenotype in all CK + specimens. The mean prevalence of putative stem/progenitor cells was 72% and median prevalence was 65% (range, 33-100%) among
the overall DTC per patient, compared with primary tumors where this phenotype is reported in <10% of cells.
Conclusions: This is the first evidence of the existence of the putative stem-like phenotype within the DTC in bone marrow in early breast
cancer patients. All patients had a putative stem cell phenotype among the DTC and most individual DTC showed such phenotype.
Future molecular characterization of these cells is warranted.
The survival of patients with non-small-cell lung cancer (NSCLC), even when resectable, remains poor. Several small studies suggest that occult metastases (OMs) in pleura, bone marrow (BM), or lymph ...nodes (LNs) are present in early-stage NSCLC and are associated with a poor outcome. We investigated the prevalence of OMs in resectable NSCLC and their relationship with survival.
Eligible patients had previously untreated, potentially resectable NSCLC. Saline lavage of the pleural space, performed before and after pulmonary resection, was examined cytologically. Rib BM and all histologically negative LNs (N0) were examined for OM, diagnosed by cytokeratin immunohistochemistry (IHC). Survival probabilities were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazards regression model were used to compare survival of groups of patients. P < .05 was considered significant.
From July 1999 to March 2004, 1,047 eligible patients (538 men and 509 women; median age, 67.2 years) were entered onto the study, of whom 50% had adenocarcinoma and 66% had stage I NSCLC. Pleural lavage was cytologically positive in only 29 patients. OMs were identified in 66 (8.0%) of 821 BM specimens and 130 (22.4%) of 580 LN specimens. In univariate and multivariable analyses OMs in LN but not BM were associated with significantly worse disease-free survival (hazard ratio HR, 1.50; P = .031) and overall survival (HR, 1.58; P = .009).
In early-stage NSCLC, LN OMs detected by IHC identify patients with a worse prognosis. Future clinical trials should test the role of IHC in identifying patients for adjuvant therapy.
Integration of molecular data with histologic, radiologic, and clinical features is imperative for accurate diagnosis of pediatric central nervous system (CNS) tumors. Whole transcriptome RNA ...sequencing (RNAseq), a genome-wide and non-targeted approach, allows for the detection of novel or rare oncogenic fusion events that contribute to the tumorigenesis of a substantial portion of pediatric low- and high-grade glial and glioneuronal tumors. We present two cases of pediatric glioneuronal tumors occurring in the occipital region with a CLIP2::MET fusion detected by RNAseq. Chromosomal microarray studies revealed copy number alterations involving chromosomes 1, 7, and 22 in both tumors, with Case 2 having an interstitial deletion breakpoint in the CLIP2 gene. By methylation profiling, neither tumor had a match result, but both clustered with the low-grade glial/glioneuronal tumors in the UMAP. Histologically, in both instances, our cases displayed characteristics of a low-grade tumor, notably the absence of mitotic activity, low Ki-67 labeling index and the lack of necrosis and microvascular proliferation. Glial and neuronal markers were positive for both tumors. Clinically, both patients achieved clinical stability post-tumor resection and remain under regular surveillance imaging without adjuvant therapy at the last follow-up, 6 months and 3 years, respectively. This is the first case report demonstrating the presence of a CLIP2::MET fusion in two pediatric low-grade glioneuronal tumors (GNT). Conservative clinical management may be considered for patients with GNT and CLIP2:MET fusion in the context of histologically low-grade features.
Medulloblastoma (MB) is a malignant, heterogenous brain tumor. Advances in molecular profiling have led to identifying four molecular subgroups of MB (WNT, SHH, Group 3, Group 4), each with distinct ...clinical behaviors. We hypothesize that (1) aggressive MB tumors, growing heterogeneously, induce pronounced local structural deformations in the surrounding parenchyma, and (b) these local deformations as captured on Gadolinium (Gd)-enhanced-T1w MRI are independently associated with molecular subgroups, as well as overall survival in MB patients.
In this work, a total of 88 MB studies from 2 institutions were analyzed. Following tumor delineation, Gd-T
scan for every patient was registered to a normal age-specific T
-MRI template via deformable registration. Following patient-atlas registration, local structural deformations in the brain parenchyma were obtained for every patient by computing statistics from deformation magnitudes obtained from every 5mm annular region, 0 < d < 60 mm, where d is the distance from the tumor infiltrating edge.
Multi-class comparison via ANOVA yielded significant differences between deformation magnitudes obtained for Group 3, Group 4, and SHH molecular subgroups, observed up to 60-mm outside the tumor edge. Additionally, Kaplan-Meier survival analysis showed that the local deformation statistics, combined with the current clinical risk-stratification approaches (molecular subgroup information and Chang's classification), could identify significant differences between high-risk and low-risk survival groups, achieving better performance results than using any of these approaches individually.
These preliminary findings suggest there exists significant association of our tumor-induced deformation descriptor with overall survival in MB, and that there could be an added value in using the proposed radiomic descriptor along with the current risk classification approaches, towards more reliable risk assessment in pediatric MB.
Leptomeningeal metastasis remains a difficult clinical challenge. Some success has been achieved by direct administration of therapeutics into the cerebrospinal fluid (CSF) circumventing limitations ...imposed by the blood brain barrier. Here we investigated continuous infusion versus bolus injection of therapy into the CSF in a preclinical model of human Group 3 medulloblastoma, the molecular subgroup with the highest incidence of leptomeningeal disease. Initial tests of selected Group 3 human medulloblastoma cell lines in culture showed that D283 Med and D425 Med were resistant to cytosine arabinoside and methotrexate. D283 Med cells were also resistant to topotecan, whereas 1 μM topotecan killed over 99% of D425 Med cells. We therefore introduced D425 Med cells, modified to express firefly luciferase, into the CSF of immunodeficient mice. Mice were then treated with topotecan or saline in five groups: continuous intraventricular (IVT) topotecan via osmotic pump (5.28 μg/day), daily bolus IVT topotecan injections with a similar daily dose (6 μg/day), systemic intraperitoneal injections of a higher daily dose of topotecan (15 μg/day), daily IVT pumped saline and daily intraperitoneal injections of saline. Bioluminescence analyses revealed that both IVT topotecan treatments effectively slowed leptomeningeal tumor growth in the brains. Histological analysis showed that they were associated with localized brain necrosis, possibly due to backtracking of topotecan around the catheter. In the spines, bolus IVT topotecan showed a trend towards slower tumor growth compared to continuous (pump) IVT topotecan, as measured by bioluminescence. Both continuous and bolus topotecan IVT showed longer survival compared to other groups. Thus, both direct IVT topotecan CSF delivery methods produced better anti-medulloblastoma effect compared to systemic therapy at the dosages used here.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The receptor tyrosine kinase EphB2 is expressed by colon progenitor cells; however, only 39% of colorectal tumors express EphB2 and expression levels decline with disease progression. Conversely, ...EphB4 is absent in normal colon but is expressed in all 102 colorectal cancer specimens analyzed, and its expression level correlates with higher tumor stage and grade. Both EphB4 and EphB2 are regulated by the Wnt pathway, the activation of which is critically required for the progression of colorectal cancer. Differential usage of transcriptional coactivator cyclic AMP-responsive element binding protein-binding protein (CBP) over p300 by the Wnt/beta-catenin pathway is known to suppress differentiation and increase proliferation. We show that the beta-catenin-CBP complex induces EphB4 and represses EphB2, in contrast to the beta-catenin-p300 complex. Gain of EphB4 provides survival advantage to tumor cells and resistance to innate tumor necrosis factor-related apoptosis-inducing ligand-mediated cell death. Knockdown of EphB4 inhibits tumor growth and metastases. Our work is the first to show that EphB4 is preferentially induced in colorectal cancer, in contrast to EphB2, whereby tumor cells acquire a survival advantage.
Summary Chemotherapy resistance is a significant contributor to treatment failure and death in men with hormone-refractory prostate cancer. One unexplored mechanism for drug resistance is the ...induction of stress response proteins referred to as the glucose-regulated proteins (GRPs). We sought to determine the level of expression of GRP78, the best characterized GRP in lymph node–positive prostate cancer. Archived, paraffin-embedded, radical prostatectomy specimens were obtained from 153 patients with lymph node–positive prostate cancer (stage D1). The level of GRP78 expression was determined by immunohistochemistry. We assessed the expression and specificity of GRP78 immunoreactivity in benign prostatic tissue, prostate cancer, and lymph node metastasis. We correlated the intensity of immunopositivity with prostate cancer recurrence and survival. Whereas immunohistochemical staining demonstrated that all prostate tissue was immunoreactive for GRP78, the intensity of expression was markedly higher in the primary tumor compared with areas of benign epithelium. GRP78 expression was also evident in lymph node metastases although less intensely than in the primary tumor. Patients with strong GRP78 immunoreactivity in the primary tumor are at higher risk for clinical recurrence (relative risk = 2.0, P = .019) and death (relative risk = 1.8, P = .024) than patients with weak GRP78 expression. This finding confirms that GRP78 protein expression is significantly higher in prostate cancer than in benign prostatic tissue. The intensity of expression is significantly associated with survival and clinical recurrence. GRP78 has considerable potential not only as a prognostic indicator but also as a potential therapeutic target.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background: Induction of molecular chaperone Grp78 (78-kDa glucose-regulated protein) occurs in stress conditions that often characterize
tumor microenvironments. We investigated the role of Grp78 in ...prostate cancer progression and the development of castration
resistance, where cancer cells continue to survive despite the stress of an androgen-starved environment.
Experimental Design: Immunohistochemistry was done to examine Grp78 expression in 219 prostate cancers from patients with pathologic stage T 3 N 0 M 0 disease androgen ablation naive (untreated) and androgen ablation exposed (treated) and castration-resistant prostate cancer.
Classification of tumors was based on intensity of Grp78 cytoplasmic immunoreactivity and percentage of immunoreactive tumor
cells. The associations of Grp78 expression with prostate cancer recurrence (clinical and/or serum prostate-specific antigen)
and survival were examined in the untreated stage T 3 N 0 M 0 group. Grp78 expression was also analyzed in the androgen-dependent LNCaP and castration-resistant C42B cell lines.
Results: The percentage of tumor cells expressing Grp78 was strongly associated with castration-resistant status ( P = 0.005). Increased Grp78 expression was consistently associated with greater risk of prostate cancer recurrence and worse
overall survival in patients who had not undergone prior hormonal manipulation. Grp78 expression was also increased in the
castration-resistant LNCaP-derived cell line C42B and in LNCaP cells grown in androgen-deprived conditions compared with LNCaP
cells grown in androgen-rich media.
Conclusion: Our findings show that up-regulation of Grp78 is associated with the development of castration resistance, possibly in part
by augmenting cell survival as previously suggested, and may serve as an important prognostic indicator of recurrence in a
subset of patients with T 3 N 0 M 0 disease.
•Layer specific quantitative MRI (qMRI) estimates of dentate gyrus in AD are reported.•T2, R2, and SWI values were significantly correlated with neurofilament.•T2, R2, and SWI values were ...significantly correlated with neurofibrillary tangle.•High-resolution qMRI has clinical utility given the pathological specificity.
The dentate gyrus (DG) is an integral portion of the hippocampal formation, and it is composed of three layers. Quantitative magnetic resonance (MR) imaging has the capability to map brain tissue microstructural properties which can be exploited to investigate neurodegeneration in Alzheimer’s disease (AD). However, assessing subtle pathological changes within layers requires high resolution imaging and histological validation. In this study, we utilized a 16.4 Tesla scanner to acquire ex vivo multi-parameter quantitative MRI measures in human specimens across the layers of the DG. Using quantitative diffusion tensor imaging (DTI) and multi-parameter MR measurements acquired from AD (N = 4) and cognitively normal control (N = 6) tissues, we performed correlation analyses with histological measurements. Here, we found that quantitative MRI measures were significantly correlated with neurofilament and phosphorylated Tau density, suggesting sensitivity to layer-specific changes in the DG of AD tissues.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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