scholarly journals FBXW11 is differentially expressed in diffuse intrinsic pontine glioma and associates with survival.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Patient Outcomes ◽  
Brain Cancer ◽  
Patient Survival ◽  
Treatment Options ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
The Poor ◽  
Genes Encoding ◽  
Poor Treatment ◽  
Median Survival Rate

Diffuse intrinsic pontine glioma (DIPG) has the lowest median survival rate of any cancer. 99% of patients will expire within 5 years (1). The poor treatment options for this brain cancer (2) demand understanding of the basic manner in which DIPG function at the level of gene expression. By comparing the tumor transcriptomes of patients with DIPG that survived more or less than six months using a published dataset (3), we found that four of the genes whose expression was most different between these patients were genes encoding Fbox proteins. Moreover, the expression of one of these genes, FBXW11, was significantly associated with patient survival. This is the first report documenting differential expression of Fbox proteins in the tumors of patients with DIPG and their association with patient outcomes.

scholarly journals Genes encoding histone proteins are differentially expressed between men and women with diffuse intrinsic pontine glioma and their expression correlates with survival.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Brain Cancer ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Histone Genes ◽  
Histone H4 ◽  
Pontine Glioma ◽  
Histone H2b ◽  
Men And Women ◽  
Genes Encoding ◽  
Pediatric Brain ◽  
Median Survival Rate

Diffuse intrinsic pontine glioma is a pediatric brain cancer and has the lowest median survival rate of all cancers known to man (1). 99% of patients diagnosed with DIPG will expire within 5 years (1). Understanding the transcriptional behavior of tumors in DIPG is critical for the development of novel therapies. In this study, I compared the transcriptomes of tumors from men with DIPG versus that of tumors from women diagnosed with DIPG using a published dataset (2). I found that three histone genes, including HIST1H4C, HIST1H2BD, and HIST1H3D, which encode Histone H4, Histone H2B Type 1D, and Histone H3.1 were among the genes whose expression was most different between the DIPG tumors of men and women. Importantly, the expression level of two of these genes significantly correlated in a linear fashion with the amount of time the patient survived. It has previously been reported that 78% of DIPG tumors contain a mutation in Histone H3.1 (HIST1H3B) (3). This is the first report of differential expression of histone genes in tumors of patients with DIPG.

scholarly journals DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii294-iii295
Author(s):  
Jovana Pavisic ◽  
Chankrit Sethi ◽  
Chris Jones ◽  
Stergios Zacharoulis ◽  
Andrea Califano
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Treatment Options ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Low Grade ◽  
Precision Oncology ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Master Regulator

Abstract Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with no effective drugs to date. Mutation-based precision oncology approaches are limited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease drivers—master regulator proteins (MRs)—in DIPG to expand treatment options. Using the metaVIPER algorithm, we interrogated an integrated low grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective in murine proneural gliomas in which TOP2 was identified as a MR while RRM2—targetable by drugs such as cladribine—has been shown to be a positive regulator of glioma progression whose knock-down inhibits tumor growth. We also prioritized drugs by their ability to reverse MR-activity signatures using a large drug-perturbation database. Patients clustered by predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which have early evidence in treating gliomas. We will refine this analysis in a multi-institutional study of >100 patient gene expression profiles to define MR signatures driving known biological/molecular disease subtypes, use DIPG cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.

scholarly journals Advances in systemic therapy for advanced pancreatobiliary malignancies

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 105
Author(s):  
Thorvardur R Halfdanarson ◽  
Sigurdis Haraldsdottir ◽  
Mitesh J Borad
Keyword(s):  
Radiation Therapy ◽  
Systemic Therapy ◽  
Patient Survival ◽  
Advanced Disease ◽  
Treatment Options ◽  
Locally Advanced ◽  
Current Treatment ◽  
Targeted Treatments ◽  
Poor Treatment ◽  
Novel Approaches

Pancreatobiliary malignancies are relatively uncommon and the overall prognosis is poor. Treatment options for advanced disease are limited to systemic therapy for metastatic disease and a combination of systemic therapy and radiation therapy for locally advanced but unresectable tumors. There have been significant advances in the treatment of pancreatobiliary cancers in recent years but the prognosis for patient survival remains disappointingly poor. We review the current treatment options for locally advanced pancreatobiliary malignancies and highlight recent advances in systemic therapy, including novel approaches using targeted treatments.

scholarly journals Repression of RNA message for F-box proteins in the tumors of patients with glioblastoma.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
Brain Cancer ◽  
Gene Expression Analysis ◽  
Normal Brain ◽  
Significant Differential Expression ◽  
Differential Gene Expression Analysis ◽  
Genes Encoding ◽  
Differential Gene ◽  
The Brain ◽  
Median Survival Rate

Glioblastoma is the most common brain cancer in adults and has a 15 month median survival rate (1, 2). We performed differential gene expression analysis, comparing the glioblastoma transcriptome from 17 patients to the transcriptome of 8 non-affected, “normal” brain samples using a published dataset (3). Three separate genes encoding F-box proteins (4), including FBXW7, FBXO41, and FBXL16 were differentially expressed and at significantly lower levels in the tumors of patients with glioblastoma than in the brain. Significant differential expression of FBXW7, FBXO41 and FBXL16 was also observed in glioblastomas from the REMBRANDT study (5).

scholarly journals In diffuse intrinsic pontine gliomas, non-coding RNA expression is significantly varied dependent on overall survival

2021 ◽  
Author(s):  
Rucha ◽  
Vijay S
Keyword(s):  
Overall Survival ◽  
Brain Cancer ◽  
Transcriptional Activity ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Rna Expression ◽  
Pontine Glioma ◽  
Non Coding Rna ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
New Treatments ◽  
Pediatric Brain

Abstract Diffuse intrinsic pontine glioma is a kind of pediatric brain cancer that kills 99 percent of patients within five years and for which there are no conventional chemotherapies. It is crucial for new treatments to comprehend the cancer's transcriptional activity. Using a published dataset, we compared the transcriptomes of tumors from patients who lived longer or less than six months. Among the genes whose expression changed most, we observed that numerous microRNAs and snoRNAs were present. The publication's findings are the first evidence of variable levels of non-coding RNA expression in diffuse intrinsic pontine glioma.

scholarly journals PDTM-04. EARLY DETECTION BY MRI OF MOUSE MODELS WITH DIFFUSE INTRINSIC PONTINE GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi187-vi187
Author(s):  
Lincy Thomas ◽  
Rheal Towner ◽  
Rafal Gulej ◽  
Nataliya Smith ◽  
Michelle Zalles ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Treatment Options ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Control Group ◽  
Pontine Glioma ◽  
Dismal Prognosis ◽  
Magnetic Resonance Imaging Mri ◽  
Tumor In Childhood

Abstract Diffuse intrinsic pontine glioma (DIPG) is the most common brainstem tumor in childhood with a very devastating prognosis and no curative treatment options as of yet. Approximately 300 children in the U.S. are diagnosed with DIPG each year. Our project hopes to assess the effectiveness of OKlahoma Nitrone-007 (OKN-007) as a therapeutic agent for DIPG. This agent has shown promise in prior studies involving pediatric glioma mouse models by decreasing growth of blood vessels, which is essential for any tumor progression, and by decreasing temozolomide (TMZ) resistance when used as adjunct therapy in adult GBM. We have successfully created an in vivo DIPG model using post-mortem patient-derived neurospheres, harboring the H3 K27M mutation, injected into the pontine region of immunocompromised mouse (SCID) brainstems via a stereotaxic device. After surgical implantation, mice are imaged every week using a 7.0 Tesla 30-cm bore Bruker Biospec Magnetic Resonance Imaging (MRI) system to assess tumor growth and progression of disease. We describe to you the first pre-clinical DIPG mouse model that shows evidence of tumor growth as early as 42 days, as detected on T2-weighted MR images. Another characteristic feature is that the blood-brain barrier (BBB) is intact in this DIPG model, as assessed by contrast-enhanced MRI. Additional MRI methods, including diffusion-weighted imaging (DWI), and perfusion imaging (arterial spin labeling) are also evaluated. Prior pre-clinical DIPG mouse models only had tumor detection by MRI 78 days after implantation. Once the tumors are large enough for treatment (clinically relevant), we separate the mice into a control group (no treatment), OKN-007 treatment alone, as well as combination therapy with OKN-007 and TMZ. With the dismal prognosis and limited effective chemotherapy available for DIPG, there is significant room for continued research studies to help clinicians better understand and treat pediatric DIPG patients.

scholarly journals Non-coding RNA are differentially expressed in diffuse intrinsic pontine gliomas based on overall survival.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
Brain Cancer ◽  
Expression Profiling ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Novel Therapies ◽  
Pontine Glioma ◽  
Non Coding Rna ◽  
Differential Gene ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
Pediatric Brain

Diffuse intrinsic pontine glioma is a pediatric brain cancer; 99% of patients diagnosed with this disease will expire within 5 years (1) and there are no standard chemotherapies available for it (2). Understanding the transcriptional behavior of this cancer is critical for the development of novel therapies. We performed global differential gene expression profiling of tumors from patients with DIPG by comparing the transcriptomes of tumors from those who survived greater or less than six months using a published dataset (3). We found that multiple microRNAs and snoRNAs were among the genes whose expression was most different between those who survived greater or less than six months. This is the first report of outcome-associated differential expression of non-coding RNA in diffuse intrinsic pontine glioma.

scholarly journals Iroquois transcription factors are perturbed in diffuse intrinsic pontine glioma.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Brain Cancer ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Differentially Expressed ◽  
Normal Brain ◽  
Pontine Glioma ◽  
Control Brain ◽  
Cancer Transcriptome ◽  
Tissue Of Origin ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
The Brain

The brain cancer diffuse intrinsic pontine glioma (DIPG) is the most fatal of all cancers with a 5-year survival rate of less than 1%, meaning greater than 99% of patients diagnosed with DIPG will expire within 5 years (1). Systems-level analyses of the cancer transcriptome compared to the tissue from which it arises presents a unique opportunity to gain insights into the transcriptional behavior of each cancer and how it differs from its tissue of origin (2). In this study I used published microarray data to compare the DIPG tumor transcirptomes to that of the normal brain (3). In both datasets, I found differential expression of an Iroquois transcription factor in DIPG tumors: in one dataset, IRX2, IRX5 and IRX3 were among the most differentially expressed genes in the tumors of patients with DIPG, and in a separate dataset, IRX4 was significantly differentially expressed when compared to control brain tissues. IRX proteins may be important molecules in the biology of diffuse intrinsic pontine gliomas.

scholarly journals RNA helicase DDX52 is produced in significantly higher quantities in the tumors of males with DIPG.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Pediatric Cancer ◽  
Sex Chromosome ◽  
Rna Helicase ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Men And Women ◽  
The Poor ◽  
Basic Understanding ◽  
Tissue Of Origin ◽  
Poor Outcomes

Diffuse intrinsic pontine glioma (DIPG) is a pediatric cancer with the worst prognosis of any cancer known to man. 99% of patients will expire within 5 years (1). The poor outcomes in this disease demand a basic understanding of the transcriptional behavior of DIPG tumors, how they differ from the tissue of origin and how they differ between patients. We compared the transcriptomes of tumors from men and women diagnosed with the disease using a published dataset (2) to more thoroughly understand sex-specific transcriptional differences in cancer and found that RNA helicase DDX52 (3) was among the genes most differentially expressed based on the sex of the patient. DDX52 is not located on a sex chromosome. Multiple DDX genes have been found to be dysregulated in a variety of cancers (4-16); this is the first report of dysregulation of a DDX gene in males with diffuse intrinsic pontine glioma.

scholarly journals RTHP-36. REIRRADIATION FOR DIFFUSE INTRINSIC PONTINE GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF PATIENT OUTCOMES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi217-vi217
Author(s):  
Victor Lu ◽  
John Welby ◽  
Nadia Laack ◽  
Anita Mahajan ◽  
David Daniels
Keyword(s):  
Systematic Review ◽  
Patient Outcomes ◽  
Meta Analysis ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Limited Evidence ◽  
Dismal Prognosis ◽  
Clinical Consequences ◽  
Pediatric Brain

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor with dismal prognosis despite initial radiation therapy (RT). The clinical consequences of attempting reirradiation (reRT) in these patients to alleviate both symptomatology and improve prognosis are currently unclear. Thus, the aim of this systematic review and meta-analysis was to clarify the efficacy and safety of reRT in DIPG. METHODS Searches of 7 electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against pre-specified criteria. The incidence and duration of clinical outcomes were then extracted and pooled by means of meta-analysis from the included studies. RESULTS A total of 7 studies satisfied all criteria, describing 90 cases of DIPG in which reRT was attempted 11.8–14 months after initial RT. Based on a random-effects model, the incidences of clinical improvement and radiologic response following reRT were 87% (95% CI, 78–95%) and 69% (95% CI, 52–84%) respectively. The incidence of acute serious toxicity was 0% (95% CI, 0–4%). Pooled overall survivals from initial diagnosis, and time of reRT, were 18.0 months (95% CI, 14.2–21.7) and 6.2 months (95% CI, 5.5–7.0) respectively. CONCLUSIONS Based on these results, the clinical consequences of reRT for DIPG when administered appropriately and safely at first progression appear acceptable, and potentially favorable, based on the limited evidence in the current literature. Concerns regarding acute serious toxicity were not realized. It is likely a sub-cohort of all DIPG diagnoses will be most amenable to improved prognosis with reRT, and greater investigation is required to identify their characteristics.

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