CDK4/6 and diffuse intrinsic pontine glioma - Evaluate at diagnosis?
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ABSTRACT:
SUBMITTER: Becher OJ
PROVIDER: S-EPMC6604365 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
Publications
CDK4/6 and diffuse intrinsic pontine glioma - Evaluate at diagnosis?
EBioMedicine 20190513
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2014-03-31 | E-GEOD-50025 | biostudies-arrayexpress
Project description:Purpose of reviewThis review of diffuse intrinsic pontine glioma (DIPG) provides clinical background, a systematic approach to diagnosis and initial care, and synthesizes historical, modern, and future directions for treatment. We present evidence supporting neurosurgical biopsy, early palliative care involvement, limitation of glucocorticoid use, and the leveraging of preclinical DIPG models as a pipeline to next-generation clinical trials.Recent findingsNew molecular understanding of pediatric high-grade gliomas has led to the reclassification of DIPG as one member of a family of diffuse gliomas occurring in the midline of the central nervous system that exhibit pathognomonic mutations in genes encoding histone 3 (H3 K27M). DIPG remains a clinically relevant term, though diagnostically the 80% of DIPG cases that exhibit the H3 K27M mutation have been reclassified as diffuse midline glioma, H3 K27M-mutant. Re-irradiation has been shown to be well-tolerated and of potential benefit. Epigenetic targeting of transcriptional dependencies in preclinical models is fueling molecularly targeted clinical trials. Chimeric antigen receptor T cell immunotherapy has also demonstrated efficacy in preclinical models and provides a promising new clinical strategy. DIPG is a universally fatal, epigenetically driven tumor of the pons that is considered part of a broader class of diffuse midline gliomas sharing H3 K27M mutations. Radiation remains the standard of care, single-agent temozolomide is not recommended, and glucocorticoids should be used only sparingly. A rapid evolution of understanding in the chromatin, signaling, and immunological biology of DIPG may soon result in clinical breakthroughs.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2014-03-31 | GSE50025 | GEO
Project description: Not available
| S-EPMC4161623 | biostudies-literature
Project description:Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor with a peak incidence in middle childhood and a median survival of less than 1 year. The dismal prognosis associated with DIPG has been exacerbated by the failure of over 250 clinical trials to meaningfully improve survival compared with radiotherapy, the current standard of care. The traditional practice to not biopsy DIPG led to a scarcity in available tissue samples for laboratory analysis that till recently hindered therapeutic advances. Over the past few years, the acquisition of patient derived tumor samples through biopsy and autopsy protocols has led to distinct breakthroughs in the identification of key oncogenic drivers implicated in DIPG development. Aberrations have been discovered in critical genetic drivers including histone H3, ACVR1, TP53, PDGFRA, and Myc. Mutations, previously not identified in other malignancies, highlight DIPG as a distinct biological entity. Identification of novel markers has already greatly influenced the direction of preclinical investigations and offers the exciting possibility of establishing biologically targeted therapies. This review will outline the current knowledge of the genomic landscape related to DIPG, overview preclinical investigations, and reflect how biological advances have influenced the focus of clinical trials toward targeted therapies.
| S-EPMC5368268 | biostudies-literature
Project description:Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology.
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Project description:Diffuse intrinsic pontine gliomas (DIPGs) are invariably fatal tumors found in the pons of elementary school aged children. These tumors are grade II-IV gliomas, with a median survival of less than 1 year from diagnosis when treated with standard of care (SOC) therapy. Nanotechnology may offer therapeutic options for the treatment of DIPGs. Multiple nanoparticle formulations are currently being investigated for the treatment of DIPGs. Nanoparticles based upon stable elements, polymer nanoparticles, and organic nanoparticles are under development for the treatment of brain tumors, including DIPGs. Targeting of nanoparticles is now possible as delivery techniques that address the difficulty in crossing the blood brain barrier (BBB) are developed. Theranostic nanoparticles, a combination of therapeutics and diagnostic nanoparticles, improve imaging of the cancerous tissue while delivering therapy to the local region. However, additional time and attention should be directed to developing a nanoparticle delivery system for treatment of the uniformly fatal pediatric disease of DIPG.
| S-EPMC5327462 | biostudies-literature
Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare but uniformly fatal cancer of the brain, with peak incidence in children of 5-7 years of age. In contrast to most types of human cancer, there has been no significant improvement in treatment outcomes for patients with DIPG. Since DIPG occurs in the brainstem, a vital region of the brain, there are no surgical options for providing relief to patients, and chemotherapy as well as radiation therapy provide palliative relief at best. To date, more than 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy, as well as newer biologic agents, have failed to improve the dismal outcome when compared with palliative radiation alone. The recent discovery of somatic oncogenic histone gene mutations affecting chromatin regulation in DIPG has dramatically improved our understanding of the disease pathogenesis in DIPG, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. This review will discuss about the role of histone modification in chromatin machinery and epigenetic therapeutic strategies for the treatment of DIPG.
| S-EPMC5566706 | biostudies-literature
Project description:Diffuse intrinsic pontine glioma is a lethal brain cancer that arises in the pons of children. The median survival for children with diffuse intrinsic pontine glioma is less than 1 year from diagnosis, and no improvement in survival has been realized in more than 30 years. Currently, the standard of care for diffuse intrinsic pontine glioma is focal radiation therapy, which provides only temporary relief. Recent genomic analysis of tumors from biopsies and autopsies, have resulted in the discovery of K27M H3.3/H3.1 mutations in 80% and ACVR1 mutations in 25% of diffuse intrinsic pontine gliomas, providing renewed hope for future success in identifying effective therapies. In addition, as stereotactic tumor biopsies at diagnosis at specialized centers have been demonstrated to be safe, biopsies have now been incorporated into several prospective clinical trials. This article summarizes the epidemiology, clinical presentation, diagnosis, prognosis, molecular genetics, current treatment, and future therapeutic directions for diffuse intrinsic pontine glioma.
| S-EPMC6025797 | biostudies-literature
Project description:Diffuse intrinsic pontine glioma (DIPG) is an aggressive tumor that is universally fatal, and to-date we are at a virtual standstill in improving its grim prognosis. Dearth of tissue due to rarity of biopsy has precluded understanding the elusive biology and frustration continues in reproducing faithful animal models for translational research. Furthermore the intricate anatomy of the pons has forestalled locoregional therapy and drug penetration. Over the last few years, biopsy-driven targeted therapy, development of vitro and xenograft animal models for therapeutic testing, profiling immunotherapeutic strategies and locoregional infusion of drugs in brain stem tumors, now provide a sense of hope in the years ahead. This review aims to discuss current status and advances in the management of these tumors.
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