The role of homeobox genes in retinal development and disease

AbstractHomeobox genes are an evolutionarily conserved class of transcription factors that are critical for development of many organ systems, including the brain and eye. During retinogenesis, homeodomain-containing transcription factors, which are encoded by homeobox genes, play essential roles in the regionalization and patterning of the optic neuroepithelium, specification of retinal progenitors and differentiation of all seven of the retinal cell classes that derive from a common progenitor. Homeodomain transcription factors control retinal cell fate by regulating the expression of target genes required for retinal progenitor cell fate decisions and for terminal differentiation of specific retinal cell types. The essential role of homeobox genes during retinal development is demonstrated by the number of human eye diseases, including colobomas and anophthalmia, which are attributed to homeobox gene mutations. In the following review, we highlight the role of homeodomain transcription factors during retinogenesis and regulation of their gene targets. Understanding the complexities of vertebrate retina development will enhance our ability to drive differentiation of specific retinal cell types towards novel cell-based replacement therapies for retinal degenerative diseases

A multi-institutional retrospective pooled outcome analysis of molecularly annotated pediatric supratentorial ZFTA-fused ependymoma

BACKGROUND ZFTA-RELA (formerly known as c11orf-RELA) fused supratentorial ependymoma (ZFTAfus ST-EPN) has been recognized as a novel entity in the 2016 WHO classification of CNS tumors and further defined in the recent 2021 edition. ZFTAfus ST-EPN was reported to portend poorer prognosis when compared to its counterpart, YAP1 ST-EPN in some previously published series. The aim of this study was to determine the treatment outcome of molecularly confirmed and conventionally treated ZFTAfus ST-EPN patients treated in multiple institutions. METHODS We conducted a retrospective analysis of all pediatric patients with molecularly confirmed ZFTAfus ST-EPN patients treated in multiple institutions in 5 different countries (Australia, Canada, Germany, Switzerland, and Czechia). Survival outcomes were analyzed and correlated with clinical characteristics and treatment approaches. RESULTS A total of 108 patients were collated from multiple institutions in 5 different countries across three continents. We found across the entire cohort that the 5- and 10-year PFS were 65% and 63%, respectively. The 5- and 10-year OS of this cohort of patients were 87% and 73%. The rates of gross total resection (GTR) were high with 84 out of 108 (77.8%) patients achieving GTR. The vast majority of patients also received post-operative radiotherapy, 98 out of 108 (90.7%). Chemotherapy did not appear to provide any survival benefit in our patient cohort. CONCLUSION This is the largest study to date of contemporaneously treated molecularly confirmed ZFTAfus ST-EPN patients which identified markedly improved survival outcomes compared to previously published series. This study also re-emphasizes the importance of maximal surgical resection in achieving optimal outcomes in pediatric patients with supratentorial ependymoma

Dlx2 homeobox gene transcriptional regulation of Trkb neurotrophin receptor expression during mouse retinal development

Dlx homeobox genes are first expressed in embryonic retina at E11.5. The Dlx1/Dlx2 null retina has a reduced ganglion cell layer (GCL), with loss of late-born differentiated retinal ganglion cells (RGCs) due to increased apoptosis. TrkB signaling is proposed to regulate the dynamics of RGC apoptosis throughout development. DLX2 expression markedly precedes the onset of TrkB expression in the GCL; TrkB co-expression with Dlx2 and RGC markers is well-established by E13.5. In the Dlx1/Dlx2 null retina, TrkB expression is significantly reduced by E16.5. We demonstrated that DLX2 binds to a specific region of the TrkB promoter in retinal neuroepithelium during embryogenesis. In vitro confirmation and the functional consequences of DLX2 binding to this TrkB regulatory region support TrkB as a Dlx2 transcriptional target. Furthermore, ectopic Dlx2 expression in retinal explants activates TrkB expression and Dlx2 knockdown in primary retinal cultures results in reduced TrkB expression. RGC differentiation and survival require the coordinated expression of transcription factors. This study establishes a direct transcriptional relationship between a homeodomain protein involved in RGC differentiation and a neurotrophin receptor implicated in RGC survival. Signaling mediated by TrkB may contribute to survival of late-born RGCs whose terminal differentiation is regulated by Dlx gene function

Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma

Background Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound-ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc. Methods Authenticity of GsONC201 was determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Biological activity was shown via assessment of on-target effects, in vitro growth, proliferation, and apoptosis analysis. Patient-derived xenograft mouse models were used to assess plasma and brain tissue pharmacokinetics, pharmacodynamics, and overall survival (OS). The clinical experience of 28 H3K27M+ mutant DIPG patients who received GsONC201 (2017-2020) was analyzed. Results GsONC201 harbored the authentic structure, however, was formulated as a free base rather than the dihydrochloride salt used in clinical trials. GsONC201 in vitro and in vivo efficacy and drug bioavailability studies showed no difference compared to Oncoceutics ONC201. Patients treated with GsONC201 (n = 28) showed a median OS of 18 months (P = .0007). GsONC201 patients who underwent reirradiation showed a median OS of 22 months compared to 12 months for GsONC201 patients who did not (P = .012). Conclusions This study confirms the biological activity of GsONC201 and documents the OS of patients who received the drug; however, GsONC201 was never used as a monotherapy

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. (C) 2017 by American Society of Clinical Oncolog