The novel BET inhibitor UM-002 reduces glioblastoma cell proliferation and invasion

Bromodomain and extraterminal domain (BET) proteins have emerged as therapeutic targets in multiple cancers, including the most common primary adult brain tumor glioblastoma (GBM). Although several BET inhibitors have entered clinical trials, few are brain penetrant. We have generated UM-002, a novel brain penetrant BET inhibitor that reduces GBM cell proliferation in vitro and in a human cerebral brain organoid model. Since UM-002 is more potent than other BET inhibitors, it could potentially be developed for GBM treatment. Furthermore, UM-002 treatment reduces the expression of cell-cycle related genes in vivo and reduces the expression of invasion related genes within the non-proliferative cells present in tumors as measured by single cell RNA-sequencing. These studies suggest that BET inhibition alters the transcriptional landscape of GBM tumors, which has implications for designing combination therapies. Importantly, they also provide an integrated dataset that combines in vitro and ex vivo studies with in vivo single-cell RNA-sequencing to characterize a novel BET inhibitor in GBM

Immunotherapy and Epigenetic Pathway Modulation in Glioblastoma Multiforme

Glioblastoma Multiforme (GBM) is the most common malignant primary brain tumor. Despite aggressive multimodality treatment it remains one of the most challenging and intractable cancers (1]. While current standard of care treatment for GBM is maximal safe surgical resection, systemic chemotherapy with Temozolimide (TMZ), and radiation therapy, the current prognosis of GBM patients remains poor, with a median overall survival of 12–15 months (2, 3). Therefore, other treatments are needed to provide better outcomes for GBM patients. Immunotherapy is one of the most promising new cancer treatment approaches. Immunotherapy drugs have obtained regulatory approval in a variety of cancers including melanoma (4), Hodgkin lymphoma (5), and non-small cell lung cancer (6). The basis of immunotherapy in cancer treatment is linked to stimulating the immune system to recognize cancer cells as foreign, thereby leading to the eventual elimination of the tumor. One form of immunotherapy utilizes vaccines that target tumor antigens (7), while other approaches utilize T-cells in patients to stimulate them to attack tumor cells (8). Despite intensive efforts all approaches have not been overtly successful (9), suggesting that we need to better understand the underlying biology of tumor cells and their environment as they respond to immunotherapy. Recent studies have elucidated epigenetic pathway regulation of GBM tumor expansion (10), suggesting that combined epigenetic pathway inhibition with immunotherapy may be feasible. In this review, we discuss current GBM clinical trials and how immune system interactions with epigenetic pathways and signaling nodes can be delineated to uncover potential combination therapies for this incurable disease

The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling

Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding of IMiDs to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates for degradation. Despite this clinical significance, the physiological regulation of CRBN remains largely unknown. Herein we demonstrate that Wnt, the extracellular ligand of an essential signal transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins. These substrates include Casein kinase 1α (CK1α), a negative regulator of Wnt signaling that functions as a key component of the β-Catenin destruction complex. Wnt stimulation induces the interaction of CRBN with CK1α and its resultant ubiquitination, and in contrast with previous reports does so in the absence of an IMiD. Mechanistically, the destruction complex is critical in maintaining CK1α stability in the absence of Wnt, and in recruiting CRBN to target CK1α for degradation in response to Wnt. CRBN is required for physiological Wnt signaling, as modulation of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes. These studies demonstrate an IMiD-independent, Wnt-driven mechanism of CRBN regulation and provide a means of controlling Wnt pathway activity by CRBN, with relevance for development and disease

CDKs Give Cdc6 a License to Drive into S Phase

The accumulation of Cdc6 promotes the initiation of DNA replication. In this issue of Cell, Mailand and Diffley (2005) show that phosphorylation of Cdc6 by cyclin-dependent kinases prevents its destruction by the anaphase promoting complex (APC). This simple mechanism explains how the APC simultaneously spares Cdc6 while targeting for destruction suppressors of DNA replication during the transition from quiescence to cell cycle reentry

Neuroinflammation Treatment via Targeted Delivery of Nanoparticles

The lack of effective treatments for most neurological diseases has prompted the search for novel therapeutic options. Interestingly, neuroinflammation is emerging as a common feature to target in most CNS pathologies. Recent studies suggest that targeted delivery of small molecules to reduce neuroinflammation can be beneficial. However, suboptimal drug delivery to the CNS is a major barrier to modulate inflammation because neurotherapeutic compounds are currently being delivered systemically without spatial or temporal control. Emerging nanomaterial technologies are providing promising and superior tools to effectively access neuropathological tissue in a controlled manner. Here we highlight recent advances in nanomaterial technologies for drug delivery to the CNS. We propose that state-of-the-art nanoparticle drug delivery platforms can significantly impact local CNS bioavailability of pharmacological compounds and treat neurological diseases

Sororin, a Substrate of the Anaphase- Promoting Complex, Is Required for Sister Chromatid Cohesion in Vertebrates

We have identified a regulator of sister chromatid cohesion in a screen for cell cycle-controlled proteins. This 35 kDa protein is degraded through anaphase-promoting complex (APC)-dependent ubiquitination in G1. The protein is nuclear in interphase cells, dispersed from the chromatin in mitosis, and interacts with the cohesin complex. In Xenopus embryos, overexpression of the protein causes failure to resolve and segregate sister chromatids in mitosis and an increase in the level of cohesin associated with metaphase chromosomes. In cultured cells, depletion of the protein causes mitotic arrest and complete failure of sister chromatid cohesion. This protein is thus an essential, cell cycle-dependent mediator of sister chromatid cohesion. Based on sequence analysis, this protein has no apparent orthologs outside of the vertebrates. We speculate that the protein, which we have named sororin, regulates the ability of the cohesin complex to mediate sister chromatid cohesion, perhaps by altering the nature of the interaction of cohesin with the chromosomes

An overview of human single-cell RNA sequencing studies in neurobiological disease

Neurobiological disorders are highly prevalent medical conditions that contribute to significant morbidity and mortality. Single-cell RNA sequencing (scRNA-seq) is a technique that measures gene expression in individual cells. In this review, we survey scRNA-seq studies of tissues from patients suffering from neurobiological disease. This includes postmortem human brains and organoids derived from peripheral cells. We highlight a range of conditions, including epilepsy, cognitive disorders, substance use disorders, and mood disorders. These findings provide new insights into neurobiological disease in multiple ways, including discovering novel cell types or subtypes involved in disease, proposing new pathophysiological mechanisms, uncovering novel drug targets, or identifying potential biomarkers. We discuss the quality of these findings and suggest potential future directions and areas open for additional research, including studies of non-cortical brain regions and additional conditions such as anxiety disorders, mood disorders, and sleeping disorders. We argue that additional scRNA-seq of tissues from patients suffering from neurobiological disease could advance our understanding and treatment of these conditions

Epigenetic pathways and plasticity in brain tumors

Clinical studies have shown that treating many primary brain tumors is challenging due in part to the lack of safe and effective compounds that cross the blood brain barrier (BBB) (Tan et al., 2018). However, if we were to imagine that we have ideal BBB penetrant compounds that target brain tumor cells selectively, recent studies suggest that those compounds may still not be effective due to the heterogenous nature of the tumors. In other words, there are many subsets of cells within a brain tumor, and compounds that target all those different populations are needed. This is a considerable challenge. Targeting of the cell-of-origin of these brain tumors is equally important. And yet another impediment we face is that brain tumor cells-of-origin may be protean and are able to differentiate into other cell types to drive recurrence. Therefore, an ideal BBB-penetrant compound targeting a cell-of-origin in a brain tumor may be ineffective due to the cell's ability to differentiate into another resistant cell type. One possible means of combating the plastic nature of these cells is targeting epigenetic pathways used by the cells to differentiate into other cell types along with standard treatment regimens. We summarize here some of the epigenetic pathways that have been shown to be active in three different primary brain tumors, glioblastoma (GBM), medulloblastoma (MB), and diffuse intrinsic pontine glioma (DIPG). We also compare recent single-cell RNA sequencing analyses of these tumors in order to identify common epigenetic pathways to treat the respective cells-of-origin for these tumors. Lastly, we discuss possible combination therapies that may be generalizable for treating these and other brain tumors using multi-omics approaches. While our focus on these three tumor types is not exhaustive and certainly other brain tumors can have similar mechanisms, there has been significant recent evidence linking epigenetics, plasticity, and intratumor heterogeneity in these tumors