Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.

Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.

Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma.

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

A CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics.

Combination chemotherapy is crucial for successfully treating cancer. However, the enormous number of possible drug combinations means discovering safe and effective combinations remains a significant challenge. To improve this process, we conduct large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics. We prioritize neuroblastoma, the most common extracranial pediatric solid tumor, where ~50% of high-risk patients do not survive. Our screen examines all druggable gene knockouts in 18 cell lines (10 neuroblastoma, 8 others) treated with 8 widely used drugs, resulting in 94,320 unique combination-cell line perturbations, which is comparable to the largest existing drug combination screens. Using dense drug-drug rescreening, we find that the top CRISPR-nominated drug combinations are more synergistic than standard-of-care combinations, suggesting existing combinations could be improved. As proof of principle, we discover that inhibition of PRKDC, a component of the non-homologous end-joining pathway, sensitizes high-risk neuroblastoma cells to the standard-of-care drug doxorubicin in vitro and in vivo using patient-derived xenograft (PDX) models. Our findings provide a valuable resource and demonstrate the feasibility of using targeted CRISPR knockout to discover combinations with common chemotherapeutics, a methodology with application across all cancers.

7-Dehydrocholesterol Encapsulated Polymeric Nanoparticles As a Radiation-Responsive Sensitizer for Enhancing Radiation Therapy.

Therapeutics that can be activated by radiation in situ to enhance the efficacy of radiotherapy are highly desirable. Herein, 7-Dehydrocholesterol (7-DHC), a biosynthetic precursor of cholesterol, as a radiosensitizer, exploiting its ability to propagate the free radical chain reaction is explored. The studies show that 7-DHC can react with radiation-induced reactive oxygen species and in turn promote lipid peroxidation, double-strand breaks, and mitochondrial damage in cancer cells. For efficient delivery, 7-DHC is encapsulated into poly(lactic-co-glycolic acid) nanoparticles, forming 7-DHC@PLGA NPs. When tested in CT26 tumor bearing mice, 7-DHC@PLGA NPs significantly enhanced the efficacy of radiotherapy, causing complete tumor eradication in 30% of the treated animals. After treatment, 7-DHC is converted to cholesterol, causing no detectable side effects or hypercalcemia. 7-DHC@PLGA NPs represent a radiation-responsive sensitizer with great potential in clinical translation.

Monodisperse nanoparticles for catalysis and nanomedicine.

The growth and breadth of nanoparticle (NP) research now encompasses many scientific and technologic fields, which has driven the want to control NP dimensions, structures and properties. Recent advances in NP synthesis, especially in solution phase synthesis, and characterization have made it possible to tune NP sizes and shapes to optimize NP properties for various applications. In this review, we summarize the general concepts of using solution phase chemistry to control NP nucleation and growth for the formation of monodisperse NPs with polyhedral, cubic, octahedral, rod, or wire shapes and complex multicomponent heterostructures. Using some representative examples, we demonstrate how to use these monodisperse NPs to tune and optimize NP catalysis of some important energy conversion reactions, such as the oxygen reduction reaction, electrochemical carbon dioxide reduction, and cascade dehydrogenation/hydrogenation for the formation of functional organic compounds under greener chemical reaction conditions. Monodisperse NPs with controlled surface chemistry, morphologies and magnetic properties also show great potential for use in biomedicine. We highlight how monodisperse iron oxide NPs are made biocompatible and target-specific for biomedical imaging, sensing and therapeutic applications. We intend to provide readers some concrete evidence that monodisperse NPs have been established to serve as successful model systems for understanding structure-property relationships at the nanoscale and further to show great potential for advanced nanotechnological applications.

Nanoparticles to mediate X-ray-induced photodynamic therapy and Cherenkov radiation photodynamic therapy.

Photodynamic therapy (PDT) has emerged as an attractive option for cancer treatment. However, conventional PDT is activated by light that has poor tissue penetration depths, limiting its applicability in the clinic. Recently the idea of using X-ray sources to activate PDT and overcome the shallow penetration issue has garnered significant interest. This can be achieved by external beam irradiation and using a nanoparticle scintillator as transducer. Alternatively, research on exploiting Cherenkov radiation from radioisotopes to activate PDT has also begun to flourish. In either approach, the most auspicious success is achieved using nanoparticles as either a scintillator or a photosensitizer to mediate energy transfer and radical production. Both X-ray induced PDT (X-PDT) and Cherenkov radiation PDT (CR-PDT) contain a significant radiation therapy (RT) component and are essentially PDT and RT combination. Unlike the conventional combination, however, in X-PDT and CR-PDT, one energy source simultaneously activates both processes, making the combination always in synchronism and the synergy potential maximized. While still in early stage of development, X-PDT and CR-PDT address important issues in the clinic and hold great potential in translation. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Nanoparticle-Laden Macrophages for Tumor-Tropic Drug Delivery.

Macrophages hold great potential in cancer drug delivery because they can sense chemotactic cues and home to tumors with high efficiency. However, it remains a challenge to load large amounts of therapeutics into macrophages without compromising cell functions. This study reports a silica-based drug nanocapsule approach to solve this issue. The nanocapsule consists of a drug-silica complex filling and a solid silica sheath, and it is designed to minimally release drug molecules in the early hours of cell entry. While taken up by macrophages at high rates, the nanocapsules minimally affect cell migration in the first 6-12 h, buying time for macrophages to home to tumors and release drugs in situ. In particular, it is shown that doxorubicin (Dox) as a representative drug can be loaded into macrophages up to 16.6 pg per cell using this approach. When tested in a U87MG xenograft model, intravenously (i.v.) injected Dox-laden macrophages show comparable tumor accumulation as untreated macrophages. Therapy leads to efficient tumor growth suppression, while causing little systematic toxicity. This study suggests a new cell platform for selective drug delivery, which can be readily extended to the treatment of other types of diseases.

Oxygenating the way for enhanced chemophototherapy.

Hypoxia is behind tumor resistance in both chemotherapy and photodynamic therapy. This editorial highlights a study by Cai et al. [12] that a hemoglobin and human serum albumin hybrid protein nanoparticle can simultaneously deliver O2, chemotherapeutics, and photosensitizers to tumors for enhanced chemophototherapy.

Surface impact on nanoparticle-based magnetic resonance imaging contrast agents.

Magnetic resonance imaging (MRI) is one of the most widely used diagnostic tools in the clinic. To improve imaging quality, MRI contrast agents, which can modulate local T1 and T2 relaxation times, are often injected prior to or during MRI scans. However, clinically used contrast agents, including Gd3+-based chelates and iron oxide nanoparticles (IONPs), afford mediocre contrast abilities. To address this issue, there has been extensive research on developing alternative MRI contrast agents with superior r1 and r2 relaxivities. These efforts are facilitated by the fast progress in nanotechnology, which allows for preparation of magnetic nanoparticles (NPs) with varied size, shape, crystallinity, and composition. Studies suggest that surface coatings can also largely affect T1 and T2 relaxations and can be tailored in favor of a high r1 or r2. However, the surface impact of NPs has been less emphasized. Herein, we review recent progress on developing NP-based T1 and T2 contrast agents, with a focus on the surface impact.