ABSTRACT
We describe the utilization of SpaceOAR Vue™, a new iodinated rectal spacer, during Robotic Stereotactic Body Radiation Therapy (SBRT) for a Prostate Cancer Patient with a contraindication to Magnetic Resonance Imaging. A 69-year-old Caucasian male presented with unfavorable intermediate risk prostate cancer and elected to undergo SBRT. His medical history was significant for atrial fibrillation on Rivaroxaban with a pacemaker. He was felt to be at increased risk of radiation proctitis following SBRT due to the inability to accurately contour the anterior rectal wall at the prostate apex without a treatment planning MRI and an increased risk of late rectal bleeding due to prescribed anticoagulants. In this case report, we discuss the technical aspects of appropriate placement and treatment planning for utilizing SpaceOAR Vue™ with Robotic SBRT.
ABSTRACT
Nuclear protein in testis (NUT) carcinoma (NC) is a rare, distinctly aggressive subtype of squamous carcinoma defined by the presence of NUT-fusion oncogenes resulting from chromosomal translocation. In most cases, the NUT gene (NUTM1) is fused to bromodomain containing 4 (BRD4) forming the BRD4-NUT oncogene. Here, a novel fusion partner to NUT was discovered using next-generation sequencing and FISH from a young patient with an undifferentiated malignant round cell tumor. Interestingly, the NUT fusion identified involved ZNF592, a zinc finger containing protein, which was previously identified as a component of the BRD4-NUT complex. In BRD4-NUT-expressing NC cells, wild-type ZNF592 and other associated "Z4" complex proteins, including ZNF532 and ZMYND8, colocalize with BRD4-NUT in characteristic nuclear foci. Furthermore, ectopic expression of BRD4-NUT in a non-NC cell line induces sequestration of Z4 factors to BRD4-NUT foci. Finally, the data demonstrate the specific dependency of NC cells on Z4 modules, ZNF532 and ZNF592. IMPLICATIONS: This study establishes the oncogenic role of Z4 factors in NC, offering potential new targeted therapeutic strategies in this incurable cancer.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/12/1826/F1.large.jpg.
Subject(s)
Carcinoma, Squamous Cell/genetics , DNA-Binding Proteins/genetics , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Oncogene Proteins, Fusion/genetics , Tumor Suppressor Proteins/metabolism , Adolescent , Cell Line, Tumor , Cell Nucleus/genetics , Cell Nucleus/metabolism , Cell Survival , DNA-Binding Proteins/metabolism , Female , High-Throughput Nucleotide Sequencing , Humans , In Situ Hybridization, Fluorescence , Neoplasm Proteins/metabolism , Nuclear Proteins/metabolism , Oncogene Proteins, Fusion/metabolism , Sequence Analysis, DNAABSTRACT
Bromodomains have been pursued intensively over the past several years as emerging targets for the development of anticancer and anti-inflammatory agents. It has recently been shown that some kinase inhibitors are able to potently inhibit the bromodomains of BRD4. The clinical activities of PLK inhibitor BI-2536 and JAK2-FLT3 inhibitor TG101348 have been attributed to this unexpected polypharmacology, indicating that dual-kinase/bromodomain activity may be advantageous in a therapeutic context. However, for target validation and biological investigation, a more selective target profile is desired. Here, we report that benzo[e]pyrimido-[5,4- b]diazepine-6(11H)-ones, versatile ATP-site directed kinase pharmacophores utilized in the development of inhibitors of multiple kinases, including several previously reported kinase chemical probes, are also capable of exhibiting potent BRD4-dependent pharmacology. Using a dual kinase-bromodomain inhibitor of the kinase domains of ERK5 and LRRK2, and the bromodomain of BRD4 as a case study, we define the structure-activity relationships required to achieve dual kinase/BRD4 activity, as well as how to direct selectivity toward inhibition of either ERK5 or BRD4. This effort resulted in identification of one of the first reported kinase-selective chemical probes for ERK5 (JWG-071), a BET selective inhibitor with 1 µM BRD4 IC50 (JWG-115), and additional inhibitors with rationally designed polypharmacology (JWG-047, JWG-069). Co-crystallography of seven representative inhibitors with the first bromodomain of BRD4 demonstrate that distinct atropisomeric conformers recognize the kinase ATP-site and the BRD4 acetyl lysine binding site, conformational preferences supported by rigid docking studies.
