PSMA-PET Detection of Unusual Metastases in Castrate-Sensitive Prostate Carcinoma.

Prostate cancer (PCa) is a multifaceted, heterogeneous disease (with 7 molecular subtypes), which can metastasize to common sites, such as bone, lymph nodes, liver, and lungs. However, with PSMA PET imaging, rare sites of metastasis are increasingly discovered. We report 5 cases of unusual metastases in patients with castrate-sensitive PCa: solitary right inguinal nodal metastasis, solitary abdominal wall metastasis, penile shaft metastases, solitary perineum metastasis, and pleural metastases.

Enhancing SIRT1 Gene Expression Using Small Activating RNAs: A Novel Approach for Reversing Metabolic Syndrome.

Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Sirtuin 1 (SIRT1), a highly conserved histone deacetylase, is characterized as a key metabolic regulator and protector against aging-associated pathologies, including MetS. In this study, we investigate the therapeutic potential of activating SIRT1 using small activating RNAs (saRNA), thereby reducing inflammatory-like responses and re-establishing normal lipid metabolism.

MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models.

The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models.

Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug.

Targeted delivery of oligonucleotides to liver hepatocytes using N-acetylgalactosamine (GalNAc) conjugates that bind to the asialoglycoprotein receptor has become a breakthrough approach in the therapeutic oligonucleotide field. This technology has led to the approval of givosiran for the treatment of acute hepatic porphyria, and there are another seven conjugates in registrational review or phase 3 trials and at least another 21 conjugates at earlier stages of clinical development. This review highlights some of the recent chemical and preclinical advances in this space, leading to a large number of clinical candidates against a diverse range of targets in liver hepatocytes.

MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial.

Purpose: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α.

Patients And Methods: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases.

Adoption of hypofractionated radiation therapy for early breast cancer in private practice: the GenesisCare experience 2014–2016.

Introduction: Cancer Australia guidelines recommend that hypofractionation should be considered for women over the age of 50 years with early breast cancer. GenesisCare is the largest provider of radiation therapy services in Australia. This study aimed to investigate variation in hypofractionation across 4 states encompassing the period when the most recent guidelines had been released.

Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice.

Excessive or inappropriate inflammatory responses can cause serious and even fatal diseases. The CCAAT/enhancer-binding protein alpha (CEBPA) gene encodes C/EBPα, a transcription factor that plays a fundamental role in controlling maturation of the myeloid lineage and is also expressed during the late phase of inflammatory responses when signs of inflammation are decreasing. MTL-CEBPA, a small activating RNA targeting for upregulation of C/EBPα, is currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma.

Intensity-modulated Radiotherapy for Anal Cancer: Dose-Volume Relationship of Acute Gastrointestinal Toxicity and Disease Outcomes.

Aims: Intensity-modulated radiotherapy (IMRT) is increasingly used in the treatment delivery of chemoradiotherapy in anal cancer with the ability to reduce toxicity. We report on 4 year outcomes since the introduction of IMRT and identify the most predictive bowel organ at risk that correlates with acute diarrhoea.

Materials And Methods: Fifty-eight patients receiving definitive chemoradiotherapy for squamous or basaloid cell anal carcinoma (T1-4NanyM0) were reviewed.

Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer.

Liver diseases are a growing epidemic worldwide. If unresolved, liver fibrosis develops and can lead to cirrhosis and clinical decompensation. Around 5% of cirrhotic liver diseased patients develop hepatocellular carcinoma (HCC), which in its advanced stages has limited therapeutic options and negative survival outcomes.

Development and Mechanism of Small Activating RNA Targeting CEBPA, a Novel Therapeutic in Clinical Trials for Liver Cancer.

Small activating RNAs (saRNAs) are short double-stranded oligonucleotides that selectively increase gene transcription. Here, we describe the development of an saRNA that upregulates the transcription factor CCATT/enhancer binding protein alpha (CEBPA), investigate its mode of action, and describe its development into a clinical candidate. A bioinformatically directed nucleotide walk around the CEBPA gene identified an saRNA sequence that upregulates CEBPA mRNA 2.

Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS.

Activating mutations in underlie the pathogenesis of up to 20% of human tumors, and is one of the most frequently mutated genes in cancer. Developing therapeutics to block KRAS activity has proven difficult, and no direct inhibitor of KRAS function has entered clinical trials. We describe the preclinical evaluation of AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting mRNA.

AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer.

Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver.

Identification of novel vascular targets in lung cancer.

Background: Lung cancer remains the leading cause of cancer-related death, largely owing to the lack of effective treatments. A tumour vascular targeting strategy presents an attractive alternative; however, the molecular signature of the vasculature in lung cancer is poorly explored. This work aimed to identify novel tumour vascular targets in lung cancer.

Novel neutralizing hedgehog antibody MEDI-5304 exhibits antitumor activity by inhibiting paracrine hedgehog signaling.

The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays.

Inhibition of platelet-derived growth factor receptor α by MEDI-575 reduces tumor growth and stromal fibroblast content in a model of non-small cell lung cancer.

Platelet-derived growth factor receptor α (PDGFRα) is a receptor tyrosine kinase that promotes cell survival and is expressed in both the tumor and the stromal components of human cancers. We have developed a fully human monoclonal antibody, MEDI-575, that selectively binds to human PDGFRα with high affinity, with no observable affinity for murine PDGFRα. To more fully characterize the role of PDGFRα in the regulation of tumor stroma, we evaluated the in vivo antitumor effects of MEDI-575 in tumor-bearing severe combined immunodeficient (SCID) mice and in genetically altered SCID mice expressing human PDGFRα in place of murine PDGFRα.

A screening tool to prioritize public health risk associated with accidental or deliberate release of chemicals into the atmosphere.

The Chemical Events Working Group of the Global Health Security Initiative has developed a flexible screening tool for chemicals that present a risk when accidentally or deliberately released into the atmosphere. The tool is generic, semi-quantitative, independent of site, situation and scenario, encompasses all chemical hazards (toxicity, flammability and reactivity), and can be easily and quickly implemented by non-subject matter experts using freely available, authoritative information. Public health practitioners and planners can use the screening tool to assist them in directing their activities in each of the five stages of the disaster management cycle.

Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology.

Enhanced permeability of the tumor vasculature allows macromolecules to enter the tumor interstitial space, whereas the suppressed lymphatic filtration allows them to stay there. This phenomenon, enhanced permeability and retention (EPR), has been the basis of nanotechnology platforms to deliver drugs to tumors. However, progress in developing effective drugs using this approach has been hampered by heterogeneity of EPR effect in different tumors and limited experimental data from patients on effectiveness of this mechanism as related to enhanced drug accumulation.

A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo.

αvβ6 integrin expression is upregulated on a wide range of epithelial tumours, and is thought to play a role in modulating tumour growth. Here we describe a human therapeutic antibody 264RAD, which binds and inhibits αvβ6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey αvβ6, and inhibits binding to all ligands including the latency-associated peptide of TGF-β.

MEDI0639: a novel therapeutic antibody targeting Dll4 modulates endothelial cell function and angiogenesis in vivo.

The Notch signaling pathway has been implicated in cell fate determination and differentiation in many tissues. Accumulating evidence points toward a pivotal role in blood vessel formation, and the importance of the Delta-like ligand (Dll) 4-Notch1 ligand-receptor interaction has been shown in both physiological and tumor angiogenesis. Disruption of this interaction leads to a reduction in tumor growth as a result of an increase in nonfunctional vasculature leading to poor perfusion of the tumor.

Termination and initial branch formation of SNAP-25-deficient thalamocortical fibres in heterochronic organotypic co-cultures.

We are interested in the role of neural activity mediated through regulated vesicular release in the stopping and early branching of the thalamic projections in the cortex. Axon outgrowth, arrival at the cortical subplate, side-branch formation during the waiting period and cortical plate innervation of embryonic thalamocortical projections occurs without major abnormalities in the absence of regulated release in Snap25 (-/-) null mutant mice [Washbourne et al. (2002) Nat.

An antibody targeted to VEGFR-2 Ig domains 4-7 inhibits VEGFR-2 activation and VEGFR-2-dependent angiogenesis without affecting ligand binding.

Inhibition of VEGFR-2 signaling reduces angiogenesis and retards tumor growth. Current biotherapeutics that inhibit VEGFR-2 signaling by either sequestering VEGF ligand or inhibiting VEGF binding to VEGFR-2 may be compromised by high VEGF concentrations. Here we describe a biotherapeutic that targets VEGFR-2 signaling by binding to Ig domains 4-7 of VEGFR-2 and therefore has the potential to work independently of ligand concentration.

Inhibition of neutrophil infiltration into A549 lung tumors in vitro and in vivo using a CXCR2-specific antagonist is associated with reduced tumor growth.

Neutrophils are important innate immune cells that are involved in microbial clearance at sites of infection and in wound healing. The microenvironment of tumors often resembles that of chronic inflammation and increased numbers of neutrophils have been observed in several tumors and, in some cases, these positively correlate with poor prognosis. Neutrophil recruitment into tumors appears to be dependent on chemokines that bind to CXCR1 and CXCR2 expressed by neutrophils.

Dual IGF-I/II-neutralizing antibody MEDI-573 potently inhibits IGF signaling and tumor growth.

Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF-1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented.

A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models.

Localized angiopoietin-2 (Ang2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor angiogenesis, making it an attractive candidate for antiangiogenic therapy. A fully human monoclonal antibody (3.19.

Development of a new fully human anti-CD20 monoclonal antibody for the treatment of B-cell malignancies.

Despite the widespread use of rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin's lymphomas, there is a recognized need to develop new agents with improved efficacy. Towards this end, using XenoMouse technology, a fully human IgG1 anti-CD20 monoclonal antibody was generated. This antibody, denoted mAb 1.