Application of liquid biopsies to identify genomic factors associated with therapy resistance in castration resistant prostate cancer.

For over 70 years, androgen deprivation therapy (ADT) has been a fundamental treatment paradigm for advanced prostate cancer. Despite initial effectiveness, castration resistant prostate cancer (CRPC) develops in virtually all patients while on ADT. Until recently, additional available treatment options were limited for CPRC patients. Recognition of the critical role of reactivated androgen receptor (AR) signaling in CRPC led to the development of two novel AR axis-targeting agents, abiraterone and enzalutamide. Abiraterone is a selective inhibitor of the enzyme CYP17A1 that catalyzes a critical step in androgen biosynthesis (1). Inhibition of CYP17A1 reduces available ligands that stimulate AR in CRPC tumor cells. Enzalutamide is a potent inhibitor of ligand binding to AR and leads to loss of AR-induced transcriptional activation (2). Treatment with abiraterone or enzalutamide improved CPRC clinical outcomes (3,4), but CRPC remains a terminal disease due to resistance to these agents. Approximately 20–40% of chemotherapy-treated patients, and at least 10% of chemotherapy-naïve patients present with primary resistance to these agents (i.e., no initial decrease in prostate specific antigen (PSA) within three months of initiating treatment) (3,5). Additionally, CRPC patients who experience an initial PSA response to either abiraterone or enzalutamide will eventually develop secondary resistance (6). Also, despite differing mechanisms by which these medications affect the AR signaling axis, there is likely cross-resistance between abiraterone and enzalutamide (7,8), which further complicates the treatment landscape for CRPC. Clearly, there is an urgent need to identify and validate predictive biomarkers of treatment response or resistance that can effectively guide selection of therapeutic agents

Androgen Receptor-Dependent and -Independent Mechanisms Involved in Prostate Cancer Therapy Resistance

Despite the initial efficacy of androgen deprivation in prostate cancer, virtually all patients progress to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling is critically required for CRPC. A new generation of medications targeting AR, such as abiraterone and enzalutamide, has improved survival of metastatic CRPC (mCRPC) patients. However, a significant proportion of patients presents with primary resistance to these agents, and in the remainder, secondary resistance will invariably develop, which makes mCRPC the lethal form of the disease. Mechanisms underlying progression to mCRPC and treatment resistance are extremely complex. AR-dependent resistance mechanisms include AR amplification, AR point mutations, expression of constitutively active AR splice variants, and altered intratumoral androgen biosynthesis. AR-independent resistance mechanisms include glucocorticoid receptor activation, immune-mediated resistance, and neuroendocrine differentiation. The development of novel agents, such as seviteronel, apalutamide, and EPI-001/EPI-506, as well as the identification and validation of novel predictive biomarkers of resistance, may lead to improved therapeutics for mCRPC patients

Posterior reversible encephalopathy syndrome induced by enzalutamide in a patient with castration-resistant prostate cancer

Posterior reversible encephalopathy syndrome (PRES) is a clinical/radiological syndrome characterized by symptoms that can include seizure, headache, impaired vision and hypertension, and can be confirmed by magnetic resonance imaging. Numerous reports have emerged that describe PRES in cancer patients. The list of medications linked to PRES can include traditional cytotoxic chemotherapeutics (e.g., cisplatin, cyclophosphamide, and high-dose corticosteroids), newer agents that target the vascular endothelial growth factor pathway (e.g., bevacizumab, sunitinib, and pazopanib), and supportive care mediations (e.g., granulocyte colony stimulating factors and erythropoietin). We report, for the first time, a case of PRES that is secondary to treatment with enzalutamide, a potent androgen receptor antagonist used in the treatment of metastatic castration-resistant prostate cancer. Enzalutamide is approved for the treatment of both docetaxel-pretreated and chemotherapy-naïve metastatic castration-resistant prostate cancer. Enzalutamide has been previously linked to the increased risk of seizures. Clinicians should be aware that, in rare cases, patients treated with enzalutamide could potentially be at risk for PRES. If symptoms suggestive of PRES arise in patients receiving enzalutamide, the drug should be discontinued immediately and the diagnostic process should be initiated

Androgen receptor targeting drugs in castration-resistant prostate cancer and mechanisms of resistance

Reactivated androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC). Novel AR targeting drugs abiraterone and enzalutamide have improved survival of CRPC patients. However, resistance to these agents develops and patients ultimately succumb to CRPC. Potential mechanisms of resistance include the following: 1) Expression of AR splice variants such as the AR-V7 isoform which lacks the ligand-binding domain, 2) AR missense mutations in the ligand-binding domain, such as F876L and T877A, and 3) Mutation or overexpression of androgen biosynthetic enzymes or glucocorticoid receptor. Several novel agents may overcome resistance mechanisms. Galeterone acts through multiple mechanisms that include degradation of AR protein and is being evaluated in CRPC patients positive for AR-V7. EPI-001 and related compounds inhibit AR splice variants by targeting the N-terminal transactivation domain of AR. Promising therapies and novel biomarkers, such as AR-V7, may lead to improved outcomes for CRPC patients

Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer

This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoid DM1 in patients with progressive metastatic castration-resistant prostate cancer

Genetic Variants of VEGFA and FLT4 Are Determinants of Survival in Renal Cell Carcinoma Patients Treated with Sorafenib

Molecular markers of sorafenib efficacy in patients with metastatic renal cell carcinoma (mRCC) are not available. The purpose of this study was to discover genetic markers of survival in patients with mRCC treated with sorafenib. Germline variants from 56 genes were genotyped in 295 patients with mRCC. Variant-overall survival (OS) associations were tested in multivariate regression models. Mechanistic studies were conducted to validate clinical associations. VEGFA rs1885657, ITGAV rs3816375, and WWOX rs8047917 (sorafenib arm), and FLT4 rs307826 and VEGFA rs3024987 (sorafenib and placebo arms combined) were associated with shorter OS. FLT4 rs307826 increased VEGFR-3 phosphorylation, membrane trafficking, and receptor activation. VEGFA rs1885657 and rs58159269 increased transcriptional activity of the constructs containing these variants in endothelial and RCC cell lines, and VEGFA rs58159269 increased endothelial cell proliferation and tube formation. FLT4 rs307826 and VEGFA rs58159269 led to reduced sorafenib cytotoxicity. Genetic variation in VEGFA and FLT4 could affect survival in sorafenib-treated patients with mRCC. These markers should be examined in additional malignancies treated with sorafenib and in other angiogenesis inhibitors used in mRCC. Significance: Clinical and mechanistic data identify germline genetic variants in VEGFA and FLT4 as markers of survival in patients with metastatic renal cell carcinoma.Peer reviewe

Elasticity in ecosystem services: Exploring the variable relationship between ecosystems and human well-being

Although ecosystem services are increasingly recognized as benefits people obtain from nature, we still have a poor understanding of how they actually enhance multidimensional human well-being, and how well-being is affected by ecosystem change. We develop a concept of “ecosystem service elasticity” (ES elasticity) that describes the sensitivity of human well-being to changes in ecosystems. ES Elasticity is a result of complex social and ecological dynamics and is context dependent, individually variable, and likely to demonstrate nonlinear dynamics such as thresholds and hysteresis. We present a conceptual framework that unpacks the chain of causality from ecosystem stocks through flows, goods, value, and shares to contribute to the well-being of different people. This framework builds on previous conceptualizations, but places multidimensional well-being of different people as the final element. This ultimately disaggregated approach emphasizes how different people access benefits and how benefits match their needs or aspirations. Applying this framework to case studies of individual coastal ecosystem services in East Africa illustrates a wide range of social and ecological factors that can affect ES elasticity. For example, food web and habitat dynamics affect the sensitivity of different fisheries ecosystem services to ecological change. Meanwhile high cultural significance, or lack of alternatives enhance ES elasticity, while social mechanisms that prevent access can reduce elasticity. Mapping out how chains are interlinked illustrates how different types of value and the well-being of different people are linked to each other and to common ecological stocks. We suggest that examining chains for individual ecosystem services can suggest potential interventions aimed at poverty alleviation and sustainable ecosystems while mapping out of interlinkages between chains can help to identify possible ecosystem service trade-offs and winners and losers. We discuss conceptual and practical challenges of applying such a framework and conclude on its utility as a heuristic for structuring interdisciplinary analysis of ecosystem services and human wellbeing.This paper results from the project Sustainable Poverty Alleviation from Coastal Ecosystem Services (SPACES) project number NE-K010484-1, funded by the Ecosystem Services for Poverty Alleviation (ESPA) programme. The ESPA programme is funded by the Department for International Development (DFID), the Economic and Social Research Council (ESRC), and the Natural Environment Research Council (NERC).

Earth observation for citizen science validation, or citizen science for earth observation validation? The role of quality assurance of volunteered observations

Environmental policy involving citizen science (CS) is of growing interest. In support of this open data stream of information, validation or quality assessment of the CS geo-located data to their appropriate usage for evidence-based policy making needs a flexible and easily adaptable data curation process ensuring transparency. Addressing these needs, this paper describes an approach for automatic quality assurance as proposed by the Citizen OBservatory WEB (COBWEB) FP7 project. This approach is based upon a workflow composition that combines different quality controls, each belonging to seven categories or “pillars”. Each pillar focuses on a specific dimension in the types of reasoning algorithms for CS data qualification. These pillars attribute values to a range of quality elements belonging to three complementary quality models. Additional data from various sources, such as Earth Observation (EO) data, are often included as part of the inputs of quality controls within the pillars. However, qualified CS data can also contribute to the validation of EO data. Therefore, the question of validation can be considered as “two sides of the same coin”. Based on an invasive species CS study, concerning Fallopia japonica (Japanese knotweed), the paper discusses the flexibility and usefulness of qualifying CS data, either when using an EO data product for the validation within the quality assurance process, or validating an EO data product that describes the risk of occurrence of the plant. Both validation paths are found to be improved by quality assurance of the CS data. Addressing the reliability of CS open data, issues and limitations of the role of quality assurance for validation, due to the quality of secondary data used within the automatic workflow, are described, e.g., error propagation, paving the route to improvements in the approach

DNA building blocks: keeping control of manufacture

Ribonucleotide reductase (RNR) is the only source for de novo production of the four deoxyribonucleoside triphosphate (dNTP) building blocks needed for DNA synthesis and repair. It is crucial that these dNTP pools are carefully balanced, since mutation rates increase when dNTP levels are either unbalanced or elevated. RNR is the major player in this homeostasis, and with its four different substrates, four different allosteric effectors and two different effector binding sites, it has one of the most sophisticated allosteric regulations known today. In the past few years, the structures of RNRs from several bacteria, yeast and man have been determined in the presence of allosteric effectors and substrates, revealing new information about the mechanisms behind the allosteric regulation. A common theme for all studied RNRs is a flexible loop that mediates modulatory effects from the allosteric specificity site (s-site) to the catalytic site for discrimination between the four substrates. Much less is known about the allosteric activity site (a-site), which functions as an on-off switch for the enzyme's overall activity by binding ATP (activator) or dATP (inhibitor). The two nucleotides induce formation of different enzyme oligomers, and a recent structure of a dATP-inhibited α6β2 complex from yeast suggested how its subunits interacted non-productively. Interestingly, the oligomers formed and the details of their allosteric regulation differ between eukaryotes and Escherichia coli Nevertheless, these differences serve a common purpose in an essential enzyme whose allosteric regulation might date back to the era when the molecular mechanisms behind the central dogma evolved