Search

Summary: Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapeutics. The luminal androgen receptor (LAR) subtype constitutes 15% of TNBC and is enriched for androgen receptor (AR) and AR target genes. Here, we show that a cohort of TNBC not only expresses AR at a much higher rate (∼80%) but also expresses AR splice variants (AR-SVs) (∼20%), further subclassifying LAR-TNBC. Higher AR and AR-SV expression and corresponding aggressive phenotypes are observed predominantly in specimens obtained from African American women. LAR TNBC specimens are enriched for interferon, Janus kinase (JAK)-signal activator and transducer (STAT), and androgen signaling pathways, which are exclusive to AR-expressing epithelial cancer cells. AR- and AR-SV-expressing TNBC cell proliferation and xenograft and patient-tumor explant growth are inhibited by AR N-terminal domain-binding selective AR degrader or by a JAK inhibitor. Biochemical analysis suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacologically targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling.

Cancers develop resistance to inhibitors of oncogenes mainly due to target-centric mechanisms such as mutations and splicing. While inhibitors or antagonists force targets to unnatural conformation contributing to protein instability and resistance, activating tumor suppressors may maintain the protein in an agonistic conformation to elicit sustainable growth inhibition. Due to the lack of tumor suppressor agonists, this hypothesis and the mechanisms underlying resistance are not understood. In estrogen receptor (ER)-positive breast cancer (BC), androgen receptor (AR) is a druggable tumor suppressor offering a promising avenue for this investigation. Spatial genomics suggests that the molecular portrait of AR-expressing BC cells in tumor microenvironment corresponds to better overall patient survival, clinically confirming AR's role as a tumor suppressor. Ligand activation of AR in ER-positive BC xenografts reprograms cistromes, inhibits oncogenic pathways, and promotes cellular elasticity toward a more differentiated state. Sustained AR activation results in cistrome rearrangement toward transcription factor PROP paired-like homeobox 1, transformation of AR into oncogene, and activation of the Janus kinase/signal transducer (JAK/STAT) pathway, all culminating in lineage plasticity to an aggressive resistant subtype. While the molecular profile of AR agonist-sensitive tumors corresponds to better patient survival, the profile represented in the resistant phenotype corresponds to shorter survival. Inhibition of activated oncogenes in resistant tumors reduces growth and resensitizes them to AR agonists. These findings indicate that persistent activation of a context-dependent tumor suppressor may lead to resistance through lineage plasticity-driven tumor metamorphosis. Our work provides a framework to explore the above phenomenon across multiple cancer types and underscores the importance of factoring sensitization of tumor suppressor targets while developing agonist-like drugs. [ABSTRACT FROM AUTHOR]

New insights into G protein coupled receptor regulation of glucose metabolism by β-cells, skeletal muscle and liver hepatocytes identify GPRC6A as a potential therapeutic target for treating type 2 diabetes mellitus (T2D). Activating GPRC6A with a small molecule drug represents a potential paradigm-shifting opportunity to make significant strides in regulating glucose homeostasis by simultaneously correcting multiple metabolic derangements that underlie T2D, including abnormalities in β-cell proliferation and insulin secretion and peripheral insulin resistance. Using a computational, structure-based high-throughput screening approach, we identified novel tri-phenyl compounds predicted to bind to the venus fly trap (VFT) and 7-transmembrane (7-TM) domains of GPRC6A. Experimental testing found that these compounds dose-dependently stimulated GPRC6A signaling in a heterologous cell expression system. Additional chemical modifications and functional analysis identified one tri-phenyl lead compound, DJ-V-159 that demonstrated the greatest potency in stimulating insulin secretion in β-cells and lowering serum glucose in wild-type mice. Collectively, these studies show that GPRC6A is a "druggable" target for developing chemical probes to treat T2DM.

Androgen receptor (AR) and its splice variants (AR-SVs) promote prostate cancer (PCa) growth by orchestrating transcriptional reprogramming. Mechanisms by which the low complexity and intrinsically disordered primary transactivation domain (AF-1) of AR and AR-SVs regulate transcriptional programming in PCa remains poorly defined. Using omics, live and fixed fluorescent microscopy of cells, and purified AF-1 and AR-V7 recombinant proteins we show here that AF-1 and the AR-V7 splice variant form molecular condensates by liquid-liquid phase separation (LLPS) that exhibit disorder characteristics such as rapid intracellular mobility, coactivator interaction, and euchromatin induction. The LLPS and other disorder characteristics were reversed by a class of small-molecule-selective AR-irreversible covalent antagonists (SARICA) represented herein by UT-143 that covalently and selectively bind to C406 and C327 in the AF-1 region. Interfering with LLPS formation with UT-143 or mutagenesis resulted in chromatin condensation and dissociation of AR-V7 interactome, all culminating in a transcriptionally incompetent complex. Biochemical studies suggest that C327 and C406 in the AF-1 region are critical for condensate formation, AR-V7 function, and UT-143's irreversible AR inhibition. Therapeutically, UT-143 possesses drug-like pharmacokinetics and metabolism properties and inhibits PCa cell proliferation and tumor growth. Our work provides critical information suggesting that clinically important AR-V7 forms transcriptionally competent molecular condensates and covalently engaging C327 and C406 in AF-1, dissolves the condensates, and inhibits its function. The work also identifies a library of AF-1-binding AR and AR-SV-selective covalent inhibitors for the treatment of PCa. [ABSTRACT FROM AUTHOR]

Extensive research over the last decade has resulted in a number of highly potent tubulin polymerization inhibitors acting either as microtubule stabilizing agents (MSAs) or microtubule destabilizing agents (MDAs). These inhibitors have potent cytotoxicity against a broad spectrum of human tumor cell lines. In addition to cytotoxicity, a number of these tubulin inhibitors have exhibited abilities to inhibit formation of new blood vessels as well as disrupt existing blood vessels. Tubulin inhibitors as a vascular disrupting agents (VDAs), mainly from the MDA family, induce rapid tumor vessel occlusion and massive tumor necrosis. Thus, tubulin inhibitors have become increasingly popular in the field of tumor vasculature. However, their pharmaceutical application is halted by a number of limitations including poor solubility and toxicity. Thus, recently, there has been considerable interests in the nanoparticle drug delivery of tubulin inhibitors to circumvent those limitations. This article reviews recent advances in nanoparticle based drug delivery for tubulin inhibitors as well as their tumor vasculature disruption properties.

Hydrogen-blending effects in flame structure and NO emission behaviour are numerically studied with detailed chemistry in methane–air counterflow diffusion flames. The composition of fuel is systematically changed from pure methane to the blending fuel of methane–hydrogen through H2 molar addition up to 30%. Flame structure, which can be described representatively as a fuel consumption layer and a H2–CO consumption layer, is shown to be changed considerably in hydrogen-blending methane flames, compared to pure methane flames. The differences are displayed through maximum flame temperature, the overlap of fuel and oxygen, and the behaviours of the production rates of major species. Hydrogen-blending into hydrocarbon fuel can be a promising technology to reduce both the CO and CO2 emissions supposing that NOx emission should be reduced through some technologies in industrial burners. These drastic changes of flame structure affect NO emission behaviour considerably. The changes of thermal NO and prompt NO are also provided according to hydrogen-blending. Importantly contributing reaction steps to prompt NO are addressed in pure methane and hydrogen-blending methane flames. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Numerical study with momentum-balanced boundary conditions has been conducted to grasp chemical effects of added CO2, to either fuel- or oxidizer-side on flame structure and NO emission behaviour in CH4O2N2 diffusion flames. Cautious investigation is made for the comparison among the behaviours of principal chain branching and important H-removal key reactions. This describes successfully the reason why flame temperatures for fuel-side dilution are higher than those for oxidizer-side dilution. The role of the principal chain branching reaction is also recognized to be important even in the change of major flame structure caused by chemical effects.The importantly contributing reaction steps to NO production are examined. The reduced production rates of thermal NO and prompt NO due to chemical effects are much more remarkable for fuel-side dilution. It is also found that the reaction step, H+NO+M=HNO+M plays a decisive role of the formation and destruction of prompt NO. Copyright 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Numerical study on flame structure and NO emission behaviour has been conducted to grasp chemical effects of added H2O on either fuel- or oxidizer-side in CH4O2N2 counterflow diffusion flames. An artificial species, which has the same thermodynamic, transport, and radiation properties of added H2O, is introduced to feasibly isolate the chemical effects. Special concern is focused on the important role of remarkably produced OH radicals due to chemical effects of added H2O on flame structure and NO emission. The reason why the difference of behaviours between the principal chain branching reaction rate and flame temperature appear is attributed to the drastic change of reaction step (R120) from the production to the consumption of OH. It is also, however, seen that the most important contribution of produced OH due to chemical effects of added H2O is through reaction step (R127).The importantly contributing reaction steps to NO production are also examined. The production rates of thermal NO and prompt NO are suppressed by chemical effects of added H2O. The contribution of the reaction steps related to HNO intermediate species to the production of prompt NO is also stressed. Copyright 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A numerical study with momentum-balanced boundary conditions has been conducted to grasp the chemical effects of added CO2 to fuel- and oxidizer-sides on flame structure and NO emission behaviour in H2-O2 diffusion flames with varying flame location. A reaction mechanism is proposed to show better agreements with experimental results in CO2-added hydrogen flames. Oxidizer-side dilution results in significantly higher flame temperatures and NO emission. Flame location is dramatically changed due to high diffusivity of hydrogen according to variation of the composition of fuel- and oxidizer-sides. This affects flame structure and NO emission considerably especially the chemical effects of added CO2. The present work also displays separately thermal contribution and prompt NO emission due to the chemical effects caused by thermal dissociation of added CO2 in NO emission behaviour. It is found that flame temperature and the flame location affect the contribution of thermal and prompt NO due to chemical effects considerably in NO emission behaviour. [ABSTRACT FROM AUTHOR]

A numerical study has been conducted to clearly grasp the impact of chemical effects caused by added CO2 and of flame location on flame structure and NO emission behaviour. Flame location affects the major source reaction of CO formation, CO2+H→CO+OH and the H-removal reaction, CH4+H→CH3+H2. It is, as a result, seen that the reduction of maximum flame temperature due to chemical effects for fuel-side dilution is mainly caused by the competition of the principal chain branching reaction with the reaction, CH4+H→CH3+H2, while that for fuel-side dilution is attributed to the competition of the principal chain branching reaction with the reaction, CO2+H→CO+OH. The importance of the NNH mechanism for NO production, where the reaction pathway is NNH→NH→HNO, is recognized. In C-related reactions most of NO is the direct outcome of (R171) and the contribution of (R171) becomes more and more important with increasing amount of added CO2 as much as the reaction step (R171) competes with the key reaction of thermal mechanism, (R237), for N atom. This indicates a possibility that NO emission in hydrogen flames diluted with CO2 shows less dependent behaviour upon flame temperature. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Numerical simulation of CO2 addition effects to fuel and oxidizer streams on flame structure has been conducted with detailed chemistry in H2–O2 diffusion flames of a counterflow configuration. An artificial species, which displaces added CO2 in the fuel- and oxidizer-sides and has the same thermochemical, transport, and radiation properties to that of added CO2, is introduced to extract pure chemical effects in flame structure. Chemical effects due to thermal dissociation of added CO2 causes the reduction flame temperature in addition to some thermal effects. The reason why flame temperature due to chemical effects is larger in cases of CO2 addition to oxidizer stream is well explained though a defined characteristic strain rate. The produced CO is responsible for the reaction, CO2+H=CO+OH and takes its origin from chemical effects due to thermal dissociation. It is also found that the behavior of produced CO mole fraction is closely related to added CO2 mole fraction, maximum H mole fraction and its position, and maximum flame temperature and its position. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]