A First-in-Human, Phase I PET Imaging Study of 11C-YJH08, a Selective Glucocorticoid Receptor-Targeting Agent, in Patients With Advanced Solid Tumor Malignancies

This phase I trial studies if positron emission tomography (PET) imaging using 11C-YJH08 can be useful for detecting certain cell receptor expression in tumor cells in patients with cancer that has spread to other parts of the body (metastatic). 11C-YJH08 is a small-molecule radiotracer that binds to receptors on cells (glucocorticoid receptor) so that they show up better on the PET scan. Systemic therapy (including enzalutamide) can cause more glucocorticoid receptors to be produced in tumor cells, which can make the tumor cells resist hormone therapies. If researchers can find a better way to detect whether glucocorticoid receptors are increasing during therapy, it may lead to more successful therapies using glucocorticoid receptor antagonists.

开始日期2021-08-10

申办/合作机构

The University of California, San Francisco

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100 项与 11C-YJH08(University of California) 相关的转化医学

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项与 11C-YJH08(University of California) 相关的文献（医药）

2022-02-07·Molecular Pharmaceutics2区 · 医学

In Vivo Profiling with ¹⁸F-YJH08 Reveals Diverse Tissue Patterns of Antagonist/Glucocorticoid Receptor Interactions

2区 · 医学

Article

作者: Sriram, Renuka ; Wang, Yung-hua ; Sakhamuri, Sasank ; Evans, Michael J. ; Zhao, Ning ; Huang, Yangjie ; Kim, Hyunjung ; Chopra, Shalini ; Hooshdaran, Nima ; Aggarwal, Rahul

Demonstrating target engagement in vivo is an important milestone in drug development, both to establish on target, on tissue interactions but also to identify potentially undesirable off tissue binding. The glucocorticoid receptor (GR) is a long-studied yet vexing drug target that has recently re-emerged as a potential druggable driver of many solid tumor types including breast and prostate cancer, and several antagonists are currently in early phase clinical trials. Since GR is also ubiquitously expressed in normal tissues, understanding antagonist/GR interactions in normal tissues and tumor is crucial to defining a therapeutic index. Herein, we demonstrate that the GR radioligand ¹⁸F-YJH08 can map drug/GR engagement in vivo. Profiling target engagement in vivo showed that the GR antagonists RU486 (mifepristone) and CORT125281 engaged GR in fewer normal tissues compared to ORIC-101 or the agonist dexamethasone. Furthermore, ¹⁸F-YJH08 detected GR in human prostate cancer tumor models and measured receptor binding by RU486. In summary, these data show for the first time that antagonist/GR interactions can be measured in vivo with ¹⁸F-YJH08, a finding with clinical relevance as GR antagonists and ¹¹C-YJH08 are currently in clinical trials.

2007-09-01·Journal of Medicinal Chemistry1区 · 医学

Synthesis and Characterization of Nonsteroidal Glucocorticoid Receptor Modulators for Multiple Myeloma

1区 · 医学

Article

作者: Cuervo, Catalina ; Zhi, Lin ; Rungta, Deepa ; Higuchi, Robert I. ; Gharbaoui, Catherine J. ; Kallel, E. Adam ; Bissonnette, Reid P. ; Valdez, Lino J. ; Adams, Mark E. ; Yen, Jean ; Miner, Jeffrey N. ; Hudson, Andrew R. ; Vassar, Angie ; Negro-Vilar, Andrés ; Marschke, Keith B. ; Mais, Dale E. ; Li, Yongkai ; Phillips, Dean P. ; Lamph, William W. ; Roach, Steven L.

Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.

2002-08-01·Molecular Pharmacology3区 · 医学

trans-Activation and Repression Properties of the Novel Nonsteroid Glucocorticoid Receptor Ligand 2,5-Dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and Its Four Stereoisomers

3区 · 医学

Article

作者: Falls, Doug ; Miller, Loan ; Tyree, Curtis ; Stashko, Mike ; Carter, George ; Nakane, Masaki ; Kym, Philip R. ; Coghlan, Mike J. ; Rosen, John ; Lin, Chun Wel ; Lane, Ben C. ; Miner, Jeffrey N. ; Huang, Ruth ; Kuk, Jane

Glucocorticoids are potent anti-inflammatory and immunosuppressant agents. However, they also produce serious side effects that limit their usage. It has been proposed that anti-inflammatory properties of glucocorticoids are caused mostly by repression of activator protein 1- and nuclear factor kappabeta-stimulated synthesis of inflammatory mediators, whereas most of their adverse effects are associated with trans-activation of genes involved with metabolic processes. Our laboratories have sought to discover novel glucocorticoid receptor (GR) ligands that have high repression but low trans-activation activities. We describe here cellular properties of 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(1-methylcyclohexen-3-y1)-1H-[1]benzopyrano[3,4-f]quinoline (A276575) and its four enantiomers. Similar to dexamethasone, A276575 exhibited high affinity for GR and potently repressed interleukin (IL) 1beta-stimulated IL-6 production in human skin fibroblasts, prostaglandin (PG) E(2) production in A549 human lung epithelial cells, and concanavalin A-induced monocyte proliferation. In contrast to dexamethasone, A276575 caused smaller induction of aromatase activity in human skin fibroblasts and antagonized dexamethasone-induced activation of an mouse mammary tumor virus-glucocorticoid-response element (GRE) reporter gene construct. Among the four enantiomers of A276575, the two (-)-enantiomers showed 10- to 30-fold higher affinities for GR than their respective (+)-enantiomers. Both (-)-Syn and (-)-Anti enantiomers of A276575 were potent inhibitors of IL-1beta-stimulated PGE2 production in A549 lung epithelial cells; unexpectedly, however, only the (-)-Anti enantiomer inhibited regulated on T-cell activation, normal T-cell expressed and secreted (RANTES) production in A549 cells. In summary, A276575 is a novel, nonsteroidal GR ligand that possesses high repression activities against inflammatory mediator production but has lower GRE trans-activation activities than traditional steroids. Differential repression of RANTES and PGE2 production in a cell by the two (-)-enantiomers of A276575 illustrates the complexity of repression by GR.

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