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Inhibitor of Adrenal Steroid Synthesis for Cancer Treatment

用于癌症治疗的肾上腺类固醇合成抑制剂

基本信息

批准号：
7916854
负责人：
Scott McNear Thacher
金额：
$ 40万
依托单位：
ORPHAGEN PHARMACEUTICALS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7916854
关键词：
Adrenal Cortex Adrenal Gland Carcinoma Adrenal Gland Neoplasms Adrenal Glands Adrenocortical carcinoma Adverse effects Affect Aldosterone Aminoglutethimide Androgens Animals Area Binding Biological Assay CYP17A1 gene Cancer Patient Cancer cell line Cancerous Castration Cell Line Cells Cessation of life Chemicals Childhood Clinical Corticosterone Corticotropin Cushing Syndrome Cytochrome P450 DNA Binding Domain Development Differentiation and Growth Ectopic ACTH Syndrome Endocrine Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Family Feedback Genetic Transcription Glucocorticoids Goals Gonadal structure Growth Hormones Human Hydrocortisone Hypertension Hypothalamic structure Investigation Ketoconazole Life Ligand Binding Domain Ligands Liver Microsomes Lung Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of adrenal cortex Malignant neoplasm of prostate Metabolic Metabolism Mineralocorticoids Modification Monitor Mus Neoplasm Metastasis Nuclear Receptors Operative Surgical Procedures Orphan Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phase III Clinical Trials Phospholipids Pituitary Gland Plasma Pre-Clinical Model Production Prostate Public Health Publishing Recruitment Activity Recurrent tumor Regulation Repression Rodent SF1 Screening procedure Series Serum Somatotropin Specificity Steroid biosynthesis Steroids Structure Testosterone Thymus Gland Transcription Coactivator Transcription Repressor/Corepressor Tumor-Derived Unresectable abiraterone base cancer therapy dehydroepiandrosterone hormone therapy improved in vivo inhibitor/antagonist lead series member novel novel strategies novel therapeutic intervention oncology outcome forecast overexpression pre-clinical programs promoter public health relevance receptor response scaffold small molecule steroid hormone tool transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Orphagen has identified antagonists to an orphan receptor that regulates the major biosynthetic steps of steroid hormone synthesis in the adrenal cortex and gonads. Safe and effective inhibition of adrenal steroid synthesis has a number of potential applications in oncology, including treatment of two rare and very poorly managed conditions. One is life-threatening, uncontrolled glucocorticoid and/or mineralocorticoid release from metastatic adrenocortical carcinoma (ACC). The other is Cushing's syndrome resulting from unresectable ACTH-secreting tumors that stimulate adrenal steroid synthesis without normal hypothalamic feedback. In addition, these novel orphan receptor antagonists are potentially of significant value in the treatment of hormone-dependent prostate cancer as chemical castration does not block release of the adrenal androgens, DHEA and DHEA-S, which contribute significantly to the total androgen load in prostate. The novel approach of specifically antagonizing this critical orphan receptor has the potential to be both safer and more effective than mitotane, ketoconazole and aminoglutethimide, broad spectrum P450 inhibitors currently used for this purpose. We propose in Aim 1 to characterize inhibition of steroidogenesis by receptor antagonists in cultured adrenal carcinoma cell lines and in primary adrenal cultures, confirming that the antagonists suppress steroidogenesis in cancerous and normal adrenal cells. In Aim 2, we plan to synthesize a metabolically stable tool compound for animal studies by modification of current antagonists, and in Aim 3 we propose to characterize the action of these on adrenal steroidogenesis in mouse. Proof-of-principle studies demonstrating overall efficacy of the novel antagonists for suppression of adrenal steroidogenesis will provide the framework for further preclinical development as well as the investigation of preclinical models, such as steroid secretion by adrenocortical cancer cell lines, adrenal activation by ACTH-secreting tumors, and regulation of adrenal androgen production in a non-rodent species. PUBLIC HEALTH RELEVANCE: Abnormal and excessive adrenal steroid production, producing severe abnormalities of metabolism or hypertension, threatens the lives of several thousand cancer patients/year. Steroids derived from the adrenal gland also contribute to the spread of prostate cancer, which causes more than 30,000 deaths per year in the U.S. Available therapies are not adequately effective. We have identified small molecule antagonists to a novel receptor that exerts broad control over adrenal steroid synthesis. Successful clinical development of these antagonists could markedly improve clinical prognosis for these indications.

描述（由申请人提供）： Orphagen已经确定了孤儿受体的拮抗剂，该受体调节肾上腺皮质和性腺中类固醇激素合成的主要生物合成步骤。安全有效地抑制肾上腺类固醇合成在肿瘤学中有许多潜在的应用，包括治疗两种罕见且管理非常差的疾病。一种是从转移性肾上腺皮质癌（ACC）中释放的危及生命的、不受控制的糖皮质激素和/或盐皮质激素。另一种是库欣综合征，由不能切除的促肾上腺皮质激素分泌肿瘤引起，这种肿瘤刺激肾上腺类固醇合成，但没有正常的下丘脑反馈。此外，这些新的孤儿受体拮抗剂在治疗前列腺癌依赖性前列腺癌中具有潜在的重要价值，因为化学去势不阻断肾上腺雄激素DHEA和DHEA-S的释放，其对前列腺中的总雄激素负荷有显著贡献。特异性拮抗这一关键孤儿受体的新方法有可能比米托坦、酮康唑和氨鲁米特更安全、更有效，目前用于此目的的广谱P450抑制剂。我们在目的1中提出，在培养的肾上腺癌细胞系和原代肾上腺培养物中，通过受体拮抗剂来表征类固醇生成的抑制，证实拮抗剂抑制癌细胞和正常肾上腺细胞中的类固醇生成。在目标2中，我们计划通过修改当前的拮抗剂来合成用于动物研究的代谢稳定的工具化合物，并且在目标3中，我们建议表征这些化合物对小鼠肾上腺类固醇生成的作用。证明新型拮抗剂抑制肾上腺类固醇生成的总体疗效的原理验证研究将为进一步的临床前开发以及临床前模型的研究提供框架，例如肾上腺皮质癌细胞系的类固醇分泌、ACTH分泌肿瘤的肾上腺活化以及非啮齿类动物种属中肾上腺雄激素产生的调节。公共卫生关系：异常和过量的肾上腺类固醇产生，产生严重的代谢异常或高血压，每年威胁着数千名癌症患者的生命。来自肾上腺的类固醇也会导致前列腺癌的传播，在美国每年导致超过30，000人死亡。现有的治疗方法效果不佳。我们已经确定了一种新的受体，发挥广泛的控制肾上腺类固醇合成的小分子拮抗剂。这些拮抗剂的成功临床开发可以显着改善这些适应症的临床预后。