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已将拮抗剂鉴定为孤儿受体，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。对肾上腺类固醇合成的安全有效抑制在肿瘤学中具有许多潜在的应用，包括治疗两种罕见且管理不良的疾病。一种是威胁生命，不受控制的糖皮质激素和/或矿物皮质激素从转移性肾上腺皮质癌（ACC）释放。另一个是库欣的综合征，是由于无法切除的ACTH分泌肿瘤而导致的，这些肿瘤刺激肾上腺类固醇合成而没有正常的下丘脑反馈。此外，这些新型的孤儿受体拮抗剂可能在治疗激素依赖性前列腺癌中具有重要的价值，因为化学cast割不会阻止肾上腺雄激素，DHEA和DHEA-S的释放，这对前列腺中总雄激素负荷有显着贡献。特异性拮抗这种关键孤儿受体的新方法具有比Mitotane，Ketoconazole和氨基氟取酰胺更安全，更有效的潜力，目前用于此目的是广谱P450抑制剂。我们在AIM 1中提出，以表征受体拮抗剂在培养的肾上腺癌细胞系和原发性肾上腺培养物中对类固醇发生的抑制，证实拮抗剂抑制癌性和正常肾上腺细胞中的类固醇生成。在AIM 2中，我们计划通过修改当前拮抗剂来合成一种代谢稳定的工具化合物，以进行动物研究，在AIM 3中，我们建议表征它们对小鼠肾上腺类固醇生成的作用。原本研究证明了新型拮抗剂抑制肾上腺类固醇生成的总体功效，将为进一步的临床前发育以及对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，肾上腺的肾上腺激活，通过acth肿瘤肿瘤和非肾上腺生产和非肾上腺生产和非生产物质的调节。公共卫生相关性：异常和过度的肾上腺类固醇产生，产生代谢或高血压的严重异常，威胁着数千名癌症患者/年的生命。源自肾上腺的类固醇也会导致前列腺癌的传播，该癌在美国每年造成30,000多人死亡，可用的疗法没有足够的效果。我们已经将小分子拮抗剂鉴定为一种对肾上腺类固醇合成的广泛控制的新型受体。这些拮抗剂的成功临床发展可以显着改善这些适应症的临床预后。