Preclinical development of OR-449, a novel targeted therapy for adrenocortical cancer
肾上腺皮质癌新型靶向疗法 OR-449 的临床前开发
基本信息
- 批准号:10445073
- 负责人:
- 金额:$ 69.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-05 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:4 year oldAddressAdrenal Gland CancerAdrenal GlandsAdrenergic AntagonistsAdrenocortical carcinomaAdultBehavioralBinding ProteinsBiological AssayCanis familiarisCardiovascular PhysiologyCardiovascular systemChemistryChemotherapy-Oncologic ProcedureChildhoodChromosomal DuplicationClinicalClinical TrialsConsultationsCultured Tumor CellsDNA biosynthesisDataDevelopmentDevelopment PlansDiagnosisDiseaseDoseDrug KineticsEnsureEuropeExhibitsFDA approvedFormulationFutureGenetic TranscriptionGoalsGrowthGrowth and Development functionHistologyHumanImmune checkpoint inhibitorImmunocompromised HostInsecticidesInvestigational New Drug ApplicationKilogramLocalized Malignant NeoplasmMalignant NeoplasmsMalignant neoplasm of adrenal cortexMaximum Tolerated DoseMessenger RNAMolecular TargetMonitorMusNuclear Orphan ReceptorNuclear ReceptorsOncologyOperative Surgical ProceduresOralOrphanOutcomePathogenesisPatientsPharmaceutical PreparationsPhasePhase I Clinical TrialsPhase I/II Clinical TrialPlasma ProteinsPolymorphProceduresProcessPrognosisPropertyProteinsRattusRecoveryResidual stateRespiratory physiologyRoleSF1SafetySaint Jude Children&aposs Research HospitalSignal TransductionSmall Business Innovation Research GrantSurvival RateSynthesis ChemistryTestingTherapeuticTissuesToxic effectToxicokineticsToxicologyXenograft procedureabsorptionanalytical methodantagonistbasechemotherapeutic agentchemotherapyclinical candidateclinical developmentcommercializationcrystallinitydesigndiagnostic biomarkerdosageimprovedmeetingsneoplastic cellnew therapeutic targetnovel therapeuticspatient derived xenograft modelpreclinical developmentpreclinical safetyrare cancersafety studyscale upside effectsmall moleculetargeted treatmenttranscription factortumortumor growthtumor xenograftvirtual
项目摘要
ABSTRACT
Adrenocortical carcinoma (ACC) is a rare, aggressive cancer. The majority of cases are metastatic or locally
advanced at diagnosis with a dismal five-year survival of <15%. The only FDA-approved chemotherapeutic
agent, mitotane, is highly toxic, difficult to dose, and only modestly effective. Alternative chemotherapy regimens
and immune checkpoint inhibitors provide limited benefit. There is an urgent need for new therapies.
We propose to develop a targeted therapy for ACC based on first-in-class small molecule antagonists to
steroidogenic factor-1 (SF-1 or NR5A1), an orphan nuclear receptor and transcription factor that is essential for
the growth and development of the adrenal gland. Multiple findings indicate that SF-1 has a crucial role in the
pathogenesis of ACC: (i) Higher levels of intra-tumoral SF-1 expression correlate with poor prognosis in adult
ACC, (ii) SF-1 is a diagnostic marker of metastatic ACC; (iii) SF-1 is chromosomally amplified and SF-1 protein
is elevated, relative to normal adrenal tissue, in pediatric ACC. Further, the FDA, in consultation with NCI, has
included SF-1 on its Pediatric Molecular Target List for oncology.
Orphagen has identified a highly selective SF-1 antagonist, OR-449, that at 30 mg/kg daily oral dosing completely
inhibited the growth of SJ-ACC3, a pediatric ACC tumor xenograft originally isolated at St. Jude Children’s
Research Hospital. OR-449 also blocked DNA synthesis in cultures of dissociated SJ-ACC3 tumor cells. The
dose-responsive mRNA signature in the SJ-ACC3 xenografts supports direct engagement of SF1 by OR-449.
Further, OR-449 showed excellent oral absorption and pharmacokinetic (PK) properties in mouse, rat, and dog
and was well-tolerated at 100 mg/kg in an oral, two-week daily dosing murine safety study.
The proposed SBIR Direct to Phase II Project builds on the highly effective inhibition of ACC tumor growth and
promising preliminary safety profile of OR-449. Our Project goal is to complete all preclinical safety studies
required to file an Investigational New Drug application for the first clinical trial of an SF-1 antagonist in ACC.
The Aims are: 1) Conduct an exploratory (non-GLP), dose range-finding toxicity study of OR-449 in mice at
doses up to 400 mg/kg to identify any serious safety signals and to provide key dosing data for designing a 1-
month regulatory (GLP) toxicology study; 2) Optimize synthetic chemistry processes, develop analytical
methods, and complete a 1-kilogram scale-up synthesis of OR-449 to supply further nonclinical safety studies
and prepare for GMP manufacturing; 3) Conduct high-dose PK studies in dogs followed by non-GLP 7-day
toleration and 14-day dose range-finding safety studies with histology and cardiovascular monitoring; 4)
Complete 1-month repeat dose GLP general toxicology studies in mouse and dog consistent with FDA guidance.
Successful completion of the Project will provide the necessary data to select a starting dose for a Phase 1
clinical trial of OR-449 in ACC. Ultimately, commercialization of OR-449 could provide a safe and effective
targeted therapy to significantly improve survival for ACC patients.
摘要
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Scott McNear Thacher其他文献
Scott McNear Thacher的其他文献
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{{ truncateString('Scott McNear Thacher', 18)}}的其他基金
Preclinical development of OR-449, a novel targeted therapy for adrenocortical cancer
肾上腺皮质癌新型靶向疗法 OR-449 的临床前开发
- 批准号:
10326044 - 财政年份:2021
- 资助金额:
$ 69.32万 - 项目类别:
Pharmacological Suppression of Rod Opsin as Therapy for Retinitis Pigmentosa
杆状视蛋白的药理学抑制治疗色素性视网膜炎
- 批准号:
8666826 - 财政年份:2013
- 资助金额:
$ 69.32万 - 项目类别:
Pharmacological Suppression of Rod Opsin as Therapy for Retinitis Pigmentosa
杆状视蛋白的药理学抑制治疗色素性视网膜炎
- 批准号:
8516861 - 财政年份:2013
- 资助金额:
$ 69.32万 - 项目类别:
Neural Stem Cell-Selective Drug Target for Small Molecule Therapy of Brain Tumors
用于脑肿瘤小分子治疗的神经干细胞选择性药物靶点
- 批准号:
8393572 - 财政年份:2012
- 资助金额:
$ 69.32万 - 项目类别:
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
- 批准号:
8076948 - 财政年份:2010
- 资助金额:
$ 69.32万 - 项目类别:
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
- 批准号:
7916854 - 财政年份:2010
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$ 69.32万 - 项目类别:
Small Molecule Inhibitors of Effector Th-17 Cells in Inflammatory Bowel Disease
炎症性肠病中效应 Th-17 细胞的小分子抑制剂
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7485537 - 财政年份:2008
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Small molecule target for suppression of autoimmunity in rheumatoid arthritis
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7326950 - 财政年份:2007
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- 资助金额:
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