Developing an Orally Bioavailable SERD for Treatment of Metastatic/Advanced Breast Cancer

开发口服生物可利用的 SERD 来治疗转移性/晚期乳腺癌

• 批准号: 10078882
• 负责人: Guangdi Wang
• 金额: $ 25.13万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078882
• 关键词: Affect; Affinity; African American; Animals; Aromatase Inhibitors; Behavior; Binding; Binding Proteins; Bioavailable; Biological Assay; Biological Availability; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; CDK4 gene; Canis familiaris; Cardiotoxicity; Cell Proliferation; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Cytochrome P450; Data; Development; Disease; Disease-Free Survival; Dose; Drug Compounding; Drug Exposure; Drug Kinetics; ERBB2 gene; ESR1 gene; Endocrine; Enzyme Inhibition; Enzymes; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptors; Ethnic group; Excretory function; FDA approved; Formulation; Fulvestrant; Hormone Receptor; Hormones; Injections; Lead; Light; Liver; Metabolic; Metabolism; Metastatic breast cancer; Methods; Mus; Oral; Oral Administration; Patients; Pattern; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plasma; Plasma Proteins; Preparation; Prognosis; Rattus; Reaction; Regimen; Research; Resistance; Route; Safety; Solubility; Steroids; Tamoxifen; Testing; Toxicology; Treatment Efficacy; United States; Woman; advanced breast cancer; arm; chemical property; clinically relevant; comparative efficacy; dosage; drug candidate; efficacy evaluation; efficacy study; hormone receptor-positive; hormone therapy; improved; in vivo; inhibitor/antagonist; liquid formulation; malignant breast neoplasm; metabolic profile; mortality; mutant; patient derived xenograft model; physical property; pre-clinical; preclinical development; prototype; response; safety study; scale up; therapeutically effective; time interval

Project Summary Selective estrogen receptor downregulators (SERDs) are a class of endocrine therapy agents that act both as estrogen receptor (ER) antagonists and ER degraders effective in treating metastatic or advanced breast cancer that disproportionately affects African American women. Fulvestrant is the only FDA approved SERD indicated for advanced or metastatic breast cancer both as a first line and second line endocrine agent. However, this injection only drug is poorly bioavailable and it takes 30 days to reach its maximal steady-state plasma concentration, limiting the clinical response rate to lower than 20% in the hormone resistant setting. An oral SERD with greater drug exposure and faster action would bring immediate clinical benefits to patients with advanced breast cancer. Further, in light of the recent FDA approval of fulvestrant as a combination therapy with CDK4/6 inhibitor palbociclib for advanced breast cancer, the clinical utility of an oral SERD in the combination treatment setting is also very significant. Advances in oral SERDs development have been limited to nonsteroidal molecules with several being currently evaluated in phase 1 clinical trials, yet none has advanced to phase II clinical trials. Our lead compound, ZB716, has shown promising preclinical data in bioavailability, efficacy, and toxicology. ZB716 binds to ER with high affinity and exerts its antiestrogenic effect on ER-expressing breast cancer cells. In both tamoxifen naive and tamoxifen resistant breast cancer cells, ZB716 potently inhibits cell proliferation and effectively degrades the hormone receptor in a dose-dependent manner. In animals, we have shown that ZB716 has far superior oral bioavailability when compared to fulvestrant. Moreover, in direct comparison to the two oral SERDs under clinical trials, ZB716 is a stronger antiestrogen and ER-degrader. To further advance the preclinical development of ZB716 we propose to investigate the in vivo efficacy of ZB716 in endocrine resistant, patient derived breast tumor models that most closely resemble clinical settings for which SERD is indicated. We will also evaluate ZB716 efficacy in combination with a CDK4/6 inhibitor, palbociclib and investigate the mechanism of action of ZB716 on patient-derived xenografts (PDX) expressing mutant forms of ER and determine the binding behavior of ZB716 to mutant ERs and its modulation of ERα-coregulator interactions. Finally, we will determine optimal reaction conditions under which ZB716 can be prepared in larger scale, investigate its physical properties and formulation options for toxicological studies in animals, and conduct metabolic profiling, pharmacokinetics, and bioavailability studies. Accomplishing the proposed studies will provide key efficacy data to determine whether ZB716 is effective in treating endocrine resistant, ESR1 mutant breast cancer and whether it is a true antiestrogen and ER degrader by acting through the ER. The studies will also demonstrate the clinical utility of ZB716 as a combination therapy when used with a CDK4/6 inhibitor. Moreover, synthetic method optimization will pave the way for scalable manufacture of the API, and safety pharmacology and physical chemical properties will fulfill IND-enabling data. In summary, the proposed research will advance this promising oral SERD towards clinical trials to test its safety and efficacy in breast cancer patients.

项目摘要 选择性雌激素受体下调（SERDS）是一类内分泌治疗剂 它既充当雌激素受体（ER）拮抗剂和ER降解器有效治疗 转移性或晚期乳腺癌会影响非裔美国妇女。 FullVESTRANT是唯一用于晚期或转移性乳腺癌的FDA批准的SERD 都是第一行和第二线内分泌剂。但是，这种注射只有药物很差 生物利用物，需要30天才能达到其最大稳态血浆浓度， 在耐马匹耐药的环境中，将临床反应率限制在低于20％。口服 与更大的药物暴露和更快的行动有关，将立即带来临床益处 晚期乳腺癌患者。此外，鉴于最近的FDA批准 作为与CDK4/6抑制剂palbociclib进行晚期乳腺癌的组合疗法， 在组合治疗环境中口服SERD的临床效用也非常重要。 口服SERDS发育的进展仅限于非甾体类分子，有几个分子 目前正在第1阶段临床试验中进行评估，但没有一个尚未晋级II期临床 试验。我们的铅化合物ZB716在生物利用度中显示出有希望的临床前数据， 有效性和毒理学。 ZB716与ER结合高亲和力并执行其抗源性效应 关于表达ER的乳腺癌细胞。在他莫昔芬幼稚和他莫昔芬的抗乳房中 癌细胞，ZB716可能会抑制细胞增殖并有效降解马烯 接收器以剂量依赖性方式。在动物中，我们已经表明ZB716的表现要高得多 与Fulvestrant相比，口服生物利用度。而且，与两个口头直接比较 在临床试验下的SERDS，ZB716是一种更强的抗雌激素和ER-脱脂剂。进一步 推进ZB716的临床前开发，我们建议研究体内效率 ZB716在耐内分泌，衍生的乳腺肿瘤模型中，最类似于 指示SERD的临床环境。我们还将评估ZB716的效率 结合CDK4/6抑制剂Palbociclib并研究了作用机理 ZB716关于表达ER的突变体形式的患者衍生Xenographtics（PDX），并确定 ZB716与突变体的结合行为及其对ERα-核调节剂相互作用的调节。 最后，我们将确定可以在哪些ZB716中制备的最佳反应条件 更大规模，研究其物理特性和制定毒理学研究的选择 在动物中，进行代谢分析，药代动力学和生物利用度研究。 完成拟议的研究将提供关键效率数据，以确定ZB716是否是否 有效治疗内分泌耐药性ESR1突变乳腺癌以及它是否为真 通过ER作用，抗雌激素和ER降解器。研究还将证明 与CDK4/6抑制剂一起使用时，ZB716作为联合疗法的临床实用性。而且， 合成方法优化将为API的可扩展制造和安全铺平道路 药理学和物理化学特性将符合辅助数据。总而言之， 拟议的研究将使该诺言的诺言朝着临床试验进行测试以测试其安全 并缓解乳腺癌患者。