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剂（SERD）是一类内分泌治疗药物 其作为雌激素受体（ER）拮抗剂和ER降解剂有效地治疗 转移性或晚期乳腺癌，不成比例地影响非洲裔美国妇女。 氟维司群是唯一一种FDA批准的SERD，适用于晚期或转移性乳腺癌 作为一线和二线内分泌剂。然而，这种注射药物效果不佳 生物可利用，并且需要30天达到其最大稳态血药浓度， 在激素抵抗的情况下将临床反应率限制在低于20%。口头 SERD具有更大的药物暴露和更快的作用， 晚期乳腺癌患者。此外，鉴于最近FDA批准氟维司群 作为与CDK 4/6抑制剂palbociclib联合治疗晚期乳腺癌， 口服SERD在联合治疗环境中的临床应用也是非常重要的。 口服SERD开发的进展仅限于非甾体分子， 目前正在1期临床试验中进行评估，但没有一个进入II期临床试验。 审判我们的先导化合物ZB 716在生物利用度方面显示出有希望的临床前数据， 功效和毒理学。ZB 716与雌激素受体高亲和力结合并发挥抗雌激素作用 表达雌激素受体的乳腺癌细胞。在他莫昔芬初治和他莫昔芬耐药乳腺癌中， 癌细胞，ZB 716有效地抑制细胞增殖，并有效地降解激素 受体以剂量依赖性方式。在动物实验中，我们已经证明ZB 716具有远远优于其他药物的上级作用。 与氟维司群相比的口服生物利用度。此外，在直接比较两个口头 在临床试验中，ZB 716是一种较强的抗雌激素和ER降解剂。进一步 为了推进ZB 716的临床前开发，我们建议研究 ZB 716在内分泌抵抗性、患者来源的乳腺肿瘤模型中的作用， 适用于SERD的临床环境。我们还将评估ZB 716在以下方面的疗效： 与CDK 4/6抑制剂Palbociclib联合使用，并研究其作用机制 ZB 716对表达ER突变体形式的患者来源的异种移植物（PDX）的作用，并确定 ZB 716与突变型ER的结合行为及其对ERα-辅调节因子相互作用的调节。 最后，我们将确定最佳的反应条件下，可以制备ZB 716， 更大规模，研究其物理性质和毒理学研究的配方选择 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的疗效数据，以确定ZB 716是否 有效治疗内分泌抵抗性ESR 1突变型乳腺癌， 通过ER发挥作用的抗雌激素和ER降解剂。这些研究还将证明， ZB 716与CDK 4/6抑制剂联合使用时的临床效用。此外，委员会认为， 合成方法的优化将为API的规模化生产和安全性铺平道路 药理学和物理化学性质将满足IND使能数据。总而言之， 拟议的研究将推动这种有前途的口服SERD进入临床试验，以测试其安全性 和乳腺癌患者的疗效。