Co-Targeting IL-6 and CDK4/6 Pathways as a Novel Approach of Preventive Therapy for Triple-Negative Breast Cancer

共同靶向 IL-6 和 CDK4/6 通路作为三阴性乳腺癌预防性治疗的新方法

• 批准号: 10365726
• 负责人: Jiayuh Lin
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365726
• 关键词: Affect; Antineoplastic Agents; Area; Aromatase Inhibitors; Brain; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer cell line; Breast cancer metastasis; CDK4 gene; Cause of Death; Cell Survival; Chemoprevention; Clinical; Clinical Trials; Complex; Conjugated Estrogens; Data; Development; Distant; Drug Combinations; Drug Targeting; Epidermal Growth Factor Receptor; Estrogen receptor negative; Estrogen receptor positive; Excision; Experimental Models; FDA approved; Goals; Growth; Health; Human; IL-6 inhibitor; IL6ST gene; Immunocompetent; In Vitro; Injections; Interleukin Activation; Interleukin-6; Literature; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Measures; Medical; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Military Personnel; Modeling; Mus; Names; Neoplasm Circulating Cells; Neoplasm Metastasis; Oral; Organ; Outcome; Pathway interactions; Patient Care; Patient-derived xenograft models of breast cancer; Pharmaceutical Preparations; Pharmacology; Play; Postmenopausal Osteoporosis; Postmenopause; Prevention; Preventive; Preventive therapy; Primary Neoplasm; Prognosis; Recurrence; Reporting; Research Project Grants; Resistance; Role; STAT3 gene; Safety; Sampling; Selective Estrogen Receptor Modulators; Signal Transduction; Site; Tail; Testing; Therapeutic; Time; Translating; Veins; Veterans; Woman; advanced disease; bone; breast cancer progression; cancer cell; cancer chemoprevention; cancer subtypes; clinically relevant; drug development; efficacy evaluation; hormone receptor-positive; improved; in vivo; in vivo Model; inhibitor; intravenous injection; malignant breast neoplasm; mortality; mouse model; novel; novel marker; novel strategies; orthotopic breast cancer; preclinical study; predictive marker; prevent; recruit; research clinical testing; resistance mechanism; small molecule; small molecule inhibitor; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

Triple-negative breast cancer (TNBC) is highly aggressive and is associated with poor clinical outcomes. TNBC is a major cause of death among breast cancer patients; and is the only subtype of breast cancer that is still lacking effective prevention and therapeutic options. Development of novel preventive or therapeutic approach for TNBC is an important task. The priority area of this research project is on women Veteran’s health, in particular, on women Veterans with TNBC. To assist in this unmet medical need, we propose to pharmacologically target Interleukin 6 (IL-6) and cyclin-dependent kinases (CDK)4/6 pathways simultaneously; because IL-6 and CDK4/6 pathways’ co-activation is enriched in TNBC compared to other breast cancer subtypes. The co-activation is also associated with a shortened time to develop metastasis. Multiple literatures have reported that IL-6 signaling could confer resistance to anti-cancer drugs; and a report suggests that one of the mechanisms of resistance to CDK4/6 inhibitors in breast cancer cells is the activation of IL-6/STAT3 pathway. In addition, our preliminary results show that CDK4/6 inhibitor abemaciclib further induces IL-6 levels in TNBC cells, which could potentially make abemaciclib-treated TNBC cells more resistance to abemaciclib. Therefore, co-activation of IL-6 in TNBC with CDK4/6, could potentially compromise the efficacy of CDK4/6 inhibitors and provide strong rationale to co-target IL-6 and CDK4/6 pathways for effective TNBC preventive therapy. Currently, no small molecule IL-6 drugs are available in clinical trials. To target IL-6 signaling in TNBC for preventive therapy, we repurposed a FDA-approved orally bioavailable drug bazedoxifene as a novel inhibitor of the IL- 6/GP130 signaling. Bazedoxifene is marketed as DUAVEE (bazedoxifene with conjugated estrogens) for preventing postmenopausal osteoporosis. To target CDK4/6 in TNBC, we propose to test abemaciclib (Trade Name: Verzenio), which is one of the most potent CDK4/6 small molecule inhibitors. Abemaciclib has been approved by FDA for the treatments of hormone receptor positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. Our preliminary data indicate that bazedoxifene and abemaciclib combination synergistically inhibited TNBC cell viability in vitro and significantly suppressed tumor growth in vivo. In addition, preliminary results observed that bazedoxifene and abemaciclib combination prevented liver metastasis in orthotopic tumor model after the primary tumors were removed. Our central hypothesis is that dual inhibition of the IL-6 and CDK4/6 pathways by bazedoxifene and abemaciclib combination is an effective approach to prevent TNBC from further progression by suppressing tumor growth and preventing tumor metastasis and tumor recurrence. We will test the central hypothesis by three specific aims: (1) Evaluate the activity of bazedoxifene and abemaciclib combination in preventing TNBC tumor growth and tumor recurrence using clinically relevant TNBC orthotopic mouse model in vivo. (2) Evaluate the efficacy of bazedoxifene and abemaciclib combination in preventing TNBC tumor metastasis using two complementary mouse models of TNBC experimental metastasis. (3) Elucidate the mechanisms of action of the bazedoxifene and abemaciclib combination in TNBC. Successful completion of proposed studies has a potential to delay the TNBC from further progression and metastasis for years using bazedoxifene-abemaciclib combination as a novel approach for preventive therapy and presents a unique opportunity to improve patient care and survival for women Veterans and women actively serving in the military with TNBC.

三阴性乳腺癌（TNBC）具有高度侵略性，与临床结局差有关。 TNBC 是乳腺癌患者中死亡的主要原因；并且是乳腺癌的唯一亚型 缺乏有效的预防和治疗选择。开发新颖的预防或治疗方法 因为TNBC是一项重要任务。该研究项目的优先领域是关于妇女老兵健康的优先领域， 特别是关于具有TNBC的女退伍军人。为了满足这种未满足的医疗需求，我们建议 在药理学上靶向白介素6（IL-6）和细胞周期蛋白依赖性激酶（CDK）4/6途径； 因为与其他乳腺癌相比，IL-6和CDK4/6途径的共激活富含TNBC 亚型。共同激活还与发展转移的时间缩短有关。多个文献 据报道，IL-6信号传导可以赋予对抗癌药物的抵抗力。一份报告表明 乳腺癌细胞中对CDK4/6抑制剂的抗性的机制是IL-6/STAT3途径的激活。 此外，我们的初步结果表明，CDK4/6抑制剂Abemaciclib进一步影响TNBC中的IL-6水平 细胞可能会使Abemaciliclib处理的TNBC细胞对Abemaciliclib的抗性更大。所以， 与CDK4/6在TNBC中IL-6共同激活可能会损害CDK4/6抑制剂和 为有效的TNBC预防疗法提供了强大的基本原理IL-6和CDK4/6途径。现在， 在临床试验中，没有小分子IL-6药物可用。靶向TNBC中的IL-6信号传导以进行预防 治疗，我们重新使用了由FDA批准的口服生物利用药物Bazedoxifene，作为IL-的新型抑制剂 6/gp130信号。 Bazedoxifene以Duavee（带有共轭雌激素的Bazedoxifene）销售 防止绝经后骨质疏松症。为了靶向TNBC中的CDK4/6，我们建议测试Abemaciliclib（贸易 名称：Verzenio），它是最潜在的CDK4/6小分子抑制剂之一。 Abemaciclib曾经 经FDA批准用于骑马受体阳性，人表皮生长因子的治疗 受体2（HER2） - 阴性晚期或转移性乳腺癌。我们的初步数据表明 Bazedoxifene和Abemacilib联合结合在体外协同抑制TNBC细胞活力，并显着显着 体内抑制肿瘤生长。此外，初步结果观察到bazedoxifene和abemacilib 组合可以防止去除原发性肿瘤后的原位肿瘤模型中的肝转移。 我们的中心假设是通过Bazedoxifene和Abemacilib对IL-6和CDK4/6途径的双重抑制 组合是通过抑制肿瘤生长来防止TNBC进一步进展的有效方法 并防止肿瘤转移和肿瘤复发。我们将通过三个特定的中心假设检验中心假设 目的：（1）评估Bazedifene和Abemacilib组合在防止TNBC肿瘤生长中的活性 在体内使用临床相关的TNBC原位小鼠模型的肿瘤复发。 （2）评估效率 使用两种完整性 TNBC实验转移的小鼠模型。 （3）阐明Bazedoxifene的作用机理 和TNBC中的Abemaciclib组合。成功完成拟议的研究有可能延迟 使用Bazedifene-Abemaciclib组合作为一种新型 预防疗法的方法，并为改善患者护理和生存提供了独特的机会 妇女退伍军人和妇女在TNBC中积极在军队中服役。