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: 10655282
• 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/10655282
• 关键词: Affect; Antineoplastic Agents; Area; Aromatase Inhibitors; Biological Availability; Brain; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer cell line; Breast cancer metastasis; CDK4 gene; Cause of Death; Cell Survival; Cell secretion; 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; Marketing; 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; Play; Postmenopausal Osteoporosis; Prevention; Prevention approach; Preventive; Preventive therapy; Primary Neoplasm; Prognosis; Recurrent tumor; 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; pharmacologic; 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）具有高度侵袭性，并且与不良的临床结果相关。 是乳腺癌患者死亡的主要原因；并且是唯一仍然存在的乳腺癌亚型； 缺乏有效的预防和治疗方案的开发。 对于 TNBC 来说，该研究项目的优先领域是女性退伍军人的健康。 特别是患有 TNBC 的女性退伍军人，为了帮助满足这一未满足的医疗需求，我们建议： 在药理学上同时靶向白细胞介素 6 (IL-6) 和细胞周期蛋白依赖性激酶 (CDK)4/6 通路； 因为与其他乳腺癌相比，TNBC 中 IL-6 和 CDK4/6 通路的共激活更加丰富 共激活还与发生转移的时间缩短有关。 据报道，IL-6 信号传导可能会产生抗癌药物耐药性；一份报告表明，其中之一 乳腺癌细胞对CDK4/6抑制剂产生耐药的机制是IL-6/STAT3通路的激活。 此外，我们的初步结果表明CDK4/6抑制剂abemaciclib进一步诱导TNBC中IL-6水平 细胞，这可能会使经过 abemaciclib 处理的 TNBC 细胞对 abemaciclib 具有更强的抵抗力。 TNBC 中 IL-6 与 CDK4/6 的共激活可能会损害 CDK4/6 抑制剂的功效 为共同靶向 IL-6 和 CDK4/6 途径以实现有效的 TNBC 预防治疗提供了强有力的理论依据。 目前尚无小分子 IL-6 药物可用于针对 TNBC 中的 IL-6 信号传导进行预防。 疗法中，我们将 FDA 批准的口服生物可利用药物巴多昔芬重新用作 IL- 的新型抑制剂 6/GP130 信号传导 Bazedoxifene 以 DUAVEE（结合雌激素的 bazedoxifene）上市。 预防绝经后骨质疏松症 为了在 TNBC 中靶向 CDK4/6，我们建议测试 abemaciclib（Trade） 名称：Verzenio），Abemaciclib 是最有效的 CDK4/6 小分子抑制剂之一。 经 FDA 批准用于治疗激素受体阳性、人表皮生长因子 我们的初步数据表明，受体 2 (HER2) 阴性的晚期或转移性乳腺癌。 bazedoxifene 和 abemaciclib 组合在体外协同抑制 TNBC 细胞活力，并显着 此外，初步结果观察到 bazedoxifene 和 abemaciclib 抑制体内肿瘤生长。 在原位肿瘤模型中，联合用药可预防原发肿瘤切除后的肝转移。 我们的中心假设是 bazedoxifene 和 abemaciclib 对 IL-6 和 CDK4/6 途径的双重抑制 联合用药是通过抑制肿瘤生长来防止 TNBC 进一步进展的有效方法 我们将通过三个具体的方法来检验中心假设。 目的：(1) 评估巴多昔芬和 abemaciclib 组合预防 TNBC 肿瘤生长的活性 使用临床相关的 TNBC 原位小鼠模型进行体内肿瘤复发和肿瘤复发的评估（2）评估疗效。 巴多昔芬和 abemaciclib 组合使用两种互补的药物预防 TNBC 肿瘤转移 (3) 阐明巴多昔芬的作用机制 成功完成拟议的研究有可能推迟 TNBC 中的 Abemaciclib 组合。 使用 bazedoxifene-abemaciclib 组合作为新药，多年来避免 TNBC 进一步进展和转移 预防性治疗的方法，并为改善患者护理和生存提供了独特的机会 女性退伍军人和积极在 TNBC 军队服役的女性。