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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

基本信息

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
项目类别：
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

项目摘要

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，且与较差的临床结果相关。TNBC