Intermittent Ruxolitinib to Target STATS Activation for Breast Cancer Prevention

间歇性 Ruxolitinib 以 STATS 激活为目标预防乳腺癌

• 批准号: 8930094
• 负责人: Yi Li
• 金额: $ 25.92万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8930094
• 关键词: Adverse effects; Animals; Apoptosis; Apoptotic; Atypia; Breast; Breast Cancer Prevention; Breast Epithelial Cells; Cancer Model; Cell Nucleus; Cell Survival; Cells; Clinical; Clinical Trials; Collaborations; Core Biopsy; Data; Development; Disease; Dose; ERBB2 gene; Epithelial; Estrogen Antagonists; Estrogen Receptor Modulators; Event; Evolution; Excision; Gene Targeting; Genetic; Goals; High Risk Woman; Histocompatibility Testing; Human; Incidence; Intraductal Hyperplasia; JAK2 gene; Lactation; Lesion; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Menstrual cycle; Molecular Target; Mus; Mutant Strains Mice; Mutation; Noninfiltrating Intraductal Carcinoma; Oncogenes; Oncogenic; Operative Surgical Procedures; PIK3CA gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Placebos; Pregnancy; Premalignant; Prevention; Prevention strategy; Preventive; Prolactin; Proteins; Rattus; Risk; Rodent; Rodent Model; Schedule; Signal Transduction; Tamoxifen; Testing; Transducers; Translational Research; Treatment Cost; Virulent; Woman; base; breast lesion; cancer risk; cost; dimer; dimethylbenzanthracene; inhibitor/antagonist; malignant breast neoplasm; mouse model; novel; overexpression; prevent; small molecule; treatment planning; tumorigenesis

The overall goal of this proposal is to test a novel concept in breast cancer prevention. Reducing breast cancer incidence can theoretically have a profound impact on saving lives and reducing the huge cost of treatment. Antiestrogens can prevent breast cancer, but they require prolonged treatment and can have significant side effects. Therefore, new preventive therapy that does not require years of continuous treatment is urgently needed. Premalignant lesions of the breast sometimes but not always progress to invasive cancer - what causes this small subset of premalignant lesions to progress is not yet known. Studies in several tissue types indicate that apoptosis is activated in human premalignant lesions as a result of oncogene overexpression and oncogene-induced aberrant proliferation, providing a barrier to progression to malignancy. This barrier must be overcome for early lesions to develop into full-blown cancer. In our preliminary studies using mouse models, we have found that Jak2-STAT5 signaling may be a key pathway that can break this anticancer barrier. Therefore, we hypothesize that the JAK2-STAT5 pathway in human premalignant lesions promotes the progression to malignancy by lowering the apoptosis anticancer barrier; if so, inhibition of this prosurvival pathway could reduce the load of premalignant lesions in the breast and thus lower breast cancer risk. We predict that even transient or intermittent inhibition of this pathway in early lesions could devitalize them and lower the risk of invasive breast cancer, while the possible adverse effects, cost, and inconvenience to women would be small. Three aims are as follows: Aim 1: Determine if STAT5 activation accelerates tumorigenesis of premalignant lesions induced by major oncogenic events associated with breast cancer. Aim 2: Determine whether in rodent models short-term or intermittent administration of ruxolitinib causes apoptosis in pSTAT5-expressing early lesions and effectively prevents their progression to cancer. Aim 3: Determine whether in women with a premalignant lesion on core biopsy requiring subsequent surgical resection, short-term ruxolifinib blocks pSTAT5 and induces apoptosis in the lesion.

该提案的总体目标是测试乳腺癌预防的新概念。理论上，降低乳腺癌发病率可以对挽救生命和降低巨额治疗费用产生深远影响。抗雌激素可以预防乳腺癌，但需要长期治疗，并且可能有明显的副作用。因此，迫切需要不需要多年连续治疗的新预防疗法。乳房癌前病变有时但并非总是进展为浸润性癌症——导致这一小部分癌前病变进展的原因尚不清楚。对几种组织类型的研究表明，由于癌基因过度表达和癌基因诱导的异常增殖，人类癌前病变中细胞凋亡被激活，为恶性肿瘤的进展提供了屏障。必须克服这一障碍才能使早期病变发展为成熟的癌症。在我们使用小鼠模型的初步研究中，我们发现Jak2-STAT5信号传导可能是打破这一抗癌屏障的关键途径。因此，我们推测人类癌前病变中的JAK2-STAT5通路通过降低细胞凋亡抗癌屏障来促进恶性进展；如果是这样，抑制这种促生存途径可以减少乳房癌前病变的负荷，从而降低患乳腺癌的风险。我们预测，即使在早期病变中短暂或间歇性抑制该通路，也可能使它们失活并降低浸润性乳腺癌的风险，而对女性可能产生的副作用、成本和不便则很小。三个目标如下： 目标 1：确定 STAT5 激活是否加速由与乳腺癌相关的主要致癌事件诱导的癌前病变的肿瘤发生。目标 2：确定在啮齿动物模型中，短期或间歇性给予鲁索替尼是否会导致表达 pSTAT5 的早期病变发生细胞凋亡，并有效阻止其进展为癌症。目标 3：确定在需要随后进行手术切除的核心活检中具有癌前病变的女性中，短期鲁索利非尼是否会阻断 pSTAT5 并诱导病变中的细胞凋亡。