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: 8747143
• 负责人: Yi Li
• 金额: $ 25.58万
• 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/8747143
• 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预防乳腺癌的新概念。从理论上讲，减少乳腺癌的发病率可能会对挽救生命和减少巨大的治疗成本产生深远的影响。抗雌激素可以预防乳腺癌，但需要长时间治疗，并且可以产生明显的副作用。因此，迫切需要新的预防疗法，不需要多年的连续治疗。有时但并不总是会发展为侵入性癌症的乳房前病变 - 尚不清楚这一小部分导致较小的预立毒性病变子集的原因。在几种组织类型中的研究表明，由于癌基因过表达和癌基因引起的异常增殖，在人类前病变中激活了凋亡，这为恶性肿瘤发展提供了障碍。必须克服这种障碍，以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信号传导可能是可以打破这种抗癌屏障的关键途径。因此，我们假设人类前病变中的JAK2-STAT5途径通过降低凋亡抗癌屏障来促进恶性肿瘤的发展。如果是这样，抑制这种疾病的途径可能会减少乳腺癌前病变的负荷，从而降低乳腺癌的风险。我们预测，即使在早期病变中对这一途径的短暂或间歇性抑制也可能使它们失去活力并降低侵入性乳腺癌的风险，而对女性的不利影响，成本和不便可能很小。三个目的如下：目标1：确定STAT5激活是否加速了与乳腺癌相关的主要致癌事件引起的预触发病变的肿瘤发生。 AIM 2：确定在啮齿动物模型中，短期或间歇施用违反违他尼在表达PSTAT5的早期病变中会导致凋亡，并有效防止其发展为癌症。 AIM 3：确定在需要后续手术切除的核心活检前病变的女性中，短期李唑尼抑制了PSTAT5并诱导病变中的细胞凋亡。