Action of RB Pathway in Breast Cancer Therapy

RB通路在乳腺癌治疗中的作用

• 批准号: 8103142
• 负责人: Erik Knudsen
• 金额: $ 31.19万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103142
• 关键词: Ablation; Aromatase Inhibitors; Breast Cancer Cell; Breast Cancer Treatment; Cancer Patient; Cell Cycle Progression; Cell Survival; Cessation of life; Clinical; Complement; Country; Cyclin-Dependent Kinases; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Disease; Disease Resistance; Elements; Endocrine; Estrogen Receptor Status; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; Estrogens; Failure; Female; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Hormonal; Intervention; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mediating; Molecular Target; Monitor; Outcome; Pathway interactions; Pre-Clinical Model; Regimen; Regulation; Relapse; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Tamoxifen; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Treatment Efficacy; Tumor Suppressor Proteins; Xenograft Model; base; cancer therapy; cohort; cytotoxic; effective intervention; high risk; hormone therapy; improved; malignant breast neoplasm; neoplastic cell; outcome forecast; programs; public health relevance; receptor function; response; retinoblastoma tumor suppressor; therapy resistant; tumor

DESCRIPTION (provided by applicant): Approaches used to treat breast cancer include hormonal, cytotoxic, and targeted therapeutic agents. At present, breast cancer represents one of the few cancers wherein treatment options are based on molecular targets. Notably, estrogen receptor (ER) status is a critical determinant for therapy administration, wherein ER-positive tumors are treated with antagonists of ER function (e.g. tamoxifen) or through ER ligand depletion strategies (e.g. aromatase inhibitors). However, a large percentage of ER-positive tumors ultimately fail such hormone therapies, indicating that parameters independent of ER status have a major impact on therapeutic response. Conversely, for ER-negative breast cancers, there are relatively few indicators of response to cytotoxic therapies. Thus, delineating key determinants of therapeutic efficacy and identifying alternative therapeutic strategies is of high importance. Preliminary data demonstrate that the retinoblastoma tumor suppressor, RB, is a critical determinant of the response to hormone therapy. Specifically, RB-deficient breast tumors fail to effectively respond to estrogen ablation and tamoxifen treatment, as monitored in preclinical models. Additional studies revealed that the gene expression "signature" of RB loss is strongly associated with early relapse in breast cancer patients treated with tamoxifen. Importantly, elements of this same signature are observed in a number of the predictive signatures that were explicitly developed to define risk of failure with tamoxifen and similar therapeutic regimens. Thus, these combined data indicate that RB-pathway function is requisite for efficacy of the response to endocrine based therapeutic agents. Importantly, such tumors that fail endocrine therapies, including both ER-positive and ER-negative disease, are treated with cytotoxic agents. In this context, we have found that RB loss sensitizes breast cancer cells to specific cytotoxic agents. Conversely, in those tumors that harbor endogenous RB, pharmacological activation of tumor suppressor activity elicits potent activity in multiple sub-types of breast cancer. Based on these findings, we hypothesize that RB is a critical determinant of therapeutic response in breast cancer upon which interventions can be directed. This hypothesis will be interrogated in three aims that will: Define the mechanisms through which RB-mediated transcription controls the response to endocrine therapy; Determine the impact of RB activity on therapy resistant breast cancer; Delineate the action of RB loss on cytotoxic interventions in breast cancer: Combined, these analyses will define the mechanisms through which the RB pathway contributes to alterations in therapeutic response in breast cancer and will elucidate new avenues to direct therapeutic intervention rationally in this tumor type. PUBLIC HEALTH RELEVANCE: Narrative: Breast cancer is a leading cause of female cancer death in this country, indicating a key need for more effective intervention. Here we will explore the role of the RB tumor suppressor that is lost in breast cancer in controlling the response to therapy. Combined, these analyses will define the mechanisms through which the RB contributes to therapeutic response in breast cancer, elucidate new avenues to direct therapeutic intervention rationally in breast cancer, and provide additional targets for breast cancer treatment.

描述（由申请人提供）：用于治疗乳腺癌的方法包括激素，细胞毒性和靶向治疗剂。目前，乳腺癌代表了基于分子靶标的治疗选择的少数癌症之一。值得注意的是，雌激素受体（ER）状态是治疗给药的关键决定因素，其中ER阳性肿瘤用ER功能的拮抗剂（例如他莫昔芬）或通过ER配体耗尽策略（例如芳香酶抑制剂）治疗。但是，大部分的ER阳性肿瘤最终失败了这种激素疗法，表明与ER状态无关的参数对治疗反应有重大影响。相反，对于ER阴性乳腺癌，对细胞毒性疗法的反应相对较少。因此，描述治疗功效的关键决定因素并确定替代性治疗策略至关重要。 初步数据表明，视网膜细胞瘤抑制剂RB是对激素治疗反应的关键决定因素。具体而言，如临床前模型中所监测的那样，RB缺陷型乳腺肿瘤无法有效应对雌激素消融和他莫昔芬治疗。其他研究表明，在用他莫昔芬治疗的乳腺癌患者中，RB丧失的基因表达“签名”与早期复发密切相关。重要的是，在许多明确开发的预测特征中观察到了相同特征的元素，这些特征是为了定义了他莫昔芬和类似的治疗方案的失败风险。因此，这些组合数据表明RB-Pathway功能是对基于内分泌治疗剂的响应有效性的必要条件。重要的是，通过细胞毒性剂治疗这种损伤内分泌疗法的肿瘤，包括ER阳性和阴性疾病。在这种情况下，我们发现RB损失使乳腺癌细胞对特定的细胞毒性剂敏感。相反，在那些含有内源性RB的肿瘤中，肿瘤抑制活性的药理学激活会引起乳腺癌多种亚型的有效活性。基于这些发现，我们假设RB是乳腺癌治疗反应的关键决定因素，可以在其中进行干预措施。 该假设将在三个目标中进行审问：定义RB介导的转录控制对内分泌治疗的反应的机制；确定RB活性对耐药性乳腺癌的影响；描述RB损失对乳腺癌细胞毒性干预的作用：结合，这些分析将定义RB途径有助于乳腺癌治疗反应改变的机制，并将阐明新的途径以直接在这种肿瘤类型中直接治疗干预。 公共卫生相关性： 叙事：乳腺癌是该国女性癌症死亡的主要原因，表明对更有效的干预的关键需求。在这里，我们将探讨RB肿瘤抑制因子在控制治疗反应中丢失的RB肿瘤抑制剂。这些分析结合在一起，将定义RB在乳腺癌中有助于治疗反应的机制，阐明新的途径以合理地指导乳腺癌的治疗干预，并为乳腺癌治疗提供其他靶标。