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，乳腺癌是治疗选择基于分子靶标的少数癌症之一。值得注意的是，雌激素受体（ER）状态是治疗施用的关键决定因素，其中ER阳性肿瘤用ER功能拮抗剂（例如他莫昔芬）或通过ER配体耗竭策略（例如芳香酶抑制剂）治疗。然而，很大一部分 ER 阳性肿瘤最终无法接受此类激素疗法，这表明与 ER 状态无关的参数对治疗反应具有重大影响。相反，对于 ER 阴性乳腺癌，对细胞毒性疗法的反应指标相对较少。因此，描述治疗效果的关键决定因素并确定替代治疗策略非常重要。 初步数据表明，视网膜母细胞瘤肿瘤抑制因子 RB 是激素治疗反应的关键决定因素。具体而言，根据临床前模型的监测，RB 缺陷型乳腺肿瘤无法对雌激素消融和他莫昔芬治疗产生有效反应。其他研究表明，RB 丢失的基因表达“特征”与接受他莫昔芬治疗的乳腺癌患者的早期复发密切相关。重要的是，在许多预测特征中观察到了相同特征的元素，这些预测特征是为了定义他莫昔芬和类似治疗方案失败的风险而明确开发的。因此，这些组合数据表明RB途径功能对于对基于内分泌的治疗剂的反应的功效是必需的。重要的是，内分泌治疗失败的肿瘤，包括 ER 阳性和 ER 阴性疾病，可以用细胞毒性药物治疗。在这种情况下，我们发现 RB 丢失会使乳腺癌细胞对特定的细胞毒性药物敏感。相反，在那些含有内源性 RB 的肿瘤中，肿瘤抑制活性的药理激活可在多种乳腺癌亚型中引发有效活性。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，可以针对该因素进行干预。 这一假设将在三个目标上受到质疑： 定义 RB 介导的转录控制内分泌治疗反应的机制；确定 RB 活性对治疗耐药性乳腺癌的影响；描述 RB 丢失对乳腺癌细胞毒性干预的作用：结合起来，这些分析将定义 RB 途径导致乳腺癌治疗反应改变的机制，并将阐明在这种肿瘤类型中合理指导治疗干预的新途径。 公共卫生相关性： 叙述：乳腺癌是该国女性癌症死亡的主要原因，这表明迫切需要更有效的干预措施。在这里，我们将探讨乳腺癌中丢失的 RB 肿瘤抑制因子在控制治疗反应中的作用。结合起来，这些分析将定义 RB 促进乳腺癌治疗反应的机制，阐明合理指导乳腺癌治疗干预的新途径，并为乳腺癌治疗提供额外的靶点。