Action of RB Pathway in Breast Cancer Therapy

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药物。目前，乳腺癌是少数几种根据分子靶点进行治疗的癌症之一。值得注意的是，雌激素受体(ER)状态是治疗用药的关键决定因素，ER阳性肿瘤可用ER功能拮抗剂(如他莫昔芬)或通过ER配体耗竭策略(如芳香酶抑制剂)治疗。然而，很大比例的ER阳性肿瘤最终无法通过这种激素治疗，这表明与ER状态无关的参数对治疗反应有重大影响。相反，对于ER阴性的乳腺癌，对细胞毒治疗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是非常重要的。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。具体地说，在临床前模型中监测到的Rb缺乏的乳腺肿瘤对雌激素消融和他莫昔芬治疗没有有效的反应。进一步的研究表明，Rb缺失的基因表达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，在一些明确开发用于定义他莫昔芬和类似治疗方案失败风险的预测性签名中，观察到了相同签名的元素。因此，这些综合数据表明，Rb通路功能是内分泌型治疗药物疗效所必需的。重要的是，这种内分泌治疗失败的肿瘤，包括ER阳性和ER阴性的疾病，都要用细胞毒药物治疗。在此背景下，我们发现Rb丢失使乳腺癌细胞对特定的细胞毒剂敏感。相反，在那些含有内源性RB的肿瘤中，肿瘤抑制活性的药理激活在多个亚型的乳腺癌中都会引起强烈的活性。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，可以对其进行干预。这一假说将通过三个目标进行验证：定义Rb介导的转录控制内分泌治疗反应的机制；确定Rb活性在耐药乳腺癌中的影响；描述Rb丢失在乳腺癌细胞毒干预中的作用：结合这些分析，将定义Rb途径促进乳腺癌治疗反应变化的机制，并将阐明合理指导乳腺癌治疗干预的新途径。 公共卫生相关性： 简介：乳腺癌是这个国家女性癌症死亡的主要原因，这表明需要更有效的干预措施。在这里，我们将探索在乳腺癌中丢失的Rb肿瘤抑制因子在控制治疗反应中的作用。综合起来，这些分析将确定RB对乳腺癌治疗反应的作用机制，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更多靶点。

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.