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剂。目前，乳腺癌是少数几种治疗方案基于分子靶点的癌症之一。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功能的拮抗剂（例如他莫昔芬）或通过ER配体消耗策略（例如芳香酶抑制剂）治疗。然而，很大比例的ER阳性肿瘤最终失败的激素治疗，表明参数独立的ER状态有一个重大的影响，治疗反应。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，划定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。具体而言，RB缺陷型乳腺肿瘤不能有效地响应雌激素消融和他莫昔芬治疗，在临床前模型中监测。另外的研究表明，RB丢失的基因表达“特征”与用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特征中观察到了相同特征的元素。因此，这些组合的数据表明，RB途径功能是对基于内分泌的治疗剂的应答的功效所必需的。重要的是，内分泌治疗失败的这种肿瘤，包括ER阳性和ER阴性疾病，用细胞毒性剂治疗。在这种情况下，我们已经发现，RB的损失敏感的乳腺癌细胞特异性细胞毒性剂。相反，在那些具有内源性RB的肿瘤中，肿瘤抑制活性的药理学激活在多种亚型的乳腺癌中具有强效活性。基于这些发现，我们假设RB是乳腺癌治疗反应的一个关键决定因素，可以直接进行干预。这一假设将在三个目标中进行探讨，这三个目标将：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活性对治疗抵抗性乳腺癌的影响;描述RB丢失对乳腺癌细胞毒性干预的作用：结合起来，这些分析将明确RB通路改变乳腺癌治疗反应的机制，并阐明新的在这种肿瘤类型中合理地指导治疗干预的途径。

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.