Pathway Heterogeneity: Etiology and Treatment of TNBC

描述(申请人提供)：乳腺癌是一个主要的健康问题，在美国每年有超过20万例新诊断。大约每8名妇女中就有1人会患上乳腺癌；因此，在确定肿瘤发生和进展的基础上进行了大量的努力。乳腺癌是由多种疾病亚型表现出来的，这些亚型通过不同的标志物、预后和治疗方案来区分。一般来说，雌激素受体、孕激素受体和HER-2阴性的疾病(即。三阴性乳腺癌(TNBC)是一种进展更快、更难治疗的癌症。遗传学分析已经证实，在ER阴性疾病中，特定的肿瘤抑制通路受到不同程度的干扰，但这些事件与肿瘤行为或治疗反应的具体相关性仍不清楚。在这里，我们将描述RB-肿瘤抑制通路在ER阴性疾病进展中的协调作用以及基于合理药物输送的此类肿瘤的治疗。初步研究的两个主要方面支持该提议的理论基础和假设：第一，初步和独立发表的数据表明，Rb基因丢失和/或Rb途径失活在基底ER阴性乳腺癌中发生的频率很高。支持这一观点的是，对导管原位癌病变的初步分析表明，在ER阴性疾病的早期观察到Rb通路的改变。此外，Rb缺失的模型显示出基底性ER阴性乳腺癌的分子特征。因此，我们将表征Rb通路对侵袭前病变的行为、潜在的预后以及与进展为浸润性癌症相关的其他遗传事件的影响(目标1)。其次，我们在多个临床前模型中观察到，Rb的丢失增加了对细胞毒治疗的敏感性。随后对ER阴性的临床标本进行的独立分析表明，Rb的丢失与对传统细胞毒性化疗的改善反应有关。鉴于人类疾病中Rb丢失的频率，必须定义Rb状态对治疗的分子和细胞后果反应的影响，并定义新的治疗方案，以具体利用与Rb丢失编码的脆弱性(目标2)。总的来说，这里提出的研究将 测试Rb通路在调节三阴性乳腺癌的疾病进展和治疗反应中起关键作用的假设，这一假设可以合理地作为靶点。

DESCRIPTION (provided by applicant): Breast cancer is a major health concern, with over 200,000 new diagnoses rendered each year in the United States. Approximately 1 in 8 women will develop breast cancer; thus, substantial effort has been directed at defining the basis of tumor development and progression. Breast cancer is represented by multiple disease- subtypes which are distinguished by differential markers, prognoses, and treatment regimens. In general, estrogen receptor, progesterone receptor and Her 2 negative disease (ie. triple negative breast cancer-TNBC) is faster progressing and more difficult to treat. Genetic analyses have established that specific tumor suppressor pathways are differentially disrupted in ER-negative disease, but the specific relevance of these events for tumor behavior or therapeutic response remains unclear. Here, we will delineate the coordinate role of RB-tumor suppressive pathway in the progression to ER-negative disease and the treatment of such tumors based on rational drug delivery. Two major areas of preliminary investigation support the rationale and hypothesis of the proposal: First, preliminary and independently published data demonstrate that loss of RB gene, and/or inactivation of the RB-pathway occurs at high frequency in basal ER-negative breast cancer. Supporting this contention, preliminary analyses of ductal carcinoma in situ lesions demonstrate that RB- pathway alterations are observed early in ER-negative disease. Furthermore, models of RB deletion exhibit molecular signatures indicative of basal ER-negative breast cancer. Thus, we will characterize the impact of RB-pathway on the behavior of pre-invasive lesions, underlying prognosis, and additional genetic events associated with progression to invasive cancer (Aim 1). Second, we observed in multiple preclinical models that loss of RB increases sensitivity to cytotoxic therapies. Subsequent independent analyses of ER-negative clinical specimens demonstrated that loss of RB is associated with an improved response to conventional cytotoxic chemotherapy. Given the frequency of RB loss in human disease, it is essential to define the impact of RB status for the molecular and cellular consequence response to therapy and define new regimens to specifically exploit the vulnerabilities encoded with the loss of RB (Aim 2). Collectively, the studies proposed herein will test the hypothesis that the RB-pathway plays a critical role in modulating disease progression and therapeutic response in triple negative breast cancer that could be rationally targeted.