Research Project 2 Proteogenomic-guided therapeutic targeting of breast cancer patient-derived xenograft metastases

项目摘要/摘要 乳腺癌在每8名女性中就有1名被诊断出来，是VCU诊断出的最常见的癌症类型。那里 人类乳腺癌的几种不同的基因亚型主要是基于增殖状态定义的吗 以及靶向受体的表达，如雌激素受体和HER2癌基因。大多数人 用于乳腺癌研究的细胞系和PDX模型来自欧洲的白人患者 然而，所有的祖先都会受到乳腺癌的影响。在过去的二十年里，有 在根据遗传血统发现的乳腺肿瘤亚型中存在明显的差异，与Black 更常被诊断为基底细胞样三阴性乳腺癌的患者 转移性的。因此，在这些研究中，我们(1)致力于建立乳腺癌的PDX模型 病人。有了这些模型，我们将(2)定量确定它们的遗传祖先，然后(3)选择 从黑人患者那里获得的基因相似的模型，这样我们就可以(4)使用这些模型来 确定定植的器官，(5)确定肿瘤的基因组和蛋白质组图谱，以及 转移，(6)定义感兴趣的NCI-INDS的疗效，重点是基于Selinexor的药物组合 从PDX中获得的细胞，以及(7)确定在以下方面有效的新的治疗药物组合 转移的环境。在这些研究的结论中，我们可能已经确定了一种新的有效的两种药物 对于已用尽当前护理标准的类似Basal的患者可能有用的方法 转移性乳腺癌的治疗方法。

Project Summary/Abstract Breast cancer is diagnosed in 1-of-8 women and is the most common type of cancer diagnosed at VCU. There are several genetically distinct subtypes of human breast cancers defined largely based on proliferative status and expression of targetable receptors such as estrogen receptors and the HER2 oncogene. The majority of the cell lines and PDX models used for breast cancer research arise from White patients of European Ancestry, however, all ancestral groups are affected by breast cancers. Over the past twenty years, there has been a clear disparity identified in the subtype of breast tumors found based on genetic ancestry, with Black patients being diagnosed more frequently with Basal-like Triple-Negative Breast Cancers, which are highly metastatic. Therefore, in these studies, we are (1) focused on developing PDX models from breast cancer patients. With these models we will (2) quantitatively determine their genetic ancestry and then (3) select models that are genetically Basal-like and obtained from Black patients so that we can (4) use these models to determine the organs that the colonize, (5) determine the genomic and proteomic profile of the tumors and metastases, (6) define efficacy of NCI-INDs of interest, with a focus on selinexor based drug combinations on cells obtained from the PDXs, and (7) identifying new therapeutic drug combinations that are effective in the metastatic setting. At the conclusion of these studies, we may have identified a new effective two-drug approach that could be useful for Basal-like patients that have exhausted the current standard-of-care approaches for treatment of metastatic breast cancer.