Treatment Resistance Pathways & Targeting Residula Cancers

治疗耐药途径

• 批准号: 7385522
• 负责人: JENNY C-N CHANG
• 金额: $ 15.52万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385522
• 关键词: Antineoplastic Agents; Apoptotic; Biological Assay; Biopsy; Biopsy Specimen; Breast Cancer Cell; Cancer Patient; Cell Maintenance; Cell surface; Cells; Characteristics; Clinical; Clinical Trials; Cytotoxic Chemotherapy; Data; Dyes; Epigenetic Process; Epithelial Cells; Failure; Flow Cytometry; Fluorescent Dyes; Gene Expression; Growth; Human; In Vitro; Invasive; Investigation; Label; Malignant Neoplasms; Mammary gland; Messenger RNA; Methylation; Minority; Molecular; Mutation; Neoadjuvant Therapy; PKH 26; Pathway interactions; Population; Process; Property; Regulator Genes; Relapse; Relative (related person); Residual Cancers; Residual Tumors; Resistance; Rest; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Signal Pathway; Standards of Weights and Measures; Stem cells; Systemic Therapy; Testing; Time; Transplantation; Tumorigenicity; Ursidae Family; Xenograft Model; Xenograft procedure; cancer cell; cancer stem cell; cancer therapy; chemotherapy; clinical trials in animals; daughter cell; drug development; improved; inhibitor/antagonist; malignant breast neoplasm; mouse model; neoplastic cell; novel; pre-clinical; response; self-renewal; success; therapy resistant; tumor; tumor growth; tumor initiation

Systemic therapies are effective initially in controlling and reversing tumor growth. However, residual cancers will invariably re-grow despite this initial response. Historically, investigation of treatment resistance has focused on the identification of acquired genetic alterations in bulk tumor epithelial cells that confer resistance to specific agents, or to multiple agents. But our recent data supports the existence of a small but distinct subpopulation of cancer cells present in the original tumor that are greatly enriched in residual cancers after conventional therapies. These residual cancer cells are characterized by their relative quiescence and resistance to therapy, yet they possess enhanced self-renewal capacity like that of stem cells. We therefore hypothesize that a unique subpopulation of cancer cells present in the original tumors are intrinsically resistant to conventional therapies, and are responsible for tumor initiation and cancer regrowth. To test our hypothesis, we propose: (1) To determine whether treatment-resistant breast cancers from our neoadjuvant trials are enriched for subpopulations of cells with self-renewal and tumor-initiating capacity. We will use cell surface markers and fluorescent vital dye retention to identify these cells and purify them by FACS. Self-renewal and tumorigenicity will be assessed by in vitro mammosphere (MS) assays and xenograft transplantation, respectively. (2) To define the regulatory genes and signaling pathways responsible for treatment resistance and self-renewal in human breast cancers after conventional chemotherapy. This will be done using mRNA and BAG methylation microarrays to determine gene expression and epigenetic similarities among label-retaining MS-initiating cells, CD44+/CD24- putative "breast cancer stem cells", and chemoresistant residual cancer cells, and differences from differentiated primary invasive breast cancer cells. (3) To determine whether suppression of self-renewal and treatment resistance pathways can improve existing cancer therapies using MS-formation assays as well as our novel primary xenograft mouse models in "animal clinical trials", leading to human trials targeting this tumor re-initiating subpopulation directly. If our hypothesis is correct, then relapse after apparently successful therapy is due to the persistence of these resting, therapy-resistant tumor cells, thereby allowing tumor re-initiation. If so, approaches for anticancer drug development must be changed fundamentally to target these rare tumor-initiating cells, rather than only cells of the bulk tumor as has been done to date.

全身治疗最初在控制和逆转肿瘤生长方面是有效的。然而，剩余 尽管有这种最初的反应，癌症总是会重新生长。从历史上看，治疗耐药性的研究 集中于鉴定大块肿瘤上皮细胞中获得性遗传改变， 对特定药剂或多种药剂的抗性。但我们最近的数据支持存在一个小但 在原始肿瘤中存在的癌细胞的不同亚群，其在残余癌细胞中大量富集， 传统治疗后的癌症。这些残留的癌细胞的特征在于它们的相对 静止和对治疗的抵抗，但它们具有增强的自我更新能力，如茎 细胞因此，我们假设在原始肿瘤中存在独特的癌细胞亚群， 对常规疗法具有内在抗性，并且是肿瘤起始和癌症再生长的原因。 为了验证我们的假设，我们提出：（1）为了确定是否治疗抵抗性乳腺癌从 我们的新辅助试验富集了具有自我更新和肿瘤引发能力的细胞亚群。 我们将使用细胞表面标记和荧光活体染料保留来鉴定这些细胞，并通过 流式细胞仪。自我更新和致瘤性将通过体外乳腺球（MS）试验进行评估， 异种移植。(2)确定调控基因和信号通路 在常规治疗后，负责人类乳腺癌的治疗抗性和自我更新 化疗这将使用mRNA和BAG甲基化微阵列来确定基因 保留标记的MS起始细胞、CD 44 +/CD 24-假定的 “乳腺癌干细胞”，和化疗耐药的残留癌细胞，以及分化的差异 原发性浸润性乳腺癌细胞。(3)以确定是否抑制自我更新和治疗 耐药途径可以改善现有的癌症治疗，使用MS-形成测定以及我们的新的 “动物临床试验”中的主要异种移植小鼠模型，导致针对该肿瘤的人体试验 直接重新启动亚群。 如果我们的假设是正确的，那么在明显成功的治疗后复发是由于 这些静止的、对治疗有抗性的肿瘤细胞，从而允许肿瘤重新启动。如果是这样， 药物开发必须从根本上改变，以靶向这些罕见的肿瘤起始细胞，而不是 而不是像迄今为止所做的那样只切除大块肿瘤的细胞。