Targeting Notch, PI3K-AKT and other novel pathways in breast cancer stem cells

靶向乳腺癌干细胞中的 Notch、PI3K-AKT 和其他新通路

• 批准号: 8255996
• 负责人: JENNY C-N CHANG
• 金额: $ 44.63万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255996
• 关键词: Apoptotic; Biological; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; CD44 gene; Cancer Patient; Cell model; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Colony-Forming Units Assay; Correlative Study; Critical Pathways; Data; Development; Disease; Dose; Drug Kinetics; Epithelial Cells; Flow Cytometry; Future; Genes; Genetic; Human; Human Genome; Immunocompromised Host; In Vitro; Integrins; Laboratories; Libraries; Malignant Neoplasms; Measures; Molecular Target; Neoadjuvant Therapy; Neoplasm Metastasis; Outcome; Pathologic; Pathway interactions; Patients; Population; Pre-Clinical Model; Property; Proto-Oncogene Proteins c-akt; Refractory; Refractory Disease; Relapse; Research Design; Residual Cancers; Residual Tumors; Resistance; Rest; Role; SCID Beige Mouse; Sampling; Series; Signal Pathway; Signal Transduction; Small Inducible Cytokine A3; Stem cells; Subfamily lentivirinae; Systemic Therapy; Testing; Time; Toxicology; Translating; Transplantation; Tumorigenicity; Woman; Xenograft Model; Xenograft procedure; base; cancer cell; cancer stem cell; cancer therapy; chemotherapy; conventional therapy; daughter cell; design; docetaxel; functional genomics; high throughput screening; improved; inhibitor/antagonist; malignant breast neoplasm; notch protein; novel; preclinical study; prevent; prominin; response; self-renewal; small hairpin RNA; small molecule; therapy resistant; tumor; tumor growth; tumor initiation; tumor xenograft; tumorigenic

DESCRIPTION (provided by applicant): Many patients relapse over time despite initial response to systemic therapy. One explanation is that a rare sub-population of cancer stem cells with tumorigenic potential is intrinsically resistant to therapy. Consistent with this, we have shown for the first time clinically in human breast cancer patients that residual tumors after chemotherapy are 1) enriched for the tumorigenic CD44+/CD24-/low population, 2) show enhanced mammosphere-forming efficiency (MSFE), and 3) display an increase in outgrowths in xenograft transplants in immunocompromised SCID/Beige mice, thus suggesting their increased tumorigenicity. Our recent data from paired human breast cancer samples indicates that standard therapy eliminates dividing daughter cells, so that samples obtained after therapy are enriched for CD44+/CD24-/low putative "breast cancer stem cells" that have the ability to self-renew in mammosphere cultures, and to give rise to tumors upon xenograft transplantation. We have identified a cancer stem cell signature of CD44+/CD24-/low mammosphere-forming cells derived from human breast cancer biopsies. The top canonical pathways identified include Notch and PI3-AKT, and other signaling pathways. We now propose a series of preclinical and clinical studies to directly test the hypothesis that breast cancer stem cells can be specifically targeted by inhibitors of the Notch, PI3-AKT and other pathways. A unique component of our studies is the availability of human biopsy samples obtained before and after targeted therapy in breast cancer patients with residual disease after preoperative (neoadjuvant) therapy. Specific Aims and Study Design 1. To determine whether suppression of identified self-renewal and treatment resistance pathways can improve existing cancer therapies in preclinical models. Beginning with Notch and PI3-AKT inhibitors, we will determine if these will improve efficacy of conventional therapy, using MSFE and human breast cancer xenograft models. Next, we will target the top ~300 genes differentially expressed in our stem cell signature by ordered lentivirus-based shRNA libraries designed to allow genetic "knockdown" of every gene in the human genome, as well as the development of high-throughput functional genomic assays of stem cell self-renewal. 2. To conduct novel clinical trials to determine whether suppressing stem cell self-renewal and treatment resistance pathways can improve existing cancer therapies in breast cancer patients. Clinical trials with novel inhibitors of stem cell self-renewal (Notch and PI3) have been planned. We propose to include patients with advanced breast cancers refractory to conventional therapy, as these women have a poor expected clinical outcome, and who are most likely to benefit from therapies targeting self-renewal pathways. 3. To perform correlative studies using breast cancer biopsy specimens from these clinical trials. Correlative studies using human cancer biopsies from these trials will be conducted, e.g. a decrease in stem cell markers and tumorigenic potential, as well as downstream effects of inhibition of the relevant pathways.

描述（由申请人提供）：尽管最初对全身治疗的反应，但许多患者随着时间的流逝而复发。一种解释是，具有致瘤性潜力的癌症干细胞的罕见亚种群在本质上对治疗具有抗性。与此相一致的是，我们首次在人类乳腺癌患者的临床上表明，化学疗法后的残留肿瘤富含肿瘤性CD44+/CD24-/低种群，2）表现出增强的乳腺球形成效率（MSFE），3）因此，在盐酸脑植物中增加了脑植物的增加/脑含量的增加/盐酸脑的增加/盐酸症的增加。肿瘤性。我们来自配对的人类乳腺癌样品的最新数据表明，标准治疗消除了分裂的子细胞，因此在治疗后获得的样品富含CD44+/CD24-/低推定的“乳腺癌干细胞”，这些“乳腺癌干细胞”能够在哺乳动物层培养中自我更新，并在Xenogrograft植入植物上引起肿瘤。我们已经确定了CD44+/CD24-/低哺乳动物形成细胞的癌症干细胞特征，该细胞衍生自人类乳腺癌活检。确定的顶级规范途径包括Notch和Pi3-Akt以及其他信号通路。现在，我们提出了一系列临床前和临床研究，以直接检验以下假设：乳腺癌干细胞可以由Notch，PI3-AKT和其他途径的抑制剂特异性靶向。我们研究的一个独特组成部分是在术前（NEOADJUVANT）治疗后靶向治疗前后获得的人类活检样本可用。具体目标和研究设计1。确定抑制已识别的自我更新和治疗耐药性途径是否可以改善临床前模型中的现有癌症疗法。从Notch和Pi3-Akt抑制剂开始，我们将使用MSFE和人类乳腺癌异种移植模型来确定这些抑制剂是否会提高常规治疗的功效。接下来，我们将通过有序的基于慢病毒的shRNA文库来瞄准在干细胞特征中差异表达的前〜300个基因，旨在允许人类基因组中每个基因的遗传“敲低”，以及开发干细胞自我更新的高通量功能性基因组基因组。 2。进行新的临床试验，以确定抑制干细胞自我更新和治疗耐药性途径是否可以改善乳腺癌患者的现有癌症疗法。已经计划了使用新型干细胞自我更新抑制剂（Notch和PI3）进行的临床试验。我们建议包括对常规疗法难治性的晚期乳腺癌患者，因为这些妇女的预期临床结果较差，并且最有可能受益于针对自我更新途径的疗法。 3。使用这些临床试验中的乳腺癌活检标本进行相关研究。使用这些试验的人类癌症活检的相关研究将进行，例如干细胞标记和致瘤潜力的降低，以及相关途径抑制的下游影响。